medical marijuana research studies

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Welcome to the Pennsylvania-approved Medical Marijuana Academic Clinical Research Center at Penn State

The Penn State Medical Marijuana Academic Clinical Research Center (ACRC) will become an internationally recognized expert in the benefits and dangers of medicinal cannabinoids and medical cannabis.

The goal of the center is to support the development of medical marijuana pre-clinical and clinical research and provide scientific evidence on the utility of medical cannabis. Currently, there are more than 30 researchers engaged in cannabis research within the ACRC; these researchers are divided into two divisions, a basic science division and a clinical science division .

Penn State College of Medicine was recognized as a potential ACRC site with the passage of ACT 16 in 2016, which legalized medical marijuana in Pennsylvania.

A key provision of this act was to “promote high-quality research” on medical marijuana.

In May of 2018, Penn State College of Medicine was one of eight universities approved by Gov. Tom Wolf as a Certified Academic Clinical Research Center. In June 2019, the Penn State College of Medicine ACRC, in a relationship with PA Options for Wellness, was one of the first three centers approved by the Commonwealth of Pennsylvania.

Director: Kent Vrana , PhD, Elliot S. Vesell Professor and Chair, Department of Pharmacology Scientific Director: Wesley M. Raup-Konsavage , PhD, Assistant Professor, Department of Pharmacology

Research areas and current projects

Basic science division.

The basic science division utilizes pre-clinical models, such as in vitro studies and rodent models, to explore the potential therapeutic uses of cannabinoids for a variety of disease.

Current projects are exploring the efficacy of cannabinoids or cannabis to treat cancer, acute and chronic pain, anxiety, high blood pressure and post-traumatic stress disorder (PTSD).

Additional research within this group focuses on the chemistry of cannabinoids including pharmacokinetics, receptor binding and the development of novel cannabinoid-based compounds. These preclinical data will help to steer clinical research projects.

• Basic Science Team

Clinical Science Division

• Introduction

The clinical science division focuses on examining the benefits and potential harm of medical cannabis use for the current state-approved medical conditions.

Currently, there are two teams within this division. The first team is focused on health outcomes in patients currently taking medical marijuana for the treatment of state-approved conditions, with special attention on anxiety, post-traumatic stress disorder and pain. The second team focuses on clinical trials and they will be conducting double blind, placebo-controlled studies on the efficacy of cannabis to treat medical conditions and reduce reliance on opioids for pain.

• Available Clinical Trials

Cannabidiol and Management of Endometriosis Pain

The study team will be looking at the effects of cannabidiol (CBD) in patients with endometriosis. It is believed that CBD will improve both pain and quality of life. The study will last a total of 12 weeks and involve several onsite visits in addition to daily pain assessments.

Contact: Kristin Riley, MD .

• Clinical Science Team

Penn State Medical Marijuana ACRC uses the following facilities to advance research in the field.

Super critical co2 extractor.

Cannabinoid Drug Libraries

Other Reagents

Meet the team

Kent Vrana, PhD

Elliot S. Vesell Professor and Chair Department of Pharmacology

Scientific Director

Wesley M. Raup-Konsavage, PhD

Assistant Professor Department of Pharmacology

Research Technician

Diana Sepulveda

News and Resources

The strength of the Center for Cannabis and Natural Product Pharmaceutics (CCNPP) is directly linked to bringing talented investigators from across the Penn State system.  We encourage investigators interested in natural product pharmaceutics research collaborations to apply for the Penn State Center for Cannabis and Natural Product Pharmaceutics membership.  Applicants must hold an appointment at Penn State, Penn State Health, a Penn State Medical Marijuana Academic Clinical Research Center (ACRC) partner or an affiliate institution.

Acceptance and/or approval of a membership application is determined by the leadership team.

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• Open access
• Published: 29 September 2020

Medical cannabis use in the United States: a retrospective database study

• V. Kishan Mahabir 1 ,
• Jamil J. Merchant 1 ,
• Christopher Smith 1 &
• Alisha Garibaldi   ORCID: orcid.org/0000-0001-6332-7754 1  

Journal of Cannabis Research volume  2 , Article number:  32 ( 2020 ) Cite this article

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Introduction

Growing interest in the medicinal properties of cannabis has led to an increase in its use to treat medical conditions, and the establishment of state-specific medical cannabis programs. Despite medical cannabis being legal in 33 states and the District of Colombia, there remains a paucity of data characterizing the patients accessing medical cannabis programs.

We retrospectively reviewed a registry with data from 33 medical cannabis evaluation clinics in the United States, owned and operated by CB2 Insights. Data were collected primarily by face-to-face interviews for patients seeking medical cannabis certification between November 18, 2018 and March 18, 2020. Patients were removed from the analysis if they did not have a valid date of birth, were less than 18, or did not have a primary medical condition reported; a total of 61,379 patients were included in the analysis. Data were summarized using descriptive statistics expressed as a mean (standard deviation (SD)) or median (interquartile range (IQR)) as appropriate for continuous variables, and number (percent) for categorical variables. Statistical tests performed across groups included t-tests, chi-squared tests and regression.

The average age of patients was 45.5, 54.8% were male and the majority were Caucasian (87.5%). Female patients were significantly older than males (47.0 compared to 44.6). Most patients reported cannabis experience prior to seeking medical certification (66.9%). The top three mutually exclusive primary medical conditions reported were unspecified chronic pain (38.8%), anxiety (13.5%) and post-traumatic stress disorder (PTSD) (8.4%). The average number of comorbid conditions reported was 2.7, of which anxiety was the most common (28.3%). Females reported significantly more comorbid conditions than males (3.1 compared to 2.3).

This retrospective study highlighted the range and number of conditions for which patients in the US seek medical cannabis. Rigorous clinical trials investigating the use of medical cannabis to treat pain conditions, anxiety, insomnia, depression and PTSD would benefit a large number of patients, many of whom use medical cannabis to treat multiple conditions.

The cannabis plant has been used in traditional medicine for centuries, and within the last few decades it has generated considerable attention among the general population, modern medical community and regulatory bodies for its potential medicinal capabilities (Alsherbiny and Li 2018 ). The effects of cannabis are due to the action of cannabinoids, a diverse group of chemical compounds found in the cannabis plant that act on the human endocannabinoid system, via a series of interactions with cell receptors throughout the human body, and alter neurotransmitter release in the brain affecting various physiological functions (Fraguas-Sanchez and Torres-Suarez 2018 ; Vuckovic et al. 2018 ). While more than 100 cannabinoids have been identified, Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have undergone the most scientific investigation and are considered to be the greatest contributors to the medicinal effects of cannabis (Pertwee et al. 2010 ; Pertwee 1997 ).

The growing interest in medical cannabis has led to an increase in its use to treat medical conditions or symptoms thereof, such as chronic pain, anxiety, and depression. Individuals do this either through self-medication, accessing the drug via the recreational or illicit markets, or via medical cannabis programs in regions where regulations permit. Other clinical conditions that cannabis is thought to treat include multiple sclerosis, AIDS-associated wasting/cachexia, insomnia, arthritis, epilepsy, post-traumatic stress disorder (PTSD), glaucoma, headaches and migraines, and nausea (Kosiba et al. 2019 ; Lu and Anderson 2017 ; Kaur et al. 2016 ; Zaller et al. 2015 ; Klumpers and Thacker 2019 ; Institute of Medicine (U.S.) 1999 ).

Medical cannabis programs began in the United States (US) in 1996, with California becoming the first state to legalize medical cannabis (Legislatures NC of S 2020 ). Since then, other states have slowly adopted medical cannabis programs, with the programs themselves evolving over time. As of 2000, 8 states had legalized medical cannabis (Yu et al. 2020 ); by 2010, there were 16 and by 2016, there were 29 (Pacula and Smart 2017 ). As of July 2020, medical cannabis is legal in 33 states and the District of Columbia, 12 of which allow adults over the age of 21 to use cannabis recreationally (DISA Global Solutions 2019 ).

Qualifying conditions for medical cannabis vary significantly state-by-state as some states (e.g., California, Massachusetts, Oklahoma, and the District of Columbia) allow physicians to use discretion when recommending patients for certification, while other states only allow certification based on a limited set of qualifying conditions (Legislatures NC of S 2020 ). The allowable THC-percentage component of state-run programs also varies, with certain states only allowing access to high-CBD, low-THC products for medical cannabis patients. Patients seeking medical cannabis in the US in most states are required to obtain a state-specific medical cannabis identification card, allowing them to purchase cannabis products from dispensaries to treat certain medical conditions.

Despite medical cannabis being legal in many states, there remains a paucity of data characterizing the patients accessing it via state-run programs. Two large studies reviewed available state registry data of patients holding medical cannabis licenses; however, these studies came with limitations including voluntary reporting at the state-level, or inability for the authors to access the registry data (Boehnke et al. 2019 ; Fairman 2016 ). One of the studies reviewed the primary conditions for which patients sought medical cannabis, but did not report any other patient characteristics such as age or gender (Boehnke et al. 2019 ). The other reported on the age and gender of patients accessing medical cannabis, but did not report on medical conditions (Fairman 2016 ). While useful, these studies did not adequately characterize medical cannabis use through state programs by age, gender or condition. Other studies that have been published to characterize medical cannabis patients are limited by sample size and selection, include only patient-reported data, or include patients outside of the US (Sexton et al. 2016 ; Eurich et al. 2019 ; Bonn-Miller et al. 2014 ; Reinarman et al. 2011 ).

Given the need for a large data set to contribute to the medical knowledge, inform on policy and identify areas for future research, we designed a retrospective study of a registry database. The primary objective of this study was to thoroughly describe the population of patients seeking treatment with medical cannabis in the US. These data were reviewed at a high-level to answer the following questions:

What are the key demographic characteristics of patients accessing medical cannabis?

Are there differences in characteristics of males and females accessing medical cannabis?

What are the most commonly reported conditions among this sample of patients?

How many conditions do patients seek treatment for, and does this change based on age and gender?

These questions were investigated to assist the medical community in further developing an understanding of patients seeking medical cannabis for treatment of their conditions and symptoms, and to assist others in determining areas of interest for future research. This knowledge may also inform policy makers in states considering medical cannabis legalization or the further development of existing medical cannabis programs in states where medical cannabis has already been legalized.

This was a retrospective database study of patients seeking medical cannabis certification in the US. Data were extracted from the database software utilized in CB2 Insights’ clinical network. CB2 Insights operates one of the largest collections of medical cannabis evaluation clinics in the US, collectively assessing approximately 100,000 patients per year seeking access to medical cannabis, using a single and consistent software that contributes data to a patient registry. These 33 independent clinics are not connected to dispensaries or producers of medical cannabis, and are situated across 12 states (number of clinics): Colorado (6), Connecticut (1), Delaware (2), Illinois (1), Maine (1), Maryland (1), Massachusetts (10), Missouri (1), New Jersey (5), New York (1), Rhode Island (2), and Pennsylvania (2). Patients access these clinics by physician-referral or self-referral through word of mouth, community out-reach and marketing. Over 95% of data were collected via face-to-face interview, with the remaining collected via telemedicine. Patients presenting to any of the clinics are required to complete the same baseline information upon intake, including demographic, medical, and therapeutic information; however, certain characteristics such as race and gender were not made mandatory initially, and are not reported for all patients. Baseline questions include patient-reported tobacco smoking and alcohol use, current or past substance abuse of drugs and/or alcohol, use of illicit (illegal) drugs, medication use and alternative therapies. Medication use is an open-ended question that may be completed by transcribing a medication list into the software, which leaves room for errors and may be a limitation of the data. All patients indicate their primary reason for seeking access to medical cannabis and are asked to report all comorbid conditions for which they are also seeking medical cannabis. Patients are required to provide supporting documentation of their medical histories and relevant conditions for review and verification, in the form of medical records or a letter from another physician. Review of medical documentation, in combination with a medical evaluation by a state-authorized physician or nurse practitioner are used to confirm their qualification for medical cannabis within their respective state. Prior to data export, the protocol was reviewed by the Advarra Institutional Review Board (IRB) and was determined to be exempt from IRB oversight ( Pro00042652 ) as the study had minimal risk, the data exports were void of patient identifiers, and it did not require direct patient contact.

Data were exported for 62,145 patients who were seen for their initial assessment between November 18, 2018 (when the technology and standardized protocol were introduced into the clinics) and March 18, 2020. Data were exported without any patient identifiers to ensure patient anonymity. Eligibility criteria were applied to the data set and the following patients were removed: 1) 77 patients without a valid date of birth; 2) 78 patients younger than 18; and 3) 611 patients without a primary medical condition reported. Overall, 61,379 patients were included in the analysis (Fig.  1 ).

Patient Flow

Data from the database software utilized in CB2 Insights’ clinical network were also merged with US tax data, which provides tabulations of income tax data by ZIP code in order to estimate household income based on individual patients’ ZIP codes. Median household income values from the 2018 dataset purchased from Cubit Planning Inc. were used (US Income Statistics - Current Census Data for Zip Codes 2018 ). Cubit Planning Inc. summarizes the most current income statistics from the US Census Bureau.

When a final dataset was confirmed, data were analyzed using RStudio (Boston, MA). All information was summarized using descriptive statistics expressed as a mean (standard deviation (SD)) or median (interquartile range (IQR)) as appropriate for continuous variables, and number (percent) for categorical variables. Univariate analyses were conducted to inform multivariate analyses including t-tests when comparing means and chi-squared tests when comparing proportions. Regression analyses were conducted to determine if age and gender, specifically, were significant predictors of characteristics of smoking, alcohol consumption, prior cannabis use and medication usage, the number of medications being used, and the number of conditions reported. Logistic regression was used for dichotomous variables and linear regression was used for continuous variables. To analyze whether age and gender were significant predictors of reporting each primary condition, each condition was compared separately to all others using logistic regression. An interaction model with age and gender was included for all regression analyses; if the interaction effect was significant, p -values are reported for the interaction model, otherwise p-values are reported for the model without interaction. All tests were completed with a significance level of 0.05. P -values less than 0.001 are expressed as p  < 0.001, and 95% confidence intervals (CI) are provided where appropriate.

The average age of patients in the sample was 45.5 (SD = 15.8) and 54.8% were male (Table  1 ). The average age of females, 47.0 (SD = 15.7), was significantly greater than males, 44.6 (SD = 15.7) ( p  < 0.001, difference in means = 2.4, 95% CI: 2.15–2.68) (Table  2 ). Of the patients with race reported, Caucasians represented the largest group of the sample population at 87.5%. The median household income in the ZIP code in which patients resided was available for 56,083 patients. The overwhelming majority of patients lived in a ZIP code where the median household income was above $40,000 (93.7%); the median was $69,481 (IQR $35,807). Most patients (66.9%) reported that they had experience with cannabis prior to seeking medical certification, were non-smokers (81.2%), did not drink (57.5%) and did not have a history of substance abuse (94.4%). Gender was not a significant predictor of reporting prior cannabis experience or history of substance abuse ( p  = 0.929 and 0.871, respectively), but was for smoking status and alcohol consumption ( p  < 0.001) (Tables  3 and 4 ). Males reported smoking tobacco more than females, whereas females reported the use of alcohol more than males.

Less than half of patients reported prescription medication use (44.2%). Increased age and female gender were significant predictors of reporting at least one medication ( p  < 0.001) and a greater number of medications (p < 0.001) (Tables 3 and 4 ). Of patients who reported taking at least one medication ( n  = 27,106), the mean number of medications reported was 4.1 (SD = 3.7). Over half the sample (59.4%) reported currently using an alternate form of therapy. Of those who reported using a therapy, the average number reported was 2.5 (SD = 1.7), and the most commonly reported among this group were exercise (70.9%), massage therapy (36.4%), mental health counselling (30.8%) and chiropractor (30.3%). A quarter of the sample (26.1%) did not report any current use of medications or alternate therapy.

Regardless of gender, the top three primary medical conditions were unspecified chronic pain ( n  = 23,817, 38.8%), anxiety ( n  = 8280, 13.5%) and PTSD ( n  = 5143, 8.4%) (Table  5 ). Following the top three were back and neck problems ( n  = 3969, 6.5%), arthritis ( n  = 2395, 3.9%), insomnia ( n  = 2096, 3.4%) and cancer-related pain ( n  = 1641, 2.7%). Depression, migraines, muscle spasms, ADD/ADHD, chronic nausea, fibromyalgia, headaches and epilepsy were each reported as the primary medical condition for 2.0% or less of the sample. Of the primary medical conditions, 10.6% of those reported were other medical conditions each representing less than 1.0% of the entire sample. Gender was not a significant predictor of epilepsy, but was a significant predictor for all other conditions (Table  6 ); females were significantly more likely to report anxiety, PTSD, arthritis, cancer related pain, depression, migraines, chronic nausea, fibromyalgia and headaches, whereas males were significantly more likely to report unspecified chronic pain, back & neck problems, insomnia, muscle spasms and ADD/ADHD.

Patients reporting anxiety, PTSD, depression, migraines, ADD/ADHD, chronic nausea, headaches or epilepsy as their primary reason for seeking medical cannabis were significantly more likely to be younger ( p  < 0.001), whereas patients seeking medical cannabis primarily for unspecified chronic pain, back and neck problems, arthritis, insomnia, cancer related pain or fibromyalgia were significantly more likely to be older (Table 6 ). Age was not a significant predictor of reporting muscle spasms.

Patients were able to report any number of comorbid medical conditions necessary to describe their reason(s) for seeking medical cannabis (Table  7 ). The average number of comorbid medical conditions reported was 2.7 (SD = 2.6). Anxiety was the most commonly reported comorbid condition ( n  = 17,359, 28.3%), followed by back and neck problems ( n  = 14,550, 23.7%), insomnia (n = 14,247, 23.2%), depression ( n  = 13,413, 21.9%), and unspecified chronic pain ( n  = 11,199, 18.2%). Only 17.6% of the sample did not report a comorbid medical condition.

Taking into consideration all medical conditions reported (both primary and comorbid (Table 7 )), over half of the sample reported unspecified chronic pain (57.0%), followed by anxiety (41.8%), back and neck problems (30.2%), insomnia (26.6%) and depression (23.9%). Patients reported an average of 3.7 total medical conditions (SD = 2.6). Younger age and female gender were significant predictors of the number of conditions patients reported ( p  = 0.003 and p  < 0.001, respectively). Females reported an average of 4.1 (SD = 2.9) total conditions, compared to an average of 3.3 (SD = 2.3) among males.

We conducted an extensive retrospective study with the objective of describing the population of patients seeking treatment with medical cannabis at 33 clinics in the US. Our results indicate that patients seeking medical cannabis in the US most commonly report suffering from unspecified chronic pain (57.0%), regardless of age or gender, which is consistent with similar studies that report 61.2 to 82.6% of patients seeking medical cannabis for chronic pain (Boehnke et al. 2019 ; Sexton et al. 2016 ; Eurich et al. 2019 ; Reinarman et al. 2011 ). Second to unspecified chronic pain, patients were most likely to report anxiety as their primary medical condition, and anxiety was the most commonly reported comorbid condition. This finding is consistent with results from a survey completed by Sexton et al. among self-identifying medical cannabis patients, in which the second and third most common medical conditions that patients reported using medical cannabis for were anxiety (58.1%) and depression (50.3%) (Sexton et al. 2016 ). Gender was a significant predictor for most primary conditions, which is unsurprising as males and females have different risk factors, experiences and perceptions of illness and do not tend to report or be diagnosed with medical conditions in equal proportions (Seeman 1997 ; Buvinić et al. 2006 ; Westergaard et al. 2019 ).

The average number of conditions and comorbidities is not commonly stated, but has been reported at 1.8 and 3.0 in similar studies, both lower than our findings (Reinarman et al. 2011 ; Salazar et al. 2019 ). The average number of conditions reported differed between males and females, with females reporting a higher average number of conditions. This aligns with previous research that has demonstrated that females access health care services more than males and may be more diligent with providing relevant information, which may partially explain why females tend to have higher reported rates of morbidity (Bertakis et al. 2000 ; Verbrugge and Wingard 1987 ; Waldron 1983 ; MacIntyre et al. 1999 ).

Similar to the survey by Salazar et al., this study also demonstrated the wide variety of conditions for which patients access medical cannabis (Salazar et al. 2019 ). Conditions representing less than 1.0% of sample accounted for 10.6% of primary conditions reported and included more than 200 unique conditions (Table  8 ), the majority of which came from states where physicians are able to use their discretion for patients’ qualification (MA, MD, ME, MO). The information on the number and variety of conditions for which patients report seeking medical cannabis treatment is important for medical practitioners for several reasons. Firstly, it highlights the breadth of conditions for which patients are seeking medical cannabis for symptomatic relief. This is important as it identifies patients who may potentially turn to them with questions regarding their suitability for medical cannabis or who may already be seeking medical cannabis without their knowledge, demonstrating the need for practitioners to educate themselves and be prepared to discuss and provide their professional medical opinion. Secondly, these data demonstrate that patients seeking medical cannabis are complex patients who have more than a single ailment. While rigorous clinical trials are still needed to validate the use of medical cannabis for these conditions, real world data are also needed to describe these patients, as complex patients are more likely to be excluded from clinical trials evaluating the effectiveness of a medication (Hanlon et al. 2019 ). Finally, these data highlight the potential utility of medical cannabis and how it is currently utilized for treatment of multiple conditions with which a patient is suffering.

Medication use and average number of medications increased with age; however, patients reported medication use less than the general US population overall. Findings from the National Health and Nutrition Examination Survey reported that 83.6% of adults aged 60 and over used prescription medication in the previous 30 days, compared to only 56.4% of our sample aged 60 and older. For adults aged 40–59, our sample also reported less medication use; 48.3% compared to 59.5% (Martin et al. 2015 ). This difference may be a result of patients under-reporting their medications at the clinic, or medication information not being correctly transcribed into the software from practitioners’ notes. Alternatively, it may show a true difference in characteristics between the general US population and those accessing medical cannabis. The latter may suggest that those accessing medical cannabis may be doing so in lieu of using traditional pharmaceutical medications; however, this theory contradicts results of a study from 2018 that reported that medical cannabis users are more likely to use prescription medications (Caputi and Humphreys 2018 ). Reported medication use was not analyzed in reference to specific primary medical conditions for the purposes of this study, but identified it as an area of interest for future research. It is interesting to note that 26.1% of the sample did not report using medications or alternate therapies at the time of their initial assessment. This may demonstrate a limitation of the data, as there is potential that there is under-reporting at the system level; however, this may also indicate that patients are seeking medical cannabis where other treatments have failed, which would benefit from further investigation.

When comparing our results to a study of 1746 patients attending assessment clinics in California in 2006, who were primarily male (72.9%) and between the ages of 25–54 (69.2%) (Reinarman et al. 2011 ), it suggests that the medical cannabis patient population has evolved over time to include more females , and a wider range of ages; 40% of the sample who reported gender were female, and 31.5% of the patient population in this study were over the age of 54. The increasing age of medical cannabis users and increase in female users were also reported in a review completed by Fairman et al. (Fairman 2016 ). The high representation of Caucasians in this sample is consistent with the literature in which Caucasians represent the majority of medical cannabis users reported in other studies (77.0, 86.5, 61.5%) (Sexton et al. 2016 ; Reinarman et al. 2011 ; Reiman 2007 ). This is substantiated by the fact that Caucasians are the racial majority in the US, particularly in the states where the clinics are located.

The median estimated household income in the ZIP codes where our patient sample resides was higher than the US median, $69,481 compared to $61,937 (Bureau UC 2019 ). When taking into consideration the median household income from just the included states, $58,912 (US Income Statistics - Current Census Data for Zip Codes 2018 ), the median estimated household income from our sample was still higher; however, as the income data for our sample was a surrogate, this may be inflated and potentially inaccurate. Similar studies tend to report that income among medical cannabis users is lower than the average, which highlights the need for additional investigation (Sexton et al. 2016 ; Reiman 2007 ).

Data collected as part of the intake for patients in this retrospective study provide an interesting perspective on cannabis experience prior to seeking medical certification, as almost 70% reported using cannabis prior to their certification. This number is substantially higher than the lifetime cannabis use estimate among Americans from the National Survey on Drug Use and Health, which reported a lifetime cannabis use of 45.3% in 2018 (2018 NSDUH Detailed Tables | CBHSQ Data 2019 ). Unfortunately, it is not known how many of the patients in the dataset had medical certification from a separate clinic or physician elsewhere prior to becoming a patient at a CB2 Insights clinic.

Strengths of this study include the large sample of patients accessing medical cannabis across 12 states. The consistent input of data at the clinics allowed for a comprehensive review of characteristics, and most importantly, provided data on all medical conditions for which patients sought medical cannabis, rather than just one per patient. Additionally, data collection was verified by medical professionals at the time of input. Limitations of this study primarily include missing data (i.e., a large number of patients for whom gender and race were not reported), a lack of ethnicity data, the absence of data on patients who did not qualify for medical cannabis certification and were not included in the registry, and the use of surrogate income data. Another limitation is that the data came from a single network of clinics, and do not represent patients in all states where medical cannabis is legal.

Conclusion and future initiatives

This retrospective study offers insight into the characteristics and commonly reported type and number of medical conditions among patients accessing medical cannabis in the US. It highlighted the conditions that patients are seeking medical cannabis for most often that would benefit from further clinical evidence; mainly pain conditions, anxiety, insomnia, depression and PTSD. This study also demonstrated that patients often use medical cannabis to treat more than one condition, which is important for the medical community to understand and be aware of, as well as the patients who may be turning to cannabis as a treatment option. This finding in particular raises questions that are important to investigate, including why patients use medical cannabis for multiple conditions and whether they use different products to treat their various symptoms. As this study explored demographic and medical characteristics from patients in 12 different states, an in-depth review comparing states with contrasting cannabis regulations would offer further insights into medical cannabis use and access in the US.

Availability of data and materials

The datasets used for this article are not publicly available due to patients’ privacy. Data can be made available upon appropriate request to the authors.

Abbreviations

cannabidiol

confidence interval

interquartile range

institutional review board

post-traumatic stress disorder

standard deviation

Δ-9-tetrahydrocannabinol

United States

2018 NSDUH Detailed Tables | CBHSQ Data. 2019 https://www.samhsa.gov/data/report/2018-nsduh-detailed-tables . Accessed 27 Mar 2020.

Alsherbiny MA, Li CG. Medicinal Cannabis-Potential Drug Interactions. Med (Basel, Switzerland). 2018;6(1). https://doi.org/10.3390/medicines6010003 .

Bertakis K, Azari R, Helms L, Callahan E, Robbins J. Gender differences in the utilization of health care services. J Fam Pr 2000;49(2):147–152. https://pubmed.ncbi.nlm.nih.gov/10718692/ . Accessed 9 June 2020.

Boehnke KF, Gangopadhyay S, Clauw DJ, Haffajee RL. Qualifying conditions of medical cannabis license holders in the United States. Health Aff. 2019;38(2):295–302. https://doi.org/10.1377/hlthaff.2018.05266 .

Article   Google Scholar  

Bonn-Miller MO, Boden MT, Bucossi MM, Babson KA. Self-reported cannabis use characteristics, patterns and helpfulness among medical cannabis users. Am J Drug Alcohol Abuse. 2014;40(1):23–30. https://doi.org/10.3109/00952990.2013.821477 .

Article   PubMed   Google Scholar  

Bureau UC. U.S. Median Household Income Up in 2018 From 2017. 2019. https://www.census.gov/library/stories/2019/09/us-median-household-income-up-in-2018-from-2017.html . Accessed 26 Sept 2019.

Buvinić M, Medici A, Fernández E, Torres AC. Gender differentials in health. The International Bank for Reconstruction and Development / The World Bank; 2006. http://www.ncbi.nlm.nih.gov/pubmed/21250310 . Accessed 14 Aug 2020.

Caputi TL, Humphreys K. Medical marijuana users are more likely to use prescription drugs medically and nonmedically. J Addict Med. 2018;12(4):295–9. https://doi.org/10.1097/ADM.0000000000000405 .

DISA Global Solutions. Map of marijuana legality by state. Retrieved from URL https://disa.com/map-of-marijuana-legality-by-state . 2019. https://disa.com/map-of-marijuana-legality-by-state .

Eurich DT, Hanlon JG, Boisvenue JJ, Meng H, Dyck JRB. A description of the medical Cannabis use in Ontario, Canada. Cannabis Cannabinoid Res. 2019;4(2):131–5. https://doi.org/10.1089/can.2018.0036 .

Fairman BJ. Trends in registered medical marijuana participation across 13 US states and District of Columbia. Drug Alcohol Depend. 2016;159:72–9. https://doi.org/10.1016/j.drugalcdep.2015.11.015 .

Fraguas-Sanchez AI, Torres-Suarez AI. Medical use of cannabinoids. Drugs. 2018;78(16):1665–703. https://doi.org/10.1007/s40265-018-0996-1 .

Article   PubMed   CAS   Google Scholar  

Hanlon P, Hannigan L, Rodriguez-Perez J, et al. Representation of people with comorbidity and multimorbidity in clinical trials of novel drug therapies: an individual-level participant data analysis. BMC Med. 2019;17(1):201. https://doi.org/10.1186/s12916-019-1427-1 .

Article   PubMed   PubMed Central   Google Scholar  

Institute of Medicine (U.S.). Marijuana and medicine: assessing the science base. Natl Acad Press https://doi.org/1017226/6376 . 1999. https://doi.org/10.5860/choice.37-2206 .

Kaur R, Ambwani SR, Singh S. Endocannabinoid system: a multi-facet therapeutic target. Curr Clin Pharmacol. 2016;11(2):110–7.

Article   CAS   Google Scholar  

Klumpers LE, Thacker DL. A brief background on Cannabis: from plant to medical indications. J AOAC Int. 2019;102(2):412–20. https://doi.org/10.5740/jaoacint.18-0208 .

Kosiba JD, Maisto SA, Ditre JW. Patient-reported use of medical cannabis for pain, anxiety, and depression symptoms: systematic review and meta-analysis. Soc Sci Med. 2019;233:181–92. https://doi.org/10.1016/j.socscimed.2019.06.005 .

Legislatures NC of S. State Medical Marijuana Laws. https://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx . Published 2020.

Lu Y, Anderson HD. Cannabinoid signaling in health and disease. Can J Physiol Pharmacol. 2017;95(4):311–27. https://doi.org/10.1139/cjpp-2016-0346 .

MacIntyre S, Ford G, Hunt K. Do women “over-report” morbidity? Men’s and women’s responses to structured prompting on a standard question on long standing illness. Soc Sci Med. 1999;48(1):89–98. https://doi.org/10.1016/S0277-9536(98)00292-5 .

Martin CB, Hales CM, Gu Q, Ogden CL. Prescription Drug Use in the United States, 2015–2016 Key Findings Data from the National Health and Nutrition Examination Survey; 2015. https://www.cdc.gov/nchs/data/databriefs/db334_tables-508.pdf#1 . Accessed 3 Apr 2020.

Pacula RL, Smart R. Medical marijuana and marijuana legalization. Annu Rev Clin Psychol. 2017;13:397–419. https://doi.org/10.1146/annurev-clinpsy-032816-045128 .

Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74(2):129–80. https://doi.org/10.1016/s0163-7258(97)82001-3 .

Pertwee RG, Howlett AC, Abood ME, et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB(1) and CB(2). Pharmacol Rev. 2010;62(4):588–631. https://doi.org/10.1124/pr.110.003004 .

Article   PubMed   PubMed Central   CAS   Google Scholar  

Reiman A. Medical Cannabis patients: patient profiles and health care utilization patterns. Complement Health Pract Rev. 2007;12(1):31–50. https://doi.org/10.1177/1533210107301834 .

Reinarman C, Nunberg H, Lanthier F, Heddleston T. Who are medical marijuana patients? Population characteristics from nine California assessment clinics. J Psychoactive Drugs. 2011;43(2):128–35. https://doi.org/10.1080/02791072.2011.587700 .

Salazar CA, Tomko RL, Akbar SA, Squeglia LM, Mcclure EA. Medical Cannabis Use among Adults in the Southeastern United States. Cannabis. 2019;2(1):53–65.

Seeman MV. Psychopathology in women and men: focus on female hormones. Am J Psychiatry. 1997;154(12):1641–7. https://doi.org/10.1176/ajp.154.12.1641 .

Sexton M, Cuttler C, Finnell JS, Mischley LK. A cross-sectional survey of medical Cannabis users: patterns of use and perceived efficacy. Cannabis Cannabinoid Res. 2016;1(1):131–8. https://doi.org/10.1089/can.2016.0007 .

US Income Statistics - Current Census Data for Zip Codes. 2018. https://www.incomebyzipcode.com/ . Accessed 27 Mar 2020.

Verbrugge LM, Wingard DL. Sex differentials in health and mortality. Health Matrix. 1987;5(2):3–19. https://doi.org/10.1300/j013v12n02_07 .

Vuckovic S, Srebro D, Vujovic KS, Vucetic C, Prostran M. Cannabinoids and pain: new insights from old molecules. Front Pharmacol. 2018;9:1259. https://doi.org/10.3389/fphar.2018.01259 .

Waldron I. Sex differences in illness incidence, prognosis and mortality: issues and evidence. Soc Sci Med. 1983;17(16):1107–23. https://doi.org/10.1016/0277-9536(83)90004-7 .

Westergaard D, Moseley P, Sørup FKH, Baldi P, Brunak S. Population-wide analysis of differences in disease progression patterns in men and women. Nat Commun. 2019;10(1):1–14. https://doi.org/10.1038/s41467-019-08475-9 .

Yu B, Chen X, Chen X, Yan H. Marijuana legalization and historical trends in marijuana use among US residents aged 12-25: results from the 1979-2016 National Survey on drug use and health. BMC Public Health. 2020;20(1):1–10. https://doi.org/10.1186/s12889-020-8253-4 .

Zaller N, Topletz A, Frater S, Yates G, Lally M. Profiles of medicinal cannabis patients attending compassion centers in Rhode Island. J Psychoactive Drugs. 2015;47(1):18–23. https://doi.org/10.1080/02791072.2014.999901 .

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Acknowledgements

The authors would like to thank Christopher Vannabouathong for assistance with the statistical analysis.

This study was not funded by any external sources. Authors are employees of CB2 Insights and were compensated as per their contracts for the time to analyze the data and prepare the manuscript.

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Mahabir, V.K., Merchant, J.J., Smith, C. et al. Medical cannabis use in the United States: a retrospective database study. J Cannabis Res 2 , 32 (2020). https://doi.org/10.1186/s42238-020-00038-w

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Research explores liberalization of medical marijuana and mental health in the US

by University of Basel

The approval of marijuana for medical use has had little effect on the mental health of the general population in the US. But legalization for therapeutic purposes does benefit those for whom it is intended. This is the conclusion of a study by researchers at the University of Basel. The research is published in the journal Health Economics, Policy and Law .

In the US, access to marijuana has been facilitated in most states since the mid-1990s—whether through medical clearance or through decriminalization of recreational use. However, liberalization is still controversial, and the effects on the well-being of specific groups and the therapeutic value of marijuana remain debated.

While some fear negative consequences from addiction, others highlight the potential medical benefits for people suffering from chronic pain, nausea or convulsions.

In a new study, researchers from Basel have now investigated whether medical cannabis legislation in the U.S. is improving the situation for sick people and whether it has a negative impact on the mental health of the overall population.

Probability-based analysis

For their analysis, the researchers combined two large datasets. They used data from almost eight million people who took part in telephone surveys between 1993 and 2018 as part of the Behavioral Risk Factor Surveillance System, which collects data about mental well-being, among other things. But they also used data from the National Survey on Drug Use and Health, which collects information on health-related issues such as drug use in the United States.

The researchers formed different groups using statistical assignment. They include individuals who are highly likely to abstain from using marijuana, to use marijuana as a recreational drug or to use it for medical reasons. It was also possible to identify individuals with a high probability of chronic pain. Mental health was measured using self-assessment , in which respondents reported the number of days they had had mental health problems in the previous month.

Positive effects of therapeutic use

Using statistical methods , the researchers were able to estimate the impact of the legal approval of marijuana for medical use . The result: Easier access improves the mental health of individuals who use marijuana for medical reasons. The same applies to people who are very likely to suffer from pain. The study authors estimate that these two groups spend 0.3 days less per month in poor mental health due to the change in the law.

At the same time, the researchers found no effect on the mental health of recreational users or on younger populations.

"Overall, our results show that medical cannabis legislation in the U.S. benefits the people it is intended for without harming other groups," summarizes the study leader, Prof. Alois Stutzer from the University of Basel.

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Working to Reform Marijuana Laws Since 1970

Recent medical marijuana research.

Clinical Applications For Cannabis & Cannabinoids A Review of the Recent Scientific Literature, 2000 — 2021

Table of Contents

• Introduction to the Endocannabinoid System
• Why I Recommend Medical Cannabis
• Alzheimer’s Disease
• Amyotrophic Lateral Sclerosis (ALS)
• Autism Spectrum Disorder
• Chronic Pain
• Diabetes Mellitus
• Fibromyalgia
• Gastrointestinal Disorders
• Gliomas/Cancer
• Hepatitis C
• Human Immunodeficiency Virus (HIV)
• Huntington Disease
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• Methicillin-resistant Staphylococcus aureus (MRSA)
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• Parkinson’s Disease
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• Clinical Applications for Cannabis & Cannabinoids — Kindle Edition

Humans have cultivated and consumed the flowering tops of the female cannabis plant, colloquially known as marijuana , since virtually the beginning of recorded history. Cannabis-based textiles dating to 7,000 BCE have been recovered in northern China, and the plant’s use as a medicinal and mood-altering agent date back nearly as far. In 2008, archeologists in Central Asia discovered over two pounds of cannabis in the 2,700-year-old grave of an ancient shaman. After scientists conducted extensive testing on the material’s potency, they affirmed, “[T]he most probable conclusion … is that [ancient] culture[s] cultivated cannabis for pharmaceutical, psychoactive, and divinatory purposes.”

Modern cultures continue to indulge in the consumption of cannabis for these same purposes, despite a decades-long, virtual worldwide ban on the plant’s cultivation and use. In the United States, federal prohibitions outlawing cannabis’ recreational, industrial, and therapeutic use were first imposed by Congress under the Marihuana Tax Act of 1937 and then later reaffirmed by federal lawmakers’ decision to classify the cannabis plant — as well as all of its organic chemical compounds (known as cannabinoids) — as a Schedule I substance under the Controlled Substances Act of 1970. This classification, which categorizes the plant alongside heroin, defines cannabis and its dozens of distinct cannabinoids as possessing “a high potential for abuse, … no currently accepted medical use, … [and] a lack of accepted safety for the use of the drug … under medical supervision.” By contrast, cocaine and methamphetamine — which remain illicit for recreational use but may be consumed under a doctor’s supervision — are classified as Schedule II drugs. Both alcohol and tobacco are unscheduled.

Challenging Cannabis’ Schedule I Status

The ongoing classification of the cannabis plant as a Schedule I controlled substance is inconsistent with  scientific opinion ,  public attitudes , and the overwhelming majority of  state laws . Furthermore, there now exists ample scientific and empirical evidence to rebut the federal government’s contention. Despite the nearly century-long prohibition of the plant, cannabis is nonetheless one of the most investigated therapeutically active substances in history. To date, there are over 36,000 peer-reviewed papers in the scientific literature referencing the cannabis plant and its cannabinoids, according to a keyword search on the search engine PubMed Central, the US government repository for peer-reviewed scientific research. In recent years, this volume of research has grown exponentially, with more than 20,000 papers published just in the past decade. Much of this more recent research has been  dedicated  to exploring and verifying cannabis’ therapeutic activities in various patient populations – including in FDA-approved gold-standard clinical trials. A  summary of this clinical trial data concluded: “Evidence is accumulating that cannabinoids may be useful medicine for certain indications. … The classification of marijuana as a Schedule I drug as well as the continuing controversy as to whether or not cannabis is of medical value are obstacles to medical progress in this area. Based on evidence currently available the Schedule I classification is not tenable; it is not accurate that cannabis has no medical value, or that information on safety is lacking.”

The Shifting Focus of Cannabis Research

As clinical research into the therapeutic value of cannabinoids has proliferated so too has investigators’ understanding of cannabis’ remarkable capacity to combat disease. Whereas researchers in the 1970s, 80s, and 90s primarily assessed marijuana’s ability to temporarily alleviate various disease symptoms — such as the nausea associated with cancer chemotherapy — scientists today are exploring the potential role of cannabinoids to modulate disease .

For example, scientists are investigating cannabinoids’ capacity to moderate autoimmune disorders such as multiple sclerosis , rheumatoid arthritis , and inflammatory bowel disease , as well as their role in the treatment of neurological disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis (aka Lou Gehrig’s disease).

Investigators are also studying the anti-cancer activities of cannabis, as a growing body of preclinical data concludes that cannabinoids can reduce the spread of specific cancer cells via apoptosis (programmed cell death) and by the inhibition of angiogenesis (the formation of new blood vessels).

Researchers are also exploring the use of cannabis as a harm reduction alternative for many patients. To date, dozens of studies document patients’ use of cannabis as an alternative to various prescription drugs,  specifically opioids .

Arguably, these recent discoveries represent far broader and more significant applications for cannabinoid therapeutics than many researchers could have imagined some 30 or even 20 years ago.

The Safety Profile of Medical Cannabis

Cannabinoids possess a remarkable safety record, particularly when compared to conventional prescription drugs. Most significantly, the consumption of marijuana — regardless of quantity or potency — cannot induce a fatal overdose. States a World Health Organization review paper , “There are no recorded cases of overdose fatalities attributed to cannabis, and the estimated lethal dose for humans extrapolated from animal studies is so high that it cannot be achieved by … users.”

The use of cannabis for therapeutic purposes is also rarely associated with significant adverse side effects. A prominent review of clinical trial data “did not find a higher incidence rate of serious adverse events associated with medical cannabinoid use” compared to nonusing controls over a four decade period. A more recent review of the relevant literature concludes that among the average adult user, the health risks associated with marijuana “are no more likely to be dangerous” than many other behaviors or activities, including the consumption of acetaminophen (the pain relieving ingredient in Tylenol).

That said, cannabis should not be viewed as a “harmless” substance. Its active constituents may produce a variety of physiological and mood-altering effects. As a result, there may be some populations that may be vulnerable to increased risks from the use of cannabis, such as adolescents , pregnant or nursing mothers , and patients who have a family history of psychiatric illness or who possess a clinical high risk for developing a psychotic disorder. Patients with a history of cardiovascular disorders, heart disease , or stroke may also be at an elevated risk of experiencing adverse side effects from marijuana, particularly smoked cannabis. As with any medication, patients should consult thoroughly with their physician before deciding whether the medical use of cannabis is safe and appropriate.

How to Use This Publication

As states continue to approve legislation enabling the physician-supervised use of medical marijuana, more patients with varying disease types are exploring the use of therapeutic cannabis. Many of these patients and their physicians are now discussing this issue for the first time and are seeking guidance on whether the therapeutic use of cannabis may or may not be advisable. This report seeks to provide this guidance by highlighting hundreds of relevant, recently published scientific research (2000-2021) on the therapeutic potential of cannabis and cannabinoids for a variety of indications. This summary of the available peer-reviewed research is among the most comprehensive reviews available in the modern literature and is the result of hundreds of hours of research and writing.

In some of these cases, modern science is now affirming longtime anecdotal reports of medical cannabis users (e.g., the use of cannabis to alleviate GI disorders ). In other cases, this research is highlighting entirely new potential clinical utilities for cannabinoids (e.g., the use of cannabinoids to modify the progression of diabetes ). In all cases, science has sufficiently made the case that cannabis is safe and effective for certain patient populations. This fact should no longer be the subject of any serious debate.

For patients and their physicians, let this report serve as a primer for those who are considering using or recommending medical cannabis. For others, let this report serve as an introduction to the broad range of therapeutic applications for cannabis and its various compounds.

Paul Armentano Deputy Director NORML | NORML Foundation Washington, DC July 9, 2021

* The author would like to acknowledge Drs. Dale Gieringer , Estelle Goldstein, Dustin Sulak, Gregory Carter, Steven Karch, and Mitch Earleywine, as well as Bernard Ellis, MPH, former NORML interns John Lucy, Christopher Rasmussen, and Rita Bowles, for providing research assistance for this report. Oaksterdam University alumna Vanessa Garcia deserves special recognition for her significant contributions to the 2021 edition of this publication. The NORML Foundation would also like to acknowledge Dale Gieringer, Paul Kuhn, and Richard Wolfe for their financial contributions toward the publication of this report.

** Important and timely publications such as this are only made possible when concerned citizens become involved with NORML and make financial contributions. For more information, please visit:  norml.org/support . Tax-deductible donations in support of NORML’s public education campaigns should be made payable to the NORML Foundation .

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After 50 Years, U.S. Opens The Door To More Cannabis Crops For Scientists

More than 30 states have medical marijuana programs — yet scientists are only allowed to use cannabis plants from one U.S. source for their research. That's set to change, as the federal government begins to add more growers to the mix. Drew Angerer/Getty Images hide caption

More than 30 states have medical marijuana programs — yet scientists are only allowed to use cannabis plants from one U.S. source for their research. That's set to change, as the federal government begins to add more growers to the mix.

After more than 50 years, the federal government is lifting a roadblock to cannabis research that scientists and advocates say has hindered rigorous studies of the plant and possible drug development.

Since 1968, U.S. researchers have been allowed to use cannabis from only one domestic source : a facility based at the University of Mississippi, through a contract with the National Institute on Drug Abuse (NIDA).

That changed earlier this month, when the Drug Enforcement Administration announced it's in the process of registering several additional American companies to produce cannabis for medical and scientific purposes.

It's a move that promises to accelerate understanding of the plant's health effects and possible therapies for treating conditions — chronic pain, the side effects of chemotherapy, multiple sclerosis and mental illness, among many others — that are yet to be well studied .

Shots - Health News

How one boy's fight with epilepsy led to the first marijuana-derived pharmaceutical.

"This is a momentous decision," says Rick Doblin, executive director of the Multidisciplinary Association for Psychedelic Studies (MAPS), which has spearheaded research into other Schedule 1 drugs — the most restrictive class of controlled substance, which the federal government defines as "drugs with no currently accepted medical use."

"This is the last political obstruction of research with Schedule 1 drugs," he says.

About one-third of Americans currently live in a state where recreational marijuana is legal — and more than 30 states have medical marijuana programs . Yet scientists still aren't allowed to simply use the cannabis sold at state-licensed dispensaries for their clinical research because cannabis remains illegal under federal law.

Medical Marijuana's 'Catch-22': Limits On Research Hinder Patient Relief

"It is a big disconnect," says Dr. Igor Grant , a psychiatry professor and director of the Center for Medicinal Cannabis Research at University of California, San Diego.

The new DEA decision doesn't resolve the conflict between federal and state laws, but it does offer researchers a new, federally sanctioned pipeline for more products and strains of cannabis.

"We'll see a decade or more of explosive cannabis research and potential new therapies," says Dr. Steve Groff, founder and chairman of Groff North America , one of three companies that has publicly announced it has preliminary approval from the federal government to cultivate cannabis for research.

A long-running fight to overturn federal "monopoly"

Despite their efforts, scientists have encountered administrative and legal hurdles to growing pharmaceutical-grade cannabis for decades.

In 2001, Dr. Lyle Craker, a prominent plant biologist, first applied for a license to cultivate marijuana for research — only to encounter years of delay that kicked off a prolonged court battle with the DEA, which has to greenlight research into Schedule 1 drugs like cannabis.

"There's thousands of different cannabis varieties that all have unique chemical profiles and produce unique clinical effects, but we didn't have access to that normal diversity," says Dr. Sue Sisley , a cannabis researcher and president of the Scottsdale Research Institute, which also received preliminary DEA approval to produce cannabis for research.

Only in 2016 did the federal government signal a change in policy that would open the door for new growers, but applications to do so languished for years. Craker and others ended up suing the federal government over the delay.

Psychiatrist Explores Possible Benefits Of Treating PTSD With Ecstasy Or Cannabis

Sisley has long taken issue with the supply of cannabis coming from the NIDA facility in Mississippi — in particular, how it's processed. She used cannabis produced there in her recently published clinical trial on treating PTSD in military veterans.

She describes the product as an "anemic" greenish powder.

"It's very difficult to overcome the placebo effect when you have something that diluted," she says.

The 76-person study, which took 10 years to complete, concluded that smoked cannabis was generally well tolerated and did not lead to deleterious effects in this group. But it also did not find any statistically significant difference in abating the symptoms of PTSD when compared to a placebo.

For Grant of UCSD, the problem with the long-standing supply of cannabis isn't so much the quality, but the lack of different products like edibles and oils and of cannabis strains with varying concentrations of CBD and THC, the plant's main psychoactive ingredient.

"We don't have enough research on the kind of marijuana products that people in the real world are using," he says.

As CBD Oils Become More Popular, The FDA Considers Whether To Set New Rules

Because of the limited domestic supply, some researchers have resorted to importing cannabis from outside the U.S. — a legal but wildly counterintuitive arrangement that is "arduous" and prone to hiccups, says Sisley.

The constraints on research cannabis also has impeded the pathway to drug development because the NIDA facility's cannabis could only be used for academic research, not for prescription drug development . A drug studied in phase 3 clinical trials — what's required before submitting for approval from the Food and Drug Administration — must be the same as what's later marketed.

"The NIDA monopoly has primarily been why we have medical marijuana in the states, but we don't have medical marijuana through the FDA," says Doblin of MAPS. "It's a fundamental change that we can now have drug development with domestic supplies."

A few barriers still remain

The few companies that will soon land DEA spots to cultivate cannabis have an eager marketplace of researchers who are "clamoring" for the chance to study the scientific properties and medical potential of the plant, says Groff, whose company is up for DEA approval and who also has an FDA project to study the antimicrobial properties of cannabis for killing dangerous bacteria like MRSA .

By the end of next year, Groff anticipates his company will be producing up to 5,000 pounds of marijuana per year, offering researchers a "full menu of customizable options."

Biopharmaceutical Research Company — a third company that will soon cultivate cannabis with a DEA license — already has dozens of agreements in place with U.S. researchers and is hearing from more academic institutions, drugmakers and biotech companies in the wake of the change in policy, says CEO George Hodgin.

"Now there's a very clear, approved and legal path for them to legally enter the cannabis space in the United States," says Hodgin.

The Coronavirus Crisis

'illegal to essential': how the coronavirus is boosting the legal cannabis industry.

Washington State University's Center for Cannabis Policy, Research and Outreach is one of the places that expects to eventually procure cannabis from Hodgin's business.

"It's definitely a big step in the right direction because the industry is moving much faster than we are in research," says Michael McDonell , an associate professor of medicine and director of the university's cannabis center.

But he also points out that even with more growers coming online, it's still by no means easy to study cannabis, because researchers need a special license when working with a Schedule 1 drug and grants to conduct these studies are hard to come by.

Despite the widespread use of marijuana in the U.S., research into the medical potential of other Schedule 1 drugs like MDMA (ecstasy) is much further along than cannabis .

UCSD's Grant says the biggest leap forward for research would come from moving cannabis out of the Schedule 1 drug classification. "If that were to happen," he says, "that would solve a lot of these problems that we've been talking about."

• medical cannabis
• medical marijuana

NIDA Research on Cannabis and Cannabinoids

What kinds of marijuana research does nida fund.

As part of its mandate to study drug abuse and addiction and other health effects of both legal and illegal drugs, NIDA funds a wide range of research on marijuana (cannabis); its main psychotropic ingredient, delta-9-tetrahydrocannabinol (THC); and chemicals related to THC (cannabinoids), including:

• Patterns and trends in marijuana use and attitudes, particularly among adolescents, including THC vaping
• Short- and medium-term effects of THC on the brain and behavior; driving under the influence of cannabis; and genetic, epigenetic, and environmental factors that mediate marijuana’s effects
• Long-term effects of prenatal and adolescent cannabis exposure on brain development
• Development and impact assessment of prevention programs on marijuana use
• Screening and brief assessment for cannabis use disorder
• Medications, mHealth, and behavioral treatments for cannabis use disorder
• Function of the brain’s endocannabinoid system, including its role in pain, mental illness, and HIV
• Potential therapeutic uses of THC and other cannabinoids in treatment of pain, HIV, addiction, and other health conditions
• Social, behavioral, and public health and safety impacts of policy changes related to marijuana (i.e., “medical marijuana” and recreational legalization)

Does NIH permit or fund studies on therapeutic benefits of marijuana or its constituent chemicals?

Yes. Research suggests that THC and other cannabinoids, may have potential in the treatment of pain, nausea, epilepsy, obesity, wasting disease, addiction, autoimmune disorders, and other conditions. NIDA has provided and continues to provide funding for research related to therapeutic uses of cannabinoids as it pertains to its mission, including studies on the use of THC and cannabidiol (CBD), another chemical constituent of marijuana, for the treatment of pain (as an alternative to opioid pain relievers), addiction, and other disorders. Research on therapeutic uses of marijuana or of specific chemicals in the marijuana plant for other diseases and conditions is supported by other components of the National Institute of Health (NIH) as is appropriate to their mission.  For a complete listing of all projects funded by NIH examining the potential therapeutic benefits of cannabinoids, see the Therapeutic Cannabinoid Research category in the NIH RePORT database .

The vast majority of research proposals received and funded by NIH on therapeutic benefits of cannabinoids have examined individual cannabinoid chemicals or, in a few cases, marijuana leaves delivered through some means other than smoking. Various factors make smoked marijuana less therapeutically promising than cannabinoids medications delivered through alternative routes of administration, including the potential harmful effects on the lungs and the risk for addiction. In addition, marijuana leaves contain numerous poorly understood chemicals in addition to THC and CBD. It is difficult to standardize dosages of a smoked plant with highly variable cannabinoid concentrations (see NIDA’s DrugFacts, Marijuana as Medicine ). A few medications derived from THC, however, are now approved by the U.S. Food and Drug Administration for relieving nausea associated with cancer chemotherapy and stimulating appetite in patients with wasting syndrome that often accompanies AIDS.

Research proposals submitted to any NIH Institute of Center (IC) to study therapeutic benefits of marijuana or one of its ingredients must meet the same accepted standards of scientific design as any other proposal and, on the basis of peer review, should meet public health significance and IC priorities to be competitive with other applications that qualify for funding.

Does NIDA have an official stand on legalization or decriminalization of marijuana for either recreational or therapeutic use?

No. NIDA is a scientific, not a policy-making agency. The same is true for the NIH as a whole. NIDA’s role is to conduct and support scientific research on drugs and drug abuse and to advise the public and policy-makers, such as Congress, the White House Office of the National Drug Control Policy , and the U.S. Drug Enforcement Administration on the results of that research—with the goal of ensuring that the nation’s drug policies are informed by science.That said, NIDA does closely watch legislative changes both nationally and at the state level and supports research that studies how changing drug policies—for instance laws around recreational or therapeutic use of marijuana—affect rates of substance use and related public health issues.

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Medicinal Cannabis  Research at PCOM

The rapid expansion of cannabis use for serious medical conditions across 37 states, the District of Columbia, Puerto Rico, U.S. Virgin Islands and Guam reflects the mounting recognition of the medical marijuana's therapeutic potential for a number of disorders and diseases.

Although some of cannabis' medicinal properties are well documented, rigorous research is needed to identify which patients will benefit from the drug, the most effective method of treatment, benefits versus risks and barriers to use.

What is Medical Cannabis Research?

Medical cannabis  research investigates the potential therapeutic applications and safety of marijuana and its derivatives for medical purposes. Researchers explore the effects of cannabinoids, such as THC (tetrahydrocannabinol) and CBD (cannabidiol), on various medical conditions and symptoms including chronic pain, epilepsy, multiple sclerosis, nausea, psychological trauma and more. Researchers investigate the delivery mechanisms, optimal dosage and potential side effects of medical marijuana, aiming to provide evidence-based knowledge to guide medical professionals in prescribing cannabis-based treatments and to inform healthcare policies and regulations.

Medical Marijuana Research in Pennsylvania

Pennsylvania is first in the nation to require that research accompany legalization of cannabis for serious medical conditions, thereby positioning the Commonwealth as the leader in generating new knowledge that further defines the drug's therapeutic applications.

PCOM's Medicinal Cannabis Research Programs

PCOM, in collaboration with its Clinical Registrant partner Organic Remedies , has developed a multi-study research program that will gather and share data and insights into the use and processing of medicinal cannabis and its impact on behavior, quality of life, cognition, chronic pain and opioid management.

Doctor of Pharmacy students at PCOM Georgia may now customize their degree program by pursuing a concentration in medical cannabis .

PCOM researchers found positive preliminary results from an ongoing pilot clinical study on Dronabinol, a prescription-only synthetic version of THC, as a treatment option for patients with chronic pain.

PCOM and Organic Remedies announced a strategic partnership dedicated to various physical and mental health outcomes-based research involving cannabinoids and medical marijuana.

PCOM has been approved as a certified Academic Clinical Research Center under Pennsylvania's Medical Marijuana law since 2018.

Cannabis Research Studies at PCOM

Clinical characteristics and quality of life in adults initiating medical marijuana treatment.

Principal Investigator: Michelle Lent, PhD, PCOM

The goal of this observational study is to measure changes in the health, psychosocial functioning, and quality of life of adults initiating medical marijuana for the first time for any of the qualifying medical conditions in Pennsylvania. Individuals are followed for the first year of medical marijuana use and participate in quarterly anthropometric measurements, semi-structured clinical interviews, and cognitive screens.

Buonomano, L. S., Mitnick, M. M., McCalmont, T. R., Syracuse, P., Dugosh, K. L., Festinger, D. S., & Lent, M. R. (2022). Clinical Characteristics and Quality of Life in Adults Initiating Medical Marijuana Treatment. Medical Cannabis and Cannabinoids , 5(1), 95-101.

View the abstract .

The incremental effect of medical marijuana on pain management, psychosocial functioning and treatment outcomes in patients with opioid use disorder

Co-Principal Investigator: Karen Dugosh, PhD, Public Health Management Corporation

The goal of this observational study is to evaluate the incremental effect of medical marijuana on pain functioning and illicit opioid use in individuals with chronic pain and opioid use disorder (OUD) taking buprenorphine. This study assesses pain functioning, sleep quality and duration, mood, substance use, and treatment engagement in individuals with OUD for one year.

Cognition and behavior in children and adolescents with autism spectrum disorders using medical marijuana

Principal Investigator: Elizabeth Gosch, PhD, PCOM

Co-Principal Investigator: Michelle Lent, PhD, PCOM

This observational study is designed to evaluate changes in cognition, functioning, sleep, and behavior over the first three months of medical marijuana treatment in pediatric patients with autism spectrum disorder (ASD) as reported by their adult caregivers.

Impact of medical marijuana laws on usage of marijuana in the State of Pennsylvania

Principal Investigator: Kumar Mukherjee, PhD, PCOM

Co-Investigator: Jane Dumsha, PhD, PCOM

The goal of this retrospective study is to compare marijuana use before and after the passage of the medical marijuana law in Pennsylvania. This study explores whether legalization for a limited number of disorders and diseases increases or decreases overall use of recreational and medicinal marijuana among various socio-demographic groups.

Use of medical cannabis in skilled nursing facilities in Pennsylvania

Principal Investigator: Katherine E. Galluzzi, DO, PCOM

Co-Investigator: Mindy Weinstein, PhD, PCOM

This study is designed to evaluate the current state of usage of medical marijuana in Skilled Nursing Facilities in Pennsylvania. The goal of the study is to determine the extent of use of medical marijuana in different geographic areas across Pennsylvania and identify barriers to use for residents with qualifying conditions.

Relationship between an oral medical marijuana product and analgesia in patients having neuropathic pain for two or more months

Principal Investigator: Frederick Goldstein, PhD, PCOM

Co-Investigators: Michelle Lent, PhD, PCOM , and Kumar Mukherjee, PhD, PCOM

This observational study will determine whether patients receiving a combined medical marijuana product, THC:CBD, experience reduction of pain and improvements in quality of life during 28 days of daily use.

Determination of blood levels of delta-9-Tetrahydrocannabinol (THC) following oral administration

Co-Investigator: Katherine Galluzzi, DO, PCOM

This study will measure blood levels of THC for 24 hours following oral administration of medication containing an absorption enhancer.

An analysis of the efficacy of Organic Remedies Inc. manufacturing infrastructure for the production of sterile extracts derived from contaminated marijuana plant material

Principal Investigator: Mark June-Wells, PhD, Organic Remedies

Co-Investigators: Brian Balin, PhD, PCOM ; Fred Fochtman, PhD, Duquesne University; Weston; Petroski, PhD, Organic Remedies; Daniel Niesen PhD, Steep Hill Laboratory; Eric Hauser, BS, Organic Remedies

The goal of this study is to evaluate the effectiveness of solvent based extraction methods for eliminating or substantially diminishing microbial contamination from marijuana plant material during the manufacturing process.

• Brian Balin, PhD
• Jane Dumsha, PhD
• Katherine Galluzzi, DO
• Mindy George-Weinstein, PhD
• Frederick Goldstein, PhD
• Elizabeth Gosch, PhD
• Michelle Lent, PhD

Research at PCOM

PCOM aims to develop innovative approaches to promoting health through basic, translational, clinical, behavioral, education and community research projects.

• Explore PCOM's numerous research focus areas .
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• Read PCOM's peer-reviewed academic publication The Journal of Integrated Primary Care .
• View the College's research plan .
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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington (DC): National Academies Press (US); 2017 Jan 12.

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.

• Hardcopy Version at National Academies Press

4 Therapeutic Effects of Cannabis and Cannabinoids

Chapter highlights.

• In adults with chemotherapy-induced nausea and vomiting, oral cannabinoids are effective antiemetics.
• In adults with chronic pain, patients who were treated with cannabis or cannabinoids are more likely to experience a clinically significant reduction in pain symptoms.
• In adults with multiple sclerosis (MS)-related spasticity, short-term use of oral cannabinoids improves patient-reported spasticity symptoms.
• For these conditions the effects of cannabinoids are modest; for all other conditions evaluated there is inadequate information to assess their effects.

Cannabis sativa has a long history as a medicinal plant, likely dating back more than two millennia ( Russo et al., 2007 ). It was available as a licensed medicine in the United States for about a century before the American Medical Association removed it from the 12th edition of the U.S. Pharmacopeia ( IOM, 1999 ). In 1985, pharmaceutical companies received approval to begin developing Δ 9 -tetrahydrocannabinol (THC) preparations—dronabinol and nabilone—for therapeutic use, and as a result, cannabinoids were reintroduced into the armamentarium of willing health care providers ( Grotenhermen and Müller-Vahl, 2012 ). Efforts are now being put into the trials of cannabidiol as a treatment for conditions such as epilepsy and schizophrenia, 1 although no such preparations have come to market at this time. Nabiximols, an oromucosal spray of a whole cannabis plant extract with a 1:1 ratio of THC to cannabidiol (CBD), was initially licensed and approved in Europe, the United Kingdom, and Canada for the treatment of pain and spasticity associated with multiple sclerosis ( GW Pharmaceuticals, 2016 ; Pertwee, 2012 ), but it continues to undergo evaluation in Phase III clinical trials in the United States. 2 Efforts are under way to develop targeted pharmaceuticals that are agonists or antagonists of the cannabinoid receptors or that modulate the production and degradation of the endocannabinoids, although such interventions have not yet demonstrated safety or effectiveness. Nonetheless, therapeutic agents targeting cannabinoid receptors and endocannabinoids are expected to become available in the future.

The renewed interest in the therapeutic effects of cannabis emanates from the movement that began 20 years ago to make cannabis available as a medicine to patients with a variety of conditions. It was in 1996 that Arizona and California first passed medicinal cannabis legislation, although Arizona later rescinded the approval, so it would be California that paved the way. At the time that this report was written, in 2016, 28 states and the District of Columbia had legalized the medical use of cannabis; 8 states had legalized both medical and recreational use of cannabis; and another 16 states had allowed limited access to low-THC/high-CBD products (i.e., products with low levels of THC and high levels of CBD) ( NCSL, 2016 ). A recent national survey showed that among current adult users, 10.5 percent reported using cannabis solely for medical purposes, and 46.6 percent reported a mixed medical/recreational use ( Schauer et al., 2016 ). Of the states that allow for some access to cannabis compounds, cancer, HIV/AIDS, multiple sclerosis, glaucoma, seizures/epilepsy, and pain are among the most recognized qualifying ailments ( Belendiuk et al., 2015 ; NCSL, 2016 ). There are certain states that provide more flexibility than others and that allow the use of medical cannabis for the treatment of any illness for which the drug provides relief for the individual. Given the steady liberalization of cannabis laws, the numbers of these states are likely to increase and therefore support the efforts to clarify the potential therapeutic benefits of medical cannabis on various health outcomes.

For example, the most common conditions for which medical cannabis is used in Colorado and Oregon are pain, spasticity associated with multiple sclerosis, nausea, posttraumatic stress disorder, cancer, epilepsy, cachexia, glaucoma, HIV/AIDS, and degenerative neurological conditions ( CDPHE, 2016 ; OHA, 2016 ). We added to these conditions of interest by examining lists of qualifying ailments in states where such use is legal under state law. The resulting therapeutic uses covered by this chapter are chronic pain, cancer, chemotherapy-induced nausea and vomiting, anorexia and weight loss associated with HIV, irritable bowel syndrome, epilepsy, spasticity, Tourette syndrome, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dystonia, dementia, glaucoma, traumatic brain injury, addiction, anxiety, depression, sleep disorders, posttraumatic stress disorder, and schizophrenia and other psychoses. The committee is aware that there may be other conditions for which there is evidence of efficacy for cannabis or cannabinoids. In this chapter, the committee will discuss the findings from 16 of the most recent, good- to fair-quality systematic reviews and 21 primary literature articles that best address the committee's research questions of interest.

As a reminder to the reader, several of the prioritized health endpoints discussed here in Part II are also reviewed in chapters of Part III ; however, the research conclusions within these chapters may differ. This is, in part, due to differences in the study design of the evidence reviewed (e.g., randomized controlled trials [RCTs] versus epidemiological studies), differences in the characteristics of cannabis or cannabinoid exposure (e.g., form, dose, frequency of use), and the populations studied. As such, it is important that the reader is aware that this report was not designed to reconcile the proposed harms and benefits of cannabis or cannabinoid use across chapters.

• CHRONIC PAIN

Relief from chronic pain is by far the most common condition cited by patients for the medical use of cannabis. For example, Light et al. (2014) reported that 94 percent of Colorado medical marijuana ID cardholders indicated “severe pain” as a medical condition. Likewise, Ilgen et al. (2013) reported that 87 percent of participants in their study were seeking medical marijuana for pain relief. In addition, there is evidence that some individuals are replacing the use of conventional pain medications (e.g., opiates) with cannabis. For example, one recent study reported survey data from patrons of a Michigan medical marijuana dispensary suggesting that medical cannabis use in pain patients was associated with a 64 percent reduction in opioid use ( Boehnke et al., 2016 ). Similarly, recent analyses of prescription data from Medicare Part D enrollees in states with medical access to cannabis suggest a significant reduction in the prescription of conventional pain medications ( Bradford and Bradford, 2016 ). Combined with the survey data suggesting that pain is one of the primary reasons for the use of medical cannabis, these recent reports suggest that a number of pain patients are replacing the use of opioids with cannabis, despite the fact that cannabis has not been approved by the U.S. Food and Drug Administration (FDA) for chronic pain.

Are Cannabis or Cannabinoids an Effective Treatment for the Reduction of Chronic Pain?

Systematic reviews.

Five good- to fair-quality systematic reviews were identified. Of those five reviews, Whiting et al. (2015) was the most comprehensive, both in terms of the target medical conditions and in terms of the cannabinoids tested. Snedecor et al. (2013) was narrowly focused on pain related to spinal cord injury, did not include any studies that used cannabis, and only identified one study investigating cannabinoids (dronabinol). Two reviews on pain related to rheumatoid arthritis did not contribute unique studies or findings ( Fitzcharles et al., 2016 ; Richards et al., 2012 ). Finally, one review ( Andreae et al., 2015 ) conducted a Bayesian analysis of five primary studies of peripheral neuropathy that had tested the efficacy of cannabis in flower form administered via inhalation. Two of the primary studies in that review were also included in the Whiting review, while the other three were not. It is worth noting that the conclusions across all of the reviews were largely consistent in suggesting that cannabinoids demonstrate a modest effect on pain. For the purposes of this discussion, the primary source of information for the effect on cannabinoids on chronic pain was the review by Whiting et al. (2015) . Whiting et al. (2015) included RCTs that compared cannabinoids to usual care, a placebo, or no treatment for 10 conditions. Where RCTs were unavailable for a condition or outcome, nonrandomized studies, including uncontrolled studies, were considered. This information was supplemented by a search of the primary literature from April 2015 to August 2016 as well as by additional context from Andreae et al. (2015) that was specific to the effects of inhaled cannabinoids.

The rigorous screening approach used by Whiting et al. (2015) led to the identification of 28 randomized trials in patients with chronic pain (2,454 participants). Twenty-two of these trials evaluated plant-derived cannabinoids (nabiximols, 13 trials; plant flower that was smoked or vaporized, 5 trials; THC oramucosal spray, 3 trials; and oral THC, 1 trial), while 5 trials evaluated synthetic THC (i.e., nabilone). All but 1 of the selected primary trials used a placebo control, while the remaining trial used an active comparator (amitriptyline). The medical condition underlying the chronic pain was most often related to a neuropathy (17 trials); other conditions included cancer pain, multiple sclerosis, rheumatoid arthritis, musculoskeletal issues, and chemotherapy-induced pain. Analyses across 7 trials that evaluated nabiximols and 1 that evaluated the effects of inhaled cannabis suggested that plant-derived cannabinoids increase the odds for improvement of pain by approximately 40 percent versus the control condition (odds ratio [OR], 1.41, 95% confidence interval [CI] = 0.99–2.00; 8 trials). The effects did not differ significantly across pain conditions, although it was not clear that there was adequate statistical power to test for such differences.

Only 1 trial (n = 50) that examined inhaled cannabis was included in the effect size estimates from Whiting et al. (2015) . This study ( Abrams et al., 2007 ) also indicated that cannabis reduced pain versus a placebo (OR, 3.43, 95% CI = 1.03–11.48). It is worth noting that the effect size for inhaled cannabis is consistent with a separate recent review of 5 trials of the effect of inhaled cannabis on neuropathic pain ( Andreae et al., 2015 ). The pooled ORs from these trials contributed to the Bayesian pooled effect estimate of 3.22 for pain relief versus placebo (95% CI = 1.59–7.24) tested across 9 THC concentrations. There was also some evidence of a dose-dependent effect in these studies.

Primary Literature

In the addition to the reviews by Whiting et al. (2015) and Andreae et al. (2015) , the committee identified two additional studies on the effect of cannabis flower on acute pain ( Wallace et al., 2015 ; Wilsey et al., 2016 ). One of those studies found a dose-dependent effect of vaporized cannabis flower on spontaneous pain, with the high dose (7 percent THC) showing the strongest effect size ( Wallace et al., 2015 ). The other study found that vaporized cannabis flower reduced pain but did not find a significant dose-dependent effect ( Wilsey et al., 2016 ). These two studies are consistent with the previous reviews by Whiting et al. (2015) and Andreae et al. (2015) , suggesting a reduction in pain after cannabis administration.

Discussion of Findings

The majority of studies on pain cited in Whiting et al. (2015) evaluated nabiximols outside the United States. In their review, the committee found that only a handful of studies have evaluated the use of cannabis in the United States, and all of them evaluated cannabis in flower form provided by the National Institute on Drug Abuse that was either vaporized or smoked. In contrast, many of the cannabis products that are sold in state-regulated markets bear little resemblance to the products that are available for research at the federal level in the United States. For example, in 2015 between 498,170 and 721,599 units of medical and recreational cannabis edibles were sold per month in Colorado ( Colorado DOR, 2016, p. 12 ). Pain patients also use topical forms (e.g., transdermal patches and creams). Thus, while the use of cannabis for the treatment of pain is supported by well-controlled clinical trials as reviewed above, very little is known about the efficacy, dose, routes of administration, or side effects of commonly used and commercially available cannabis products in the United States. Given the ubiquitous availability of cannabis products in much of the nation, more research is needed on the various forms, routes of administration, and combination of cannabinoids.

CONCLUSION 4-1 There is substantial evidence that cannabis is an effective treatment for chronic pain in adults.

Cancer is a broad term used to describe a wide range of related diseases that are characterized by an abnormal, unregulated division of cells; it is a biological disorder that often results in tumor growth ( NCI, 2015 ). Cancer is among the leading causes of mortality in the United States, and by the close of 2016 there will be an estimated 1.7 million new cancer diagnoses ( NCI, 2016 ). Relevant to the committee's interest, there is evidence to suggest that cannabinoids (and the endocannabinoid system more generally) may play a role in the cancer regulation processes ( Rocha et al., 2014 ). Therefore, there is interest in determining the efficacy of cannabis or cannabinoids for the treatment of cancer.

Are Cannabis or Cannabinoids an Effective Treatment for Cancer?

Using the committee's search strategy only one recent review was found to be of good to fair quality ( Rocha et al., 2014 ). 3 The review focused exclusively on the anti-tumor effects of cannabinoids on gliomas. 4 Of the 2,260 studies identified through December 2012, 35 studies met the inclusion criteria. With the exception of a small clinical trial, these studies were all preclinical studies. All 16 of the in vivo studies found an antitumor effect of cannabinoids.

The committee did not identify any good-quality primary literature that reported on cannabis or cannabinoids for the treatment of cancer that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Clearly, there is insufficient evidence to make any statement about the efficacy of cannabinoids as a treatment for glioma. However, the signal from the preclinical literature suggests that clinical research with cannabinoids needs to be conducted.

CONCLUSION 4-2 There is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for cancers, including glioma.

• CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING

Nausea and vomiting are common side effects of many cytotoxic chemotherapy agents. A number of pharmaceutical interventions in various drug classes have been approved for the treatment of chemotherapy-induced nausea and vomiting. Among the cannabinoid medications, nabilone and dronabinol were initially approved in 1985 for nausea and vomiting associated with cancer chemotherapy in patients who failed to respond adequately to conventional antiemetic treatments ( Todaro, 2012, pp. 488, 490 ).

Are Cannabis or Cannabinoids an Effective Treatment for the Reduction of Chemotherapy-Induced Nausea and Vomiting?

Whiting et al. (2015) summarized 28 trials reporting on nausea and vomiting due to chemotherapy, most published before 1984, involving 1,772 participants. The cannabinoid therapies investigated in these trials included nabilone (14), tetrahydrocannabinol (6), levonantradol (4), dronabinol (3), and nabiximols (1). Eight studies were placebo controlled, and 20 included active comparators (prochlorperazine 15; chlorpromazine 2; dromperidone 2; and alizapride, hydroxyzine, metoclopramide, and ondansetron 1 each). Two studies evaluated combinations of dronabinol with prochlorperazine or ondansetron. The average number of patients showing a complete nausea and vomiting response was greater with cannabinoids than the placebo (OR, 3.82, 95% CI = 1.55–9.42) in 3 trials of dronabinol and nabiximols that were considered low-quality evidence. Whiting et al. (2015) concluded that all trials suggested a greater benefit for cannabinoids than for both active agents and for the placebo, although these did not reach statistical significance in all trials.

Of the 23 trials summarized in a Cochrane review ( Smith et al., 2015 ), 19 were crossover design and 4 were parallel-group design. The cannabinoids investigated were nabilone (12) or dronabinol (11), with 9 placebo-controlled trials (819 participants) and 15 with active comparators (prochlorperazine, 11; metoclopramide, 2; chlorpromazine, 1; domperidone, 1). In 2 trials, a cannabinoid added to a standard antiemetic was compared to the standard alone. While 2 of the placebo-controlled trials showed no significant difference in those reporting absence of nausea with cannabinoids (relative risk [RR], 2.0, 95% CI = 0.19–21), 3 showed a greater chance of having complete absence of vomiting with cannabinoids (RR, 5.7, 95% CI = 2.16–13) and 3 showed a numerically higher chance of complete absence of both nausea and vomiting (RR, 2.9, 95% CI = 1.8–4.7). There was no difference in outcome between patients who were cannabisnaïve and those who were not (P value = 0.4). Two trials found a patient preference for cannabinoids over the comparator. When compared to prochlorperazine, there was no significant difference in the control of nausea, vomiting, or both, although in 7 of the trials there was a higher chance of patients reporting a preference for the cannabinoid therapy (RR, 3.2, 95% CI = 2.2–4.7). In their review the investigators state that cannabinoids were highly effective, being more efficacious than the placebo and similar to conventional antiemetics in treating chemotherapy-induced nausea and vomiting. Despite causing more adverse events such as dizziness, dysphoria, euphoria, “feeling high,” and sedation, there was weak evidence for a preference for cannabinoids over the placebo and stronger evidence for a preference over other antiemetics. Despite these findings, however, the authors concluded that there was no evidence to support the use of cannabinoids over current first-line antiemetic therapies and that cannabinoids should be considered as useful adjunctive treatment “for people on moderately or highly emetogenic chemotherapy that are refractory to other antiemetic treatments, when all other options have been tried” ( Smith et al., 2015, p. 23 ).

Only 3 of the 28 trials in a systematic review of antiemetic therapies in children receiving chemotherapy involved cannabinoid therapies (nabilone 2; THC 1) ( Phillips et al., 2016 ). The comparators were prochlorperazine in the first nabilone trial, domperidone in the second, and prochlorperazine and metoclopramide in two separate randomizations in the THC trial. In 1 trial with unclear risk of bias, THC dosed at 10 mg/m 2 five times on the day of chemotherapy was superior to prochlorperazine in the complete control of acute nausea (RR, 20.7, 95% CI = 17.2–36.2) and vomiting (RR, 19.0, 95% CI = 13.7–26.3). Another trial reported better nausea severity scores for nabilone compared to domperidone (1.5 versus 2.5 on a 0 to 3 [none to worst] scale) (p = 0.01). The largest and most recent trial in this review compared THC to proclorperzine and found no benefit over the control on emesis (RR, 1.0, 95% CI = 0.85–1.17).

An additional search of the primary literature since the review by Whiting et al. (2015) did not identify any additional studies. The primary literature was then searched in an effort to find studies of cannabinoids compared to the more widely used antiemetics. One trial conducted in 2007 investigated a cannabinoid therapy compared to the current generation of serotonin antagonist antiemetics, as opposed to the dopamine D2 receptor antagonists used in the earlier trials. This 64-patient study evaluated the frequently used antiemetic ondansetron versus dronabinol versus the combination of the two in delayed chemotherapy-induced nausea and vomiting ( Meiri et al., 2007 ). The two agents appeared similar in their effectiveness, with no added benefit from the combination. Hence, the cannabinoid again fared as well as the current standard antiemetic in this more recent investigation.

The oral THC preparations nabilone and dronabinol have been available for the treatment of chemotherapy-induced nausea and vomiting for more than 30 years ( Grotenhermen and Müller-Vahl, 2012 ). They were both found to be superior to the placebo and equivalent to the available antiemetics at the time that the original trials were conducted. A more recent investigation suggests that dronabinol is equivalent to ondansetron for delayed nausea and vomiting, although no comparison to the currently more widely used neurokinin-1 inhibitors has been conducted. In the earlier trials, patients reported a preference for the cannabinoids over available agents. Despite an abundance of anecdotal reports of the benefits of plant cannabis, either inhaled or ingested orally, as an effective treatment for chemotherapy-induced nausea and vomiting, there are no good-quality randomized trials investigating this option. This is, in part, due to the existing obstacles to investigating the potential therapeutic benefit of the cannabis plant. Nor have any of the reviewed trials investigated the effectiveness of cannabidiol or cannabidiol-enriched cannabis in chemotherapy-induced nausea and vomiting. Such information is frequently requested by patients seeking to control chemotherapy-induced nausea and vomiting without the psychoactive effects of the THC-based preparations. Resolving this identified research gap may be a future research priority.

CONCLUSION 4-3 There is conclusive evidence that oral cannabinoids are effective antiemetics in the treatment of chemotherapy-induced nausea and vomiting.

• ANOREXIA AND WEIGHT LOSS

Anorexia and weight loss are common side effects of many diseases, especially cancer. And prior to the availability of highly active antiretroviral therapy, a wasting syndrome was a frequent clinical manifestation in patients with human immunodeficiency virus (HIV) infection and advanced acquired immune deficiency syndrome (AIDS). The labeled indications for dronabinol were expanded in 1992 to include treatment of anorexia associated with weight loss in patients with AIDS ( IOM, 1999, p. 156 ).

Are Cannabis or Cannabinoids an Effective Treatment for Anorexia and Weight Loss Associated with HIV/AIDS, Cancer-Associated Anorexia-Cachexia Syndrome, and Anorexia Nervosa?

Aids wasting syndrome.

Systematic Reviews Two good-quality systematic reviews included trials investigating cannabinoid therapies in patients with HIV/AIDS. Four randomized controlled trials involving 255 patients were assessed by Whiting et al. (2015) , who described all of the trials to be at high risk of bias (ROB) for reasons not elaborated. 5 All four studies included dronabinol, with one investigating inhaled cannabis as well. Three trials were placebo-controlled, and one used the progestational agent megestrol acetate as the comparator. The review authors concluded that there was some evidence suggesting that cannabinoids were effective in weight gain in HIV. A second systematic review focused on morbidity and mortality in HIV/AIDS as the primary outcomes, with changes in appetite and weight as secondary endpoints ( Lutge et al., 2013 ). Seven RCTs conducted between 1993 and 2009 were included in the qualitative analysis. The trials compared dronabinol or inhaled cannabis with a placebo or with each other. In one study the individuals' weights increased significantly more (p <0.01) on higher doses of cannabis (3.9 percent THC) and dronabinol (10 mg) than on lower doses. In a second trial, median weight was increased with inhaled cannabis (3.5 percent) by 3.0 kg (p = 0.021) and dronabinol (2.5 mg) by 3.2 kg (p = 0.004) when compared with a placebo (a 1.1-kg increase over a 21-day exposure). In a study with 88 evaluable patients, the dronabinol group gained an average of 0.1 kg, while the placebo recipients lost a mean of 0.4 kg (p = 0.14). The proportion of patients gaining at least 2 kg was the same in both groups. Most of the weight gain was in the body fat compartment when this was investigated. Changes in appetite, food, and caloric intake were not deemed to be evaluable in any of the studies. These investigators concluded that the evidence for the efficacy and safety of cannabis and cannabinoids is lacking to support utility in treating AIDS-associated anorexia.

Primary Literature The committee did not identify any good-quality primary literature that reported on cannabis or cannabinoids as effective treatments for AIDS wasting syndrome that were published subsequently to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question. This is largely due to the virtual disappearance of the syndrome since effective antiretroviral therapies became available in the mid-1990s.

Cancer-Associated Anorexia-Cachexia Syndrome

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on cannabis or cannabinoids as effective treatments for cancer-associated anorexia-cachexia syndrome.

Primary Literature A Phase III multicenter, randomized, double-blind placebo-controlled trial was conducted by the Cannabis-In-Cachexia-Study-Group in patients with cancer-related anorexia-cachexia syndrome ( Strasser et al., 2006 ). Patients with advanced cancer and weight loss of greater than 5 percent over 6 months were randomized 2:2:1 to receive treatment with a cannabis extract (standardized to THC 2.5 mg and cannabidiol 1.0 mg), THC 2.5 mg, or a placebo twice daily for 6 weeks. Appetite, mood, and nausea were monitored daily. Cancer-related quality of life and cannabinoid-related toxicity were also monitored. Only 164 of the 243 patients who were randomized completed the trial. An intent-to-treat analysis yielded no difference between the groups in appetite, quality of life, or toxicity. Increased appetite was reported by 73 percent of the cannabis-extract, 58 percent of the THC group, and 69 percent of the placebo recipients. Recruitment was terminated early by the data review board because it was believed to be unlikely that differences would emerge between the treatment arms. The findings in this study reinforce the results from an earlier trial investigating dronabinol, megestrol acetate, or the combination in 469 advanced cancer patients with a loss of appetite and greater than 5 pounds weight loss over the prior 2 months ( Jatoi et al., 2002 ). Megestrol acetate was superior to dronabinol for the improvement of both appetite and weight, with the combination therapy conferring no additional benefit. Seventy-five percent of the megestrol recipients reported an improvement in appetite compared to 49 percent of those receiving dronabinol (p = 0.0001). Of those in the combination arm, 66 percent reported improvement. A weight gain greater than or equal to 10 percent over their baseline at some point during the course of the trial was reported by 11 percent of those in the megestrol arm, compared with 3 percent of the dronabinol recipients (p = 0.02). The combination arm reported a weight gain in 8 percent. These findings confirm a similarly designed trial that was conducted in patients with AIDS wasting syndrome ( Timpone et al., 1997 ).

Anorexia Nervosa

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for anorexia nervosa.

Primary Literature Pharmacological interventions in the treatment of anorexia nervosa have not been promising to date. Andries et al. (2014) conducted a prospective, randomized, double-blind, controlled crossover trial in 24 women with anorexia nervosa of at least 5 years' duration attending both psychiatric and somatic therapy as inpatients or outpatients. In addition to their standard psychotherapy and nutritional interventions, the participants received dronabinol 2.5 mg twice daily for 4 weeks and a matching placebo for 4 weeks, randomly assigned to two treatment sequences (dronabinol/placebo or placebo/dronabinol). The primary outcome was weight change assessed weekly. The secondary outcome was change in Eating Disorder Inventory-2 (EDI-2) scores. The participants had a significant weight gain of 1.00 kg (95% CI = 0.40–1.62) during dronabinol therapy and 0.34 kg (95% CI = −0.14–0.82) during the placebo (p = 0.03). No statistically different differences in EDI-2 score changes were seen during treatment with dronabinol or the placebo, suggesting that there was no real effect on the participants' attitudinal and behavioral traits related to eating disorders. The authors acknowledged the small sample size and the short duration of exposure, as well as the potential psychogenic effects, but they concluded that low-dose dronabinol is a safe adjuvant palliative therapy in a highly selected subgroup of chronically undernourished women with anorexia nervosa.

There is some evidence for oral cannabinoids being able to increase weight in patients with the HIV-associated wasting syndrome and anorexia nervosa. No benefit has been demonstrated in cancer-associated anorexia-cachexia syndrome. The studies have generally been small and of short duration and may not have investigated the optimal dose of the cannabinoid. In one study in HIV patients, both dronabinol and inhaled cannabis increased weight significantly compared to the placebo dronabinol. Cannabis has long been felt to have an orexigenic effect, increasing food intake ( Abel, 1975 ). Small residential studies conducted in the 1980s found that inhaled cannabis increased caloric intake by 40 percent, with most of the increase occurring as snacks and not during meals ( Foltin et al., 1988 ). Hence, the results of the clinical trials in AIDS wasting and cancer-associated anorexia-cachexia syndrome demonstrating little to no impact on appetite and weight were somewhat unexpected. One could postulate that perhaps other components of the plant in addition to THC may contribute to the effect of cannabis on appetite and food intake. There have not been any randomized controlled trials conducted studying the effect of plant-derived cannabis on appetite and weight with weight as the primary endpoint. This is, in part, due to existing obstacles to investigating the potential therapeutic benefit of the cannabis plant.

CONCLUSION 4-4 4-4(a) There is limited evidence that cannabis and oral cannabinoids are effective in increasing appetite and decreasing weight loss associated with HIV/AIDS. 4-4(b) There is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for cancer-associated anorexia-cachexia syndrome and anorexia nervosa.

• IRRITABLE BOWEL SYNDROME

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder commonly associated with symptoms of abdominal cramping and changes in bowel movement patterns. Irritable bowel syndrome is classified into four types based on the types of bowel movements: IBS with diarrhea, IBS with constipation, IBS mixed, and IBS unclassified ( NIDDK, 2015 ). Approximately 11 percent of the world's population suffers from at least one type of this disorder ( Canavan et al., 2014 ).

Type 1 cannabinoid (CB 1 ) receptors are present in the mucosa and neuromuscular layers of the colon; they are also expressed in plasma cells and influence mucosal inflammation ( Wright et al., 2005 ). In animal models, endocannabinoids acting on CB 1 receptors inhibit gastric and small intestinal transit and colonic propulsion ( Pinto et al., 2002 ). Studies in healthy volunteers have shown effects on gastric motility and colonic motility ( Esfandyari et al., 2006 ). Thus, cannabinoids have the potential for therapeutic effect in patients with IBS ( Wong et al., 2012 ).

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms of Irritable Bowel Syndrome?

The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for symptoms of irritable bowel syndrome.

We identified a single relevant trial ( Wong et al., 2012 ) evaluating dronabinol in patients with irritable bowel syndrome with diarrhea (IBS-D). This low-risk-of-bias trial enrolled 36 patients between the ages of 18 and 69 with IBS-D. Patients were randomized to dronabinol 2.5 mg BID 6 (n = 10), dronabinol 5 mg BID (n = 13), or a placebo (n = 13) for 2 days. No overall treatment effects of dronabinol on gastric, small bowel, or colonic transit, as measured by radioscintigraphy, were detected.

A single, small trial found no effect of two doses of dronabinol on gastrointestinal transit. The quality of evidence for the finding of no effect for irritable bowel syndrome is insufficient based on the short treatment duration, small sample size, short-term follow-up, and lack of patient-reported outcomes. Trials that evaluate the effects of cannabinoids on patient-reported outcomes are needed to further understand the clinical effects in patients with IBS.

CONCLUSION 4-5 There is insufficient evidence to support or refute the conclusion that dronabinol is an effective treatment for the symptoms of irritable bowel syndrome.

Epilepsy refers to a spectrum of chronic neurological disorders in which clusters of neurons in the brain sometimes signal abnormally and cause seizures ( NINDS, 2016a ). Epilepsy disorder affects an estimated 2.75 million Americans, across all age ranges and ethnicities ( NINDS, 2016a ). Although there are many antiepileptic medications currently on the market, about one-third of persons with epilepsy will continue to have seizures even when treated ( Mohanraj and Brodie, 2006 ). Both THC and CBD can prevent seizures in animal models ( Devinsky et al., 2014 ).

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms of Epilepsy?

We identified two systematic reviews of randomized trials assessing the efficacy of cannabis or cannabinoids, used either as monotherapy or in addition to other therapies, in reducing seizure frequency in persons with epilepsy. Gloss and Vickrey (2014) published a systematic review of randomized controlled trials. They identified four reports (including one conference abstract and one letter to the editor) of cannabinoid trials, all of which they considered to be of low quality. Combined, the trials included a total of 48 patients. The systematic review's primary prespecified outcome was freedom from seizures for either 12 months or three times the longest previous seizure-free interval. None of the four trials assessed this endpoint. Accordingly, Gloss and Vickrey asserted that no reliable conclusions could be drawn regarding the efficacy of cannabinoids for epilepsy.

Koppel et al. (2014) published a fair-quality systematic review. They identified no high-quality randomized trials and concluded that the existing data were insufficient to support or refute the efficacy of cannabinoids for reducing seizure frequency.

We identified two case series that reported on the experience of patients treated with cannabidiol for epilepsy that were published subsequent to the systematic reviews described above. The first of these was an open-label, expanded-access program of oral cannabidiol with no concurrent control group in patients with severe, intractable childhood-onset epilepsy that was conducted at 11 U.S. epilepsy centers and reported by Devinsky et al. (2016) and by Rosenberg et al. (2015) . Devinsky et al. (2016) reported on 162 patients ages 1 to 30 years; Rosenberg et al. (2015) reported on 137 of these patients. The median monthly frequency of motor seizures was 30.0 (interquartile range [IQR] 11.0–96.0) at baseline and 15.8 (IQR 5.6–57.6) over the 12-week treatment period. The median reduction in motor seizures while receiving cannabidiol in this uncontrolled case series was 36.5 percent (IQR 0–64.7).

Tzadok et al. (2016) reported on the unblinded experience of Israeli pediatric epilepsy clinics treating 74 children and adolescents with intractable epilepsy with an oral formulation of cannabidiol and tetrahydrocannabinol at a 20:1 ratio for an average of 6 months. There was no concurrent control goup. Compared with baseline, 18 percent of children experienced a 75–100 percent reduction in seizure frequency, 34 percent experienced a 50–75 percent reduction, 12 percent reported a 25–50 percent reduction, 26 percent reported a reduction of less than 25 percent, and 7 percent reported aggravation of seizures that led to a discontinuation of the cannabinoid treatment.

The lack of a concurrent placebo control group and the resulting potential for regression to the mean and other sources of bias greatly reduce the strength of conclusions that can be drawn from the experiences reported by Devinsky et al. (2016) , Rosenberg et al. (2015) , and Tzadok et al. (2016) about the efficacy of cannabinoids for epilepsy. Randomized trials of the efficacy of cannabidiol for different forms of epilepsy have been completed, 7 but their results have not been published at the time of this report.

Recent systematic reviews were unable to identify any randomized controlled trials evaluating the efficacy of cannabinoids for the treatment of epilepsy. Currently available clinical data therefore consist solely of uncontrolled case series, which do not provide high-quality evidence of efficacy. Randomized trials of the efficacy of cannabidiol for different forms of epilepsy have been completed and await publication.

CONCLUSION 4-6 There is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for epilepsy.

• SPASTICITY ASSOCIATED WITH MULTIPLE SCLEROSIS OR SPINAL CORD INJURY

Spasticity is defined as disordered sensorimotor control resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles ( Pandyan et al., 2005 ). It occurs in some patients with chronic neurological conditions such as multiple sclerosis (MS) and paraplegia due to spinal cord injury. Recent studies have shown that some individuals with MS are seeking alternative therapies, including cannabis, to treat symptoms associated with MS ( Zajicek et al., 2012 ).

Are Cannabis or Cannabinoids an Effective Treatment for Spasticity Associated with Multiple Sclerosis or Spinal Cord Injury?

We identified two recent systematic reviews that assessed the efficacy of cannabis or cannabinoids in treating muscle spasticity in patients with MS or paraplegia due to spinal cord injury—the systematic review by Whiting et al. (2015) that examined evidence for a broad range of medical uses of cannabis or cannabinoids and the systematic review by Koppel et al. (2014) that focused more narrowly on neurologic conditions. Both systematic reviews examined only randomized, placebo-controlled trials. Whiting et al. (2015) excluded from their primary analysis trials that did not use a parallel group design (i.e., they excluded crossover trials) and performed a quantitative pooling of results. In contrast, Koppel et al. (2014) included crossover trials but did not perform a quantitative pooling of results.

Whiting et al. (2015) searched for studies examining the efficacy of cannabinoids for spasticity due to MS or paraplegia. They identified 11 studies that included patients with MS and 3 that included patients with paraplegia caused by spinal cord injury. None of the studies in patients with paraplegia caused by spinal cord injury were reported as full papers or included sufficient data to allow them to be included in pooled estimates. Whiting et al. (2015) reported that in their pooled analysis of three trials in patients with MS, nabiximols and nabilone were associated with an average change (i.e., improvement) in spasticity rating assessed by a patient-reported numeric rating scale of −0.76 (95% CI = −1.38 to −0.14) on a 0 to 10 scale that was statistically greater than for the placebo. They further reported finding no evidence for a difference according to type of cannabinoid (i.e., nabiximols versus nabilone). Whiting et al. (2015) also reported that the pooled odds of patient-reported improvement on a global impression-of-change score was greater with nabiximols than with the placebo (OR, 1.44, 95% CI = 1.07–1.94).

The review by Koppel et al. (2014) restricted its focus on spasticity to that due to MS. Their conclusions were broadly in agreement with corresponding conclusions from the review by Whiting et al. (2015) . In particular, Koppel et al. (2014) concluded that in patients with MS, nabiximols and orally administered THC are “probably effective” for reducing patient-reported spasticity scores and that oral cannabis extract is “established as effective for reducing patient-reported scores” for spasticity ( Koppel et al., 2014, p. 1558 ).

A commonly used scale for rating spasticity is the Ashworth scale ( Ashworth, 1964 ). However, this scale has been criticized as unreliable, insensitive to therapeutic benefit, and reflective only of passive resistance to movement and not of other features of spasticity ( Pandyan et al., 1999 ; Wade et al., 2010 ). Furthermore, no minimally important difference in the Ashworth scale has been established. Whiting et al. (2015) calculated a pooled measure of improvement on the Ashworth scale versus placebo based on five parallel-group-design trials. They reported that nabiximols, dronabinol, and oral THC/CBD were associated with a numerically greater average improvement on the Ashworth scale than with a placebo but that this difference was not statistically significant. This conclusion is in broad agreement with corresponding conclusions reached by Koppel et al. (2014) , who concluded in particular that nabiximols, oral cannabis extract and orally administered THC are “probably ineffective” for reducing objective measures of spasticity in the short term (6–15 weeks), although oral cannabis extract and orally administered THC are “possibly effective” for objective measures at 1 year.

An additional placebo-controlled crossover trial of nabiximols for the treatment of spasticity in patients with MS was published after the period covered by the Whiting and Koppel systematic reviews ( Leocani et al., 2015 ). This study randomized 44 patients but analyzed only 34 because of post-randomization exclusions and dropouts. Such post-randomization exclusions and dropouts reduce the strength of the evidence that is provided by this study. Patient-reported measures of spasticity were not assessed. After 4 weeks of treatment, response on the modified Ashworth scale (defined as improvement of at least 20 percent) was more common in the THC/CBD group (50 percent) than in the placebo group (23.5 percent), p = 0.041.

Based on evidence from randomized controlled trials included in systematic reviews, an oral cannabis extract, nabiximols, and orally administered THC are probably effective for reducing patient-reported spasticity scores in patients with MS. The effect appears to be modest, as reflected by an average reduction of 0.76 units on a 0 to 10 scale. These agents have not consistently demonstrated a benefit on clinician-measured spasticity indices such as the modified Ashworth scale in patients with MS. Given the lack of published papers reporting the results of trials conducted in patients with spasticity due to spinal cord injury, there is insufficient evidence to conclude that cannabinoids are effective for treating spasticity in this population.

CONCLUSION 4-7 4-7(a) There is substantial evidence that oral cannabinoids are an effective treatment for improving patient-reported multiple sclerosis spasticity symptoms, but limited evidence for an effect on clinician-measured spasticity. 4-7(b) There is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for spasticity in patients with paralysis due to spinal cord injury.

• TOURETTE SYNDROME

Tourette syndrome is a neurological disorder characterized by sporadic movements or vocalizations commonly called “tics” ( NINDS, 2014 ). While there is currently no cure for Tourette syndrome, recent efforts have explored whether cannabis may be effective in reducing symptoms commonly associated with the disorder ( Koppel et al., 2014 ).

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms Associated with Tourette Syndrome?

We identified two good-quality systematic reviews ( Koppel et al., 2014 ; Whiting et al., 2015 ) that evaluated medical cannabis for Tourette syndrome. Both good-quality reviews identified the same trials, and we focus on the more recent review by Whiting et al. (2015) . The two RCTs (four reports), conducted by the same research group ( Müller-Vahl et al., 2001 , 2002 , 2003a , b ), compared THC capsules (maximum dose 10 mg daily) to a placebo in 36 patients with Tourette syndrome. Tic severity, assessed by multiple measures, and global clinical outcomes were improved with THC capsules. On a 0 to 6 severity scale, symptoms were improved by less than 1 point. These outcomes were assessed at 2 days (unclear-risk-of-bias trial) and 6 weeks (high-risk-of-bias trial). Neither trial described randomization or allocation concealment adequately, and the 6-week trial was rated high risk of bias for incomplete outcome data.

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for Tourette syndrome, and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

No clear link has been established between symptoms of Tourette syndrome and cannabinoid sites or mechanism of action. However, case reports have suggested that cannabis can reduce tics and that the therapeutic effects of cannabis might be due to the anxiety-reducing properties of marijuana rather than to a specific anti-tic effect ( Hemming and Yellowlees, 1993 ; Sandyk and Awerbuch, 1988 ). Two small trials (assessed as being of fair to poor quality) provide limited evidence for the therapeutic effects of THC capsules on tic severity and global clinical outcomes.

CONCLUSION 4-8 There is limited evidence that THC capsules are an effective treatment for improving symptoms of Tourette syndrome.

• AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons in the spinal cord, brain stem, and motor cortex, ultimately leading to complete paralysis ( Rossi et al., 2010 ). The pathogenesis of ALS remains unclear, but the disease is thought to result from the interplay of a number of mechanisms, including neurofilament accumulation, excitotoxicity, oxidative stress, and neuroinflammation ( Redler and Dokholyan, 2012 ), all of which may be amenable to manipulation of the endocannabinoid system and cannabinoid receptors.

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms Associated with Amyotrophic Lateral Sclerosis?

The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for symptoms associated with amyotrophic lateral sclerosis.

On the basis of proposed pathogenesis and anecdotal reports of symptomatic benefit from the use of cannabis in patients with ALS, two small trials of dronabinol have been conducted. In a randomized, double-blind crossover study, 19 patients with ALS were treated with dronabinol doses of 2.5 to 10 mg daily for 4 weeks ( Gelinas et al., 2002 ). Participants noted improvement in appetite and sleep but not in cramps or fasiculations (involuntary muscle twitches). The second study enrolled 27 patients with ALS who had moderate to severe cramps (greater than 4 on a 0–10 visual analogue scale) in a randomized, double-blind trial of dronabinol 5 mg twice daily or a placebo, each given for 2 weeks with an intervening 2-week washout period ( Weber et al., 2010 ). The primary endpoint was a change in cramp intensity with secondary endpoints of change in cramp number, intensity of fasciculations, quality of life, sleep, appetite, and depression. There was no difference between dronabinol and the placebo seen in any of the endpoints. The investigators reported that the dronabinol was very well tolerated and postulated that the dronabinol dose may have been too low as well as suggesting that a carryover effect in the crossover design may have obfuscated any differences in the treatment arms. The sample size was too small to discern anything but a large effect.

Two small studies investigated the effect of dronabinol on symptoms associated with ALS. Although there were no differences from placebo in either trial, the sample sizes were small, the duration of the studies was short, and the dose of dronabinol may have been too small to ascertain any activity. The effect of cannabis was not investigated.

CONCLUSION 4-9 There is insufficient evidence that cannabinoids are an effective treatment for symptoms associated with amyotrophic lateral sclerosis.

• HUNTINGTON'S DISEASE

Huntington's disease is characterized by chorea (abnormal, involuntary movement) along with cognitive decline and psychiatric impairment ( Armstrong and Miyasaki, 2012 ). Worsening chorea significantly impacts patient quality of life. The pathophysiology and neurochemical basis of Huntington's disease are incompletely understood. Neuroprotective trials often investigate agents that may decrease oxidative stress or glutamatergic changes related to excitotoxic stress. There is some preclinical evidence and limited clinical evidence that suggest that changes in the endocannabinoid system may be linked to the pathophysiology of Huntington's disease ( Pazos et al., 2008 ; van Laere et al., 2010 ).

Are Cannabis or Cannabinoids an Effective Treatment for the Motor Function and Cognitive Performance Associated with Huntington's Disease?

The systematic review from the American Academy of Neurology includes two studies on Huntington's disease ( Koppel et al., 2014 ). A randomized, double-blind, placebo-controlled crossover pilot trial investigated nabilone 1 or 2 mg daily for 5 weeks followed by a placebo in 22 patients with symptomatic Huntington's disease ( Curtis et al., 2009 ). An additional 22 patients were randomized to the placebo followed by nabilone. The primary endpoint was the total motor score of the Unified Huntington's Disease Rating Scale (UHDRS). Secondary endpoints included the chorea, cognitive performance, and psychiatric changes measured with the same instrument. No significant difference in the total motor score was seen in the 37 evaluable patients (treatment difference, 0.86, 95% CI = −1.8–3.52), with a 1-point change considered clinically significant. There was evidence of an improvement in the chorea subscore with nabilone (treatment difference, 1.68, 95% CI = 0.44–2.92). There was no difference between treatments for cognition, but there was evidence of an improvement in the two neuropsychiatric outcome measures in the nabilone arm—UHDRS behavioral assessment (4.01, 95% CI = −0.11–8.13) and neuropsychiatric inventory (6.43, 95% CI = 0.2–12.66). The small estimated treatment effect with wide confidence intervals reduces the level of evidence for nabilone's effectiveness from this pilot study. However, based on this trial, the American Academy of Neurology guideline concluded that “nabilone possibly modestly improves Huntington's disease chorea” ( Armstrong and Miyasaki, 2012, p. 601 ). The second study included in the systematic review was a lower-quality, 15-patient randomized, double-blind, placebo-controlled trial investigating the effect of cannabidiol capsules at a dose of 10 mg/kg/day in two divided doses ( Consroe et al., 1991 ). The endpoints in this study involving patients with Huntington's disease who were not on neuroleptics were chorea severity, functional limitations, and side effects. There were no statistically significant differences between cannabidiol and placebo in any outcomes, although the American Academy of Neurology considered the study to be underpowered.

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the declines in motor function and cognitive performance associated with Huntington's disease that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Two small studies have investigated the potential benefit of cannabinoids in patients with Huntington's disease. Although nabilone appeared to have some potential benefit on chorea, cannabidiol appeared to be equal to placebo in ameliorating symptoms. Both studies were of short duration and likely underpowered because of their small sample sizes. Cannabis has not been investigated in Huntington's disease.

CONCLUSION 4-10 There is insufficient evidence to support or refute the conclusion that oral cannabinoids are an effective treatment for chorea and certain neuropsychiatric symptoms associated with Huntington's disease.

• PARKINSON'S DISEASE

Parkinson's disease is a motor system disorder attributed to the loss of dopamine-producing brain cells. It is characterized clinically by tremor, rigidity, bradykinesia (slowness of movement), and impaired balance and coordination ( PDF, 2016a ). An estimated 60,000 Americans are diagnosed with this disorder each year ( PDF, 2016b ).

Although the disease is progressive and without cure, there are medications that can ameliorate some of the associated symptoms. Although levodopa has demonstrated efficacy for treating symptoms of Parkinson's disease, long-term use of levodopa is associated with the development of side effects, especially dyskinesias (involuntary movements) ( NINDS, 2015 ). Evidence suggests that the endocannabinoid system plays a meaningful role in certain neurodegenerative processes ( Krishnan et al., 2009 ); thus, it may be useful to determine the efficacy of cannabinoids in treating the symptoms of neurodegenerative diseases.

Are Cannabis or Cannabinoids an Effective Treatment for the Motor System Symptoms Associated with Parkinson's Disease or the Levodopa-Induced Dyskinesia?

The systematic review of cannabis in selected neurologic disorders ( Koppel et al., 2014 ) identified two trials of cannabinoid therapies in patients with levodopa-induced dyskinesias. Nineteen patients with levodopa-induced dyskinesia greater than or equal to 2 as determined by questions 32–34 of the Unified Parkinson's Disease Rating Scale (UPDRS) were randomized in a double-blind, placebo-controlled crossover trial to receive Cannador capsules (containing THC 2.5 mg and CBD 1.25 mg) to a maximum dose of 0.25 mg/kg of THC daily or placebo ( Carroll et al., 2004 ). The primary endpoint was the effect of treatment on the dyskinesia score of the UPDRS. Secondary endpoints included the impact of dyskinesia on function, pathophysiologic indicators of dyskinesia, duration of dyskinesia, quality of life, sleep, pain, and overall severity of Parkinson's disease. The overall treatment effect was +0.52, which indicated a worsening with Cannador, although this worsening was not statistically significant (p = 0.09). No effects were seen on the secondary outcomes. Although there were more adverse events on the drug than on the placebo, the investigators felt that the treatment was well tolerated. The study had limited statistical power to detect anything but a large treatment effect due to its small sample size. The second study included in the systematic review was an even smaller low-quality, randomized, double-blind, placebo-controlled crossover trial involving seven patients with Parkinson's disease who had stable levodopa-induced dyskinesia present for 25–50 percent of the day ( Sieradzan et al., 2001 ). Nabilone dosed at 0.03 mg/kg or a placebo was administered 12 hours and 1 hour before levodopa at a dose of 200 mg. The primary endpoint was total dyskinesia disability as measured using the Rush Dyskinesia Disability Scale. 8 The median total dyskinesia score after treatment with levodopa and nabilone was 17 (range 11–25) compared to 22 (range 16–26) after levodopa and the placebo (p <0.05). The anti-Parkinsonian actions of levodopa were not reduced by nabilone pretreatment. Although the authors stated that “nabilone significantly reduced total levodopa-induced dyskinesia compared with placebo” ( Sieradzan et al., 2001, p. 2109 ), the fact that the results were generated by only seven patients receiving only two doses clearly reduces the ability to draw such an enthusiastic conclusion. Koppel concludes that oral cannabis extract “is probably ineffective for treating levodopa-induced dyskinesias” ( Koppel et al., 2014, p. 1560 ).

Cannabidiol capsules were evaluated in a randomized, double-blind, placebo-controlled trial conducted in 21 patients with Parkinson's disease ( Chagas et al., 2014 ). The study was an exploratory trial to assess the effect of CBD in Parkinson's disease globally with the UPDRS and the Parkinson's Disease Questionnaire-39 (PDQ-39) used to assess overall functioning and well-being. Possible CBD adverse events were evaluated by a side effect rating scale. Baseline data were collected 1 week before commencing treatment with CBD at 75 mg/day or 300 mg/day or with a placebo, and the same assessments were repeated during the sixth and final week of the trial. No statistically significant differences were seen in the UPDRS between the three study arms. There was a statistically significant difference in the variation between baseline and final assessment in the overall PDQ-39 score between the placebo (6.50 ± 8.48) and CBD 300 mg/day (25.57 ± 16.30) (p = 0.034), which suggests that there might be a possible effect of CBD on improving quality of life.

An open-label observational study of 22 patients with Parkinson's disease attending a motor disorder clinic at a tertiary medical center collected data before and 30 minutes after patients smoked 0.5 grams of cannabis ( Lotan et al., 2014 ). The instruments utilized included the UPDRS, the McGill Pain Scale, and a survey of subjective efficacy and adverse effects of cannabis. In addition, the effect of cannabis on motor symptoms was evaluated by two raters. The investigators found that the total motor symptoms score on the UPDRS improved from 33.1 (± 13.8) to 23.2 (± 10.5) (p <0.001). Subcategories of the UPDRS that showed statistically significant improvement included tremor, rigidity, and bradykinesia. Pain and sleep were also reported to be improved after smoking cannabis. The results from this low-quality observational study prompted the investigators to propose that their findings should be confirmed in a larger, longer, randomized, double-blind, placebo-controlled trial.

Small trials of oral cannabinoid preparations have demonstrated no benefit compared to a placebo in ameliorating the side effects of Parkinson's disease. A seven-patient trial of nabilone suggested that it improved the dyskinesia associated with levodopa therapy, but the sample size limits the interpretation of the data. An observational study of inhaled cannabis demonstrated improved outcomes, but the lack of a control group and the small sample size are limitations.

CONCLUSION 4-11 There is insufficient evidence that cannabinoids are an effective treatment for the motor system symptoms associated with Parkinson's disease or the levodopa-induced dyskinesia.

Dystonia is a disorder characterized by sustained or repetitive muscle contractions which result in abnormal fixed postures or twisting, repetitive movements ( NINDS, 2016b ). Idiopathic cervical dystonia is the most common cause of focal dystonia. Oral pharmacological agents are generally ineffective, with repeated injections of botulinum toxin being the most effective current therapy. The pathophysiologic mechanisms of dystonia are poorly understood, but, as in other hyperkinetic movement disorders, underactivity of the output regions of the basal ganglia may be involved. Stimulation of the cannabinoid receptors has been postulated as a way to reduce dystonia ( Zadikoff et al., 2011 ). Anecdotal reports have suggested that cannabis may alleviate symptoms associated with dystonia ( Uribe Roca et al., 2005 ). In a 1986 preliminary open pilot study in which five patients with dystonic movement disorders received cannabidiol, dose-related improvements were observed in all five patients ( Consroe et al., 1986 ).

Are Cannabis or Cannabinoids an Effective Treatment for Dystonia?

The American Academy of Neurology systematic review ( Koppel et al., 2014 ) identified one study that examined the effect of dronabinol on cervical dystonia. The review described the study as being underpowered to detect any differences between dronabinol and the placebo. Overall, nine patients with cervical dystonia were randomized to receive dronabinol 15 mg daily or a placebo in an 8-week crossover trial ( Zadikoff et al., 2011 ). The primary outcome measure was the change in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) part A subscore at the beginning and the end of each 3-week treatment phase. There was no statistically significant effect of dronabinol on the dystonia compared with the placebo as measured by the TWSTRS-A (p = 0.24).

Fifteen patients with a clinical diagnosis of primary dystonia received a single dose of nabilone or placebo (0.03 mg/kg to the nearest whole milligram) on the study day ( Fox et al., 2002 ). The primary outcome measure was the dystonia-movement scale portion of the Burke-Fahn-Marsden dystonia scale. Treatment with nabilone produced no significant reduction in the total dystonia movement scale score when compared with placebo (p >0.05).

Two small trials of dronabinol and nabilone failed to demonstrate a significant benefit of the cannabinoids in improving dystonia compared with placebo. Cannabis has not been studied in the treatment of dystonia.

CONCLUSION 4-12 There is insufficient evidence to support or refute the conclusion that nabilone and dronabinol are an effective treatment for dystonia.

Dementia is characterized by a decline in cognition that typically affects multiple cognitive domains such as memory, language, executive function, and perceptual motor function ( NIH, 2013 ). Alzheimer's disease, vascular dementia, and Parkinson's disease with dementia are three prominent dementing disorders ( NIA, n.d .). Behavioral and psychological symptoms, including agitation, aggression, and food refusal, are common in the more advanced stages of dementia. These symptoms cause distress to the patient and caregivers and may precipitate the patient being placed in institutional care. Current treatments for dementia (e.g., cholinesterase inhibitors) have only modest effects, and treatments for behavioral disturbances such as antipsychotic medications have both modest benefits and substantial adverse effects ( Krishnan et al., 2009 ).

CB 1 receptors are found throughout the central nervous system, and the endogenous cannabinoid system is thought to be important in the regulation of synaptic transmission ( Baker et al., 2003 ), a process that is disordered in patients with dementia. Accumulating evidence suggests that cannabinoids have the potential for neuroprotective effects ( Grundy, 2002 ; Hampson et al., 1998 ; Shen and Thayer, 1998 ). This developing understanding of the endogenous cannabinoid system, along with cannabinoids anxiolytic and appetite-stimulating effects, provides a rationale for its study in patients with dementia.

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms Associated with Dementia?

We identified two good-quality systematic reviews ( Krishnan et al., 2009 ; van den Elsen et al., 2014 ) that evaluated cannabis for dementia. Both reviews identified the same two RCTs, which were synthesized qualitatively. A small randomized crossover trial ( Volicer et al., 1997 ) evaluated dronabinol in 15 hospitalized patients with probable Alzheimer's disease who had behavior changes and were refusing food. Patients were randomized to dronabinol (2.5 mg twice daily) for 6 weeks and to a placebo for 6 weeks. Data in this trial with a high risk of bias were presented in such a way that they could not be abstracted for analysis by systematic review authors. The primary study authors reported: increased weight during the 12 weeks regardless of order of treatment (dronabinol, 7.0 [SD 1.5] pounds, and placebo, 4.6 [SD 1.3] pounds, during the first 6 weeks); decreased disturbed behavior during dronabinol treatment, an effect that persisted in patients treated first with dronabinol, then the placebo; decreased negative affect scores in both groups during the 12 weeks, more so when taking dronabinol than the placebo; and no serious adverse events attributed to dronabinol, although one patient suffered a seizure following the first dose. One other open-label pilot study ( Walther et al., 2006 ), which evaluated six patients with severe dementia for the effects of dronabinol on nighttime agitation, did not meet eligibility criteria for the review by Krishnan et al. (2009) .

We identified one good-quality RCT that evaluated THC in 50 patients with Alzheimer's disease, vascular or mixed dementia, and neuropsychiatric symptoms ( van den Elsen et al., 2015 ). THC 1.5 mg given three times daily for 3 weeks did not improve overall neuropsychiatric symptoms, agitation, quality of life, or activities of daily living versus a placebo. Although the study recruited less than one-half of the planned sample, the authors estimated that there was only a 5 percent chance that enrolling more participants would have shown a clinically important effect on neuropsychiatric symptoms.

The authors of the good-quality Cochrane systematic review concluded that the “review finds no evidence that cannabinoids are effective in the improvement of disturbed behavior in dementia or treatment of other symptoms of dementia” ( Krishnan et al., 2009, p. 8 ). Subsequently, a larger good-quality RCT found no benefit from low-dose THC. We agree that the evidence is limited due to the small number of patients enrolled, limits in the study design and reporting, and inconsistent effects. The current limited evidence does not support a therapeutic effect of cannabinoids.

CONCLUSION 4-13 There is limited evidence that cannabinoids are ineffective treatments for improving the symptoms associated with dementia.

Glaucoma is one of the leading causes of blindness within the United States ( Mayo Clinic, 2015 ). This disorder is characterized as a group of eye conditions that can produce damage to the optic nerve and result in a loss of vision. This damage is often caused by abnormally high intraocular pressure ( NEI, n.d .). Because high intraocular pressure is a known major risk factor that can be controlled ( Prum et al., 2016, p. 52 ), most treatments have been designed to reduce it. Research suggests that cannabinoids may have potential as an effective treatment for reducing pressure in the eye ( Tomida et al., 2007 ).

Are Cannabis or Cannabinoids an Effective Treatment for Glaucoma?

We identified one good-quality systematic review ( Whiting et al., 2015 ) that evaluated medical cannabis for the treatment of glaucoma. This review identified a single randomized crossover trial (six participants) in patients with glaucoma. The trial compared THC (5 mg oromucosal spray), cannabidiol (20 mg oromucosal spray), cannabidiol spray (40 mg oromucosal spray), and a placebo, examining intraocular pressure intermittently up until 12 hours after treatment. Elevated intraocular pressure is one of the diagnostic criteria for glaucoma, and lowering intraocular pressure is a goal of glaucoma treatments ( Prum et al., 2016 ). The trial was evaluated as “unclear” risk of bias. No differences in intraocular pressure were found between placebo and cannabinoids.

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the symptoms of glaucoma and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Lower intraocular pressure is a key target for glaucoma treatments. Non-randomized studies in healthy volunteers and glaucoma patients have shown short-term reductions in intraocular pressure with oral, topical eye drops, and intravenous cannabinoids, suggesting the potential for therapeutic benefit ( IOM, 1999, pp. 174–175 ). A good-quality systemic review identified a single small trial that found no effect of two cannabinoids, given as an oromucosal spray, on intraocular pressure ( Whiting et al., 2015 ). The quality of evidence for the finding of no effect is limited. However, to be effective, treatments targeting lower intraocular pressure must provide continual rather than transient reductions in intraocular pressure. To date, those studies showing positive effects have shown only short-term benefit on intraocular pressure (hours), suggesting a limited potential for cannabinoids in the treatment of glaucoma.

CONCLUSION 4-14 There is limited evidence that cannabinoids are an ineffective treatment for improving intraocular pressure associated with glaucoma.

• TRAUMATIC BRAIN INJURY/INTRACRANIAL HEMORRHAGE

Traumatic brain injury (TBI) is an acquired brain injury that can result from a sudden or violent hit to the head ( NINDS, 2016c ). TBI accounts for about 30 percent of all injury deaths in the United States ( CDC, 2016 ). Intracranial hemorrhage (ICH), bleeding that occurs inside the skull, is a common complication of TBI which is associated with a worse prognosis of the injury ( Bullock, 2000 ; CDC, 2015 ). There is a small body of literature reporting the neuroprotective effects of cannabinoid analogues in preclinical studies of head injuries ( Mechoulam et al., 2002 ) as well as in observational studies in humans ( Di Napoli et al., 2016 ; Nguyen et al., 2014 ).

Are Cannabis or Cannabinoids an Effective Treatment or Prevention for Traumatic Brain Injury or Intracranial Hemorrhage?

The committee did not identify a good- or fair-quality systematic review that evaluated the efficacy of cannabinoids as a treatment or prevention for traumatic brain injury or intracranial hemorrhage.

There were two fair- to high-quality observational studies found in the literature. One study (n = 446) examined the TBI presentation and outcomes among patients with and without a positive THC blood test ( Nguyen et al., 2014 ). Patients who were positive for THC were more likely to survive the TBI than those who were negative for THC (OR, 0.224, 95% CI = 0.051–0.991). The authors used regression analysis to account for confounding variables (e.g., age, alcohol, Abbreviated Injury Score, Injury Severity Score, mechanism of injury, gender, and ethnicity). In the only other observational study that examined the association between cannabis use and brain outcomes, a study of intracranial hemorrhage patients (n = 725) found that individuals with a positive test of cannabis use demonstrated better primary outcome scores on the modified Rankin Scale 9 (adjusted common OR, 0.544, 95% CI = 0.330–0.895) ( Di Napoli et al., 2016 ). In their analysis, the authors adjusted for confounding variables that are known to be associated with worse ICH outcomes, including age, sex, Glasgow Coma Scale as continuous variables, and anticoagulant use.

The two studies discussed above ( Di Napoli et al., 2016 ; Nguyen et al., 2014 ) provide very modest evidence that cannabis use may improve outcomes after TBI or ICH. However, more conclusive observational studies or randomized controlled trials will be necessary before any conclusions can be drawn about the neuroprotective effect of cannabinoids in clinical populations.

CONCLUSION 4-15 There is limited evidence of a statistical association between cannabinoids and better outcomes (i.e., mortality, disability) after a traumatic brain injury or intracranial hemorrhage.

Drug addiction has been defined as a chronically relapsing disorder that is characterized by the compulsive desire to seek and use drugs with impaired control over substance use despite negative consequences ( Prud'homme et al., 2015 ). The endocannabinoid system has been found to influence the acquisition and maintenance of drug-seeking behaviors, possibly through its role in reward and brain plasticity ( Gardner, 2005 ; Heifets and Castillo, 2009 ). Furthermore, in laboratory settings orally administered dronabinol has been found to reduce cannabis withdrawal symptoms in cannabis users who were not seeking treatment to reduce cannabis use ( Budney et al., 2007 ; Haney et al., 2004 ) and therefore may be expected to be useful as a substitute to assist to achieve and maintain abstinence of cannabis.

Are Cannabis or Cannabinoids an Effective Treatment for Achieving Abstinence from Addictive Substances?

We identified two recent published reviews that examined randomized trials evaluating the effects of cannabis or cannabinoids on the use of addictive drugs, including cannabis: one systematic review by Marshall et al. (2014) and one comprehensive review by Prud'homme et al. (2015) . 10

The review by Marshall et al. (2014) is a high-quality systematic review of randomized and quasi-randomized trials assessing the efficacy of drug therapies specifically for cannabis dependence. They identified two trials examining THC: one published by Levin et al. (2011) , examining dronabinol, and one published by Allsop et al. (2014) , examining nabiximols.

The trial by Levin et al. (2011) was a randomized, placebo-controlled double-blind trial, which assigned cannabis-dependent adults to receive dronabinol (n = 79) or a placebo (n = 77) for 8 weeks, followed by a 2-week taper. Both groups received weekly individual therapy plus motivational enhancement therapy. Retention in the treatment program at the end of the maintenance phase was 77 percent in the dronabinol group and 61 percent in the placebo group (p-value for difference between groups = 0.02). Withdrawal symptoms declined more quickly in the dronabinol group than in the placebo group (p = 0.02). However, the primary outcome, the proportion of participants who achieved 2 consecutive weeks of abstinence at weeks 7 to 8, was 17.7 percent in the dronabinol group and 15.6 percent in the placebo group, which were not statistically significantly different from one another (p = 0.69).

The trial by Allsop et al. (2014) was randomized, placebo-controlled, and double-blind, and it enrolled adults seeking treatment for cannabis dependence. Subjects were patients who were hospitalized for 9 days and who received a 6-day regimen of nabiximols oromucosal spray (n = 27) or a matching placebo (n = 24) together with standardized psychosocial interventions. The primary outcome was a change in the Cannabis Withdrawal Scale, which is a 19-item scale that measures withdrawal symptom severity on an 11-point Likert scale for the previous 24 hours. Over the 6-day treatment period, subjects in the nabiximols group reported a mean 66 percent reduction from baseline in the cannabis withdrawal scale, while patients in the placebo group reported a mean increase in the cannabis withdrawal scale of 52 percent (p-value for between-group difference = 0.01). The median time between hospital discharge and relapse to cannabis use was 15 days (95% CI = 3.55–26.45) in the nabiximols group and 6 days (95% CI = 0–27.12) in the placebo group. The difference between these times was not statistically significant (p-value for between-group difference = 0.81).

Based on the Levin et al. (2011) and Allsop et al. (2014) trials, Marshall et al. (2014) concluded that there was moderate-quality evidence that users of THC preparations were more likely to complete treatment than those given a placebo (RR, 1.29, 95% CI = 1.08–1.55). However, the systematic review further concluded that, based on these two trials, the studied THC preparations were not associated with an increased likelihood of abstinence or a greater reduction in cannabis use than a placebo.

The review by Prud'homme et al. (2015) is a comprehensive review that broadly examined evidence on the effects of cannabidiol on addictive behaviors. The only randomized trial assessing the role of cannabis in reducing the use of an addictive substance was published by Morgan et al. (2013) . That study was a pilot placebo-controlled trial that randomized cigarette smokers who wished to quit smoking to receive 400 µg inhaled cannabidiol (n = 12) or inhaled placebo (n = 12) for 1 week. Participants were instructed to use the inhaler when they felt the urge to smoke. The reduction in the number of cigarettes smoked per week was higher in the cannabidiol group than in the placebo group, although the difference was not statistically significant (p = 0.054). Rates of abstinence were not reported.

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the reduction in use of addictive substances and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Based on the systematic reviews, neither of the two trials evaluating the efficacy of a cannabinoid in achieving or sustaining abstinence from cannabis showed a statistically significant effect. However, given the limited number of studies and their small size, their findings do not definitively rule out the existence of an effect. The only study examining the efficacy of a cannabinoid in cigarette smoking cessation was a pilot study that did not examine rates of abstinence. Thus, its efficacy for smoking cessation has not been thoroughly evaluated.

CONCLUSION 4-16 There is no evidence to support or refute the conclusion that cannabinoids are an effective treatment for achieving abstinence in the use of addictive substances.

Anxiety disorders share features of excessive fear and anxiety which induce psychological and physical symptoms that can cause significant distress or interfere with social, occupational, and other areas of functioning ( APA, 2013 ). In a given year, an estimated 18 percent of the U.S. adult population will suffer from symptoms associated with an anxiety disorder ( NIMH, n.d .). Given the role of the endocannabinoid system in mood regulation, the committee decided to explore the relationship between anxiety and cannabis.

Are Cannabis or Cannabinoids an Effective Treatment for the Improvement of Anxiety Symptoms?

The review by Whiting et al. (2015) was the most recent good-quality review. This review identified one randomized trial with a high risk of bias that compared a single 600 mg dose of cannabidiol to a placebo in 24 participants with generalized social anxiety disorder. Cannabidiol was associated with a greater improvement on the anxiety factor of a 100-point visual analogue mood scale (mean difference from baseline −16.52, p = 0.01) compared with a placebo during a simulated public speaking test. Four other randomized controlled trials (232 participants) enrolled patients with chronic pain and reported on anxiety symptoms. The cannabinoids studied were: dronabinol, 10–20 mg daily; nabilone, maximum dose of 2 mg daily; and nabiximols, maximum dose of 4–48 sprays/day. Outcomes were assessed from 8 hours to 6 weeks after randomization; three of the four trials were judged to have a high risk of bias. These trials suggested greater short-term benefit with cannabinoids than a placebo on self-reported anxiety symptoms.

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the improvement of anxiety symptoms and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

There is limited evidence that cannabidiol improves anxiety symptoms, as assessed by a public speaking test, in patients with social anxiety disorder. These positive findings are limited by weaknesses in the study design (e.g., an inadequate description of randomization and allocation concealment), a single dose of CBD, and uncertain applicability to patients with other anxiety disorders. Limited evidence also suggests short-term benefits in patients with chronic pain and associated anxiety symptoms. In contrast, evidence from observational studies found moderate evidence that daily cannabis use is associated with increased anxiety symptoms and heavy cannabis use is associated with social phobia disorder (see Chapter 12 ).

CONCLUSION 4-17 There is limited evidence that cannabidiol is an effective treatment for the improvement of anxiety symptoms, as assessed by a public speaking test, in individuals with social anxiety disorders.

Depression is one of the nation's most common mental health disorders ( ADAA, 2016 ). Across the many depressive disorders that exist (e.g., persistent depressive disorder, major depressive disorder, premenstrual dysphoric disorder) there are common symptomatic features of feelings of sadness, emptiness, or irritable mood, accompanied by somatic and cognitive changes that affect the individual's capacity to function ( APA, 2013, p. 155 ). The endocannabinoid system is known to play a role in mood regulation ( NIDA, 2015, p. 9 ); therefore, the committee decided to explore the association between cannabis use and depressive disorders or symptoms.

Are Cannabis or Cannabinoids an Effective Treatment to Reduce Depressive Symptoms?

The review by Whiting et al. (2015) was the most recent good-quality review. No RCTs were identified that specifically evaluated cannabis in patients with a depressive disorder. Five RCTs (634 participants) enrolled patients for other conditions (chronic pain or multiple sclerosis with spasticity) and reported on depressive symptoms. Only one study reported depressive symptoms at baseline; symptoms were mild. Nabiximols (n = 3; maximum dose ranged from 4–48 doses/day), dronabinol (10 mg and 20 mg daily), and nabilone capsules (maximum of 8 mg) were compared to placebo; nabilone was also compared to dihydrocodeine. Outcomes were assessed from 8 hours to 9 weeks following randomization. Three of the five trials were judged to have a high risk of bias and the other two as unclear risk. Three studies (nabiximols, dronabinol) showed no effect using validated symptom scales. One study that evaluated three doses of nabiximols found increased depressive symptoms at the highest dose (11–14 sprays/day), but no difference compared to the placebo at lower doses. The comparison of nabilone to dihydrocodone showed no difference in depressive symptoms.

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment to reduce depressive symptoms and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Although patients report using cannabinoids for depression, our search for a good-quality systematic review did not identify any RCTs evaluating the effects of medical cannabis in patients with depressive disorders. Trials in patients with chronic pain or multiple sclerosis with uncertain baseline depressive symptoms did not show an effect. There are no trial data addressing the effects of cannabinoids for major depressive disorder.

In Chapter 12 (Mental Health), the committee reviews epidemiological evidence to examine the association between cannabis use and the development of depressive disorders as well as the impact of cannabis use on the disorder's course or symptoms.

CONCLUSION 4-18 There is limited evidence that nabiximols, dronabinol, and nabilone are ineffective treatments for the reduction of depressive symptoms in individuals with chronic pain or multiple sclerosis.

• SLEEP DISORDERS

Sleep disorders can be classified into major groups that include insomnia, sleep-related breathing disorders, parasomnias, sleep-related movement disorders, and circadian rhythm sleep–wake disorders ( Sateia, 2014 ). Fifty million to 70 million adults in the United States report having some type of sleep disorder ( ASA, 2016 ). In 2010, insomnia generated 5.5 million office visits in the United States ( Ford et al., 2014 ). There is some evidence to suggest that the endocannabinoid system may have a role in sleep. THC is associated in a dose-dependent manner with changes in slow-wave sleep, which is critical for learning and memory consolidation. Cannabis may also have effects on sleep latency, decreasing time to sleep onset at low doses and increasing time to sleep onset at higher doses ( Garcia and Salloum, 2015 ). Thus, cannabinoids could have a role in treating sleep disorders.

Are Cannabis or Cannabinoids an Effective Treatment for Improving Sleep Outcomes?

The review by Whiting et al. (2015) was the most recent good-quality review. Two RCTs (54 participants) evaluated cannabinoids (nabilone, dronabinol) for the treatment of sleep problems. A trial deemed to have a high risk of bias conducted in 22 patients with obstructive sleep apnea showed a greater benefit of dronabinol (maximum dose of 10 mg daily) than with a placebo on sleep apnea/hypopnea index (mean difference from baseline −19.64, p = 0.02) at 3 weeks follow-up. A crossover trial deemed to have a low risk of bias in 32 patients with fibromyalgia found improvements for nabilone 0.5 mg daily compared with 10 mg amitriptyline in insomnia (mean difference from baseline, −3.25, 95% CI = −5.26 to −1.24) and greater sleep restfulness (mean difference from baseline, 0.48, 95% CI = 0.01–0.95) at 2 weeks follow-up. Although the antidepressant amitriptyline is an established treatment for fibromyalgia, it is not FDA approved for insomnia, and its use is limited by adverse effects.

Nineteen trials (3,231 participants) enrolled patients with other conditions (chronic pain or multiple sclerosis) and reported on sleep outcomes. Nabiximols (13 studies), THC/CBD capsules (2 studies), smoked THC (2 studies), and dronabinol or nabilone were compared to a placebo. Sleep outcomes were assessed at 2–15 weeks after randomization. Eleven of the 19 trials were judged to have a high risk of bias, 6 had an uncertain risk of bias, and the other 2 were judged to have a low risk of bias. The meta-analysis found greater improvements with cannabinoids in sleep quality among 8 trials (weighted mean difference [WMD], −0.58, 95% CI = −0.87 to −0.29) and sleep disturbance among 3 trials (WMD, −0.26, 95% CI = −0.52 to 0.00). These improvements in sleep quality and sleep disturbance were rated on a 10-point scale and would be considered small improvements. The summary estimate showing benefit was based primarily on studies of nabiximols.

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment to improve sleep outcomes and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

A high-quality systematic review found moderate evidence suggesting that cannabinoids (primarily nabiximols) improve short-term sleep outcomes in patients with sleep disturbance associated with obstructive sleep apnea, fibromyalgia, chronic pain, or multiple sclerosis. However, the single study using an active comparator used a drug (amitriptyline) that is considered second-line treatment due to the availability of newer, more effective treatments that have fewer adverse effects. The committee did not identify any clinical trials that evaluated the effects of cannabinoids in patients with primary chronic insomnia.

CONCLUSION 4-19 There is moderate evidence that cannabinoids, primarily nabiximols, are an effective treatment to improve short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis.

• POSTTRAUMATIC STRESS DISORDER

Posttraumatic stress disorder (PTSD) falls within the broader trauma- and stressor-related disorders categorized by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). The diagnostic criteria of PTSD include an exposure to a traumatic event (e.g., the threat of death, serious injury, or sexual violence) and exhibiting psychological distress symptoms that occur as a result of that exposure (e.g., intrusion symptoms, such as distressing memories; avoidance of stimuli that are associated with the traumatic event; negative alterations in mood and cognition; alterations in arousal and reactivity associated with the traumatic event; functional impairment) ( APA, 2013, pp. 271–272 ). Given the known psychoactive effects of cannabis, the committee decided to explore the association between PTSD and cannabis use.

Are Cannabis or Cannabinoids an Effective Treatment for PTSD Symptoms?

The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for PTSD symptoms.

We identified a fair-quality double-blind, randomized crossover trial ( Jetly et al., 2015 ) conducted with Canadian male military personnel with trauma-related nightmares despite standard treatments for PTSD. Ten participants were randomized to either nabilone 0.5 mg that was titrated to a daily maximum of 3.0 mg or else to a placebo for 7 weeks. Following a 2-week washout period, subjects were then treated with the other study treatment and followed for an additional 7 weeks. Effects on sleep, nightmares, and global clinical state were assessed by the investigators; sleep time and general well-being were self-reported. Nightmares, global clinical state, and general well-being were improved more with nabilone treatment than with the placebo treatment (p <0.05). There was no effect on sleep quality and quantity. Global clinical state was rated as very much improved or much improved for 7 of 10 subjects in the nabilone treatment period and 2 of 10 subjects in the placebo treatment period.

A single, small crossover trial suggests potential benefit from the pharmaceutical cannabinoid nabilone. This limited evidence is most applicable to male veterans and contrasts with non-randomized studies showing limited evidence of a statistical association between cannabis use ( plant derived forms ) and increased severity of posttraumatic stress disorder symptoms among individuals with posttraumatic stress disorder (see Chapter 12 ). A search of the grey literature identified several recently initiated randomized controlled trials examining the harms and benefits of marijuana for PTSD. 11 One trial examines the effects of four different types of cannabis with varying THC and CBD content on PTSD symptoms in 76 veterans ( Bonn-Miller, 2016 ). Another trial is a Canadian study that evaluates different formulations of THC and CBD in 42 adults with PTSD ( Eades, 2016 ). If these trials are successfully completely, they will add substantially to the knowledge base, expanding the range of cannabinoids evaluated and the opportunity to examine the consistency of effects across studies.

CONCLUSION 4-20 There is limited evidence (a single, small fair-quality trial) that nabilone is effective for improving symptoms of posttraumatic stress disorder.

• SCHIZOPHRENIA AND OTHER PSYCHOSES

Schizophrenia spectrum disorders and other psychotic disorders are mental health disorders characterized by three different classes of symptoms: positive symptoms (e.g., delusions, hallucinations, or disorganized or abnormal motor behavior), negative symptoms (e.g., diminished emotional expression, lack of interest or motivation to engage in social settings, speech disturbance, or anhedonia), and impaired cognition (e.g., disorganized thinking) ( APA, 2013, p. 87 ; NIMH, 2015 ). Evidence suggests that the prevalence of cannabis use among people with schizophrenia is generally higher than among the general population ( McLoughlin et al., 2014 ). In most of the studies reviewed below, schizophrenia, schizophreniform disorder, schizoaffective disorder, and psychotic disorders are used as aggregate endpoints.

Are Cannabis or Cannabinoids an Effective Treatment for the Mental Health Outcomes of Patients with Schizophrenia or Other Psychoses?

Two good-quality reviews ( McLoughlin et al., 2014 ; Whiting et al., 2015 ) evaluated cannabinoids for the treatment of psychosis. We focus on the good-quality review by Whiting et al. (2015) as it is more current. Two RCTs with high risk of bias (71 total participants with schizophrenia or schizophreniform psychosis) compared cannabidiol to the atypical antipsychotic amisulpride or a placebo. One trial reported no difference on mental health between CBD (maximum dose 800 mg/day) and amisulpride (maximum dose 800 mg/day) at 4 weeks (brief psychiatric rating scale mean difference, −0.10, 95% CI = −9.20–8.90) or on mood (positive and negative syndrome scale mean difference, 1.0; 95% CI = −12.6–14.6). A crossover trial showed no difference in effect on mood between CBD (maximum dose 600 mg/day) and placebo (positive and negative symptom scale mean difference, 1, 95% CI = −12.60–14.60; scale range 30–210).

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the mental health outcomes of patients with schizophrenia or other psychoses and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Good-quality systematic reviews identified only two small, unclear-to high-risk-of-bias trials evaluating cannabinoids for the treatment of schizophrenia. These studies provide only limited evidence due to the risk of bias, the short-term follow-up, and the evaluation of a single cannabinoid. Furthermore, the larger trial was designed to detect a moderate benefit of cannabidiol compared to the antipsychotic amisulpride, but it enrolled only 60 percent of the planned sample. Thus, it did not have the statistical power to detect small or moderate differences between CBD and amisulpride. Overall, the evidence is insufficient to determine if cannabidiol is an effective treatment for individuals with schizophrenia or schiophreniform psychosis.

In Chapter 12 , the committee reviews epidemiological evidence to examine the association between cannabis use and the development of schizophrenia and other psychoses, as well as the impact of cannabis use on the disorder's course or symptoms.

CONCLUSION 4-21 There is insufficient evidence to support or refute the conclusion that cannabidiol is an effective treatment for the mental health outcomes in individuals with schizophrenia or schizophreniform psychosis.

• RESEARCH GAPS

In reviewing the research evidence described above, the committee has identified that research gaps exist concerning the effectiveness of cannabidiol or cannabidiol-enriched cannabis in treating the following:

• cancer in general
• treating chemotherapy-induced nausea and vomiting
• symptoms of irritable bowel syndrome
• spasticity due to paraplegia from spinal cord injury
• symptoms associated with amyotrophic lateral sclerosis
• motor function and cognitive performance associated with Huntington's Disease
• motor system symptoms associated with Parkinson's disease or levodopa-induced dyskinesia
• achieving abstinence or reduction in the use of addictive substances, including cannabis itself
• sleep outcomes in individuals with primary chronic insomnia
• posttraumatic stress disorder symptoms
• mental health outcomes in individuals with schizophrenia or schizophreniform psychosis
• cannabidiol short-term relief from anxiety symptoms

This chapter outlines the committee's efforts to review the current evidence base for the potential efficacy of cannabis or cannabinoids on prioritized health conditions. The health conditions reviewed in this chapter include chronic pain, cancer, chemotherapy-induced nausea and vomiting, anorexia and weight loss associated with HIV, irritable bowel syndrome, epilepsy, spasticity, Tourette syndrome, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dystonia, dementia, glaucoma, traumatic brain injury, addiction, anxiety, depression, sleep disorders, posttraumatic stress disorder, and schizophrenia and other psychoses. The committee has formed a number of research conclusions related to these health endpoints; however, it is important that the chapter conclusions be interpreted within the context of the limitations discussed in the Discussion of Findings sections above. See Box 4-1 for a summary list of the chapter's conclusions.

Summary of Chapter Conclusions .

We found conclusive or substantial evidence (ranging in modest to moderate effect) for benefit from cannabis or cannabinoids for chronic pain, chemotherapy-induced nausea and vomiting, and patient-reported symptoms of spasticity associated with multiple sclerosis. For chemotherapy-induced nausea and vomiting and spasticity associated with multiple sclerosis, the primary route of administration examined was the oral route. For chronic pain, most studies examined oral cannabis extract, although some examined smoked or vaporized cannabis. It is unknown whether and to what degree the results of these studies can be generalized to other products and routes of administration. For many of the other conditions discussed above, there is insufficient or no evidence upon which to base conclusions about therapeutic effects. The potential efficacy of cannabinoids for several of these conditions, such as epilepsy and posttraumatic stress disorder, should be prioritized, given the substantial number of persons using cannabis for those conditions ( Cougle et al., 2011 ; Massot-Tarrús and McLachlan, 2016 ). As identified in the chapter's Discussion of Findings sections, there are common themes in the type of study limitations found in this evidence base. The most common are limitations in the study design (e.g., a lack of appropriate control groups, a lack of long-term follow-ups), small sample sizes, and research gaps in examining the potential therapeutic benefits of different forms of cannabis (e.g., cannabis plant). These limitations highlight the need for substantial research to provide comprehensive and conclusive evidence on the therapeutic effects of cannabis and cannabinoids.

• Abel EL. Cannabis: Effects on hunger and thirst. Behavioral Biology. 1975; 15 (3):255–281. [ PubMed : 1106391 ]
• Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, Petersen KL. Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial. Neurology. 2007; 68 (7):515–521. [ PubMed : 17296917 ]
• ADAA (Anxiety and Depression Association of America). Depression. 2016. [November 17, 2016]. https://www ​.adaa.org ​/understanding-anxiety/depression .
• Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, Sadler C, Rivas GR, Holland RM, Muhleisen P, Norberg MM, Booth J, McGregor IS. Nabiximols as an agonist replacement therapy during cannabis withdrawal: A randomized clinical trial. JAMA Psychiatry. 2014; 71 (3):281–291. [ PubMed : 24430917 ]
• Andreae MH, Carter GM, Shaparin N, Suslov K, Ellis RJ, Ware MA, Abrams DI, Prasad H, Wilsey B, Indyk D, Johnson M, Sacks HS. Inhaled cannabis for chronic neuropathic pain: A meta-analysis of individual patient data. Journal of Pain. 2015; 16 (12):1121–1232. [ PMC free article : PMC4666747 ] [ PubMed : 26362106 ]
• Andries A, Frystyk J, Flyvbjerg A, Støving RK. Dronabinol in severe, enduring anorexia nervosa: A randomized controlled trial. International Journal of Eating Disorders. 2014; 47 (1):18–23. [ PubMed : 24105610 ]
• APA (American Psychiatric Association). Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
• Armstrong MJ, Miyasaki JM. Evidence-based guideline: Pharmacologic treatment of chorea in Huntington disease: Report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2012; 79 (6):597–603. [ PMC free article : PMC3413759 ] [ PubMed : 22815556 ]
• ASA (American Sleep Association). Sleep and sleep disorder statistics. 2016. [October 25, 2016]. https://www ​.sleepassociation ​.org/sleep/sleep-statistics .
• Ashworth B. Preliminary trial of carisoprodol in multiple sclerosis. The Practitioner. 1964; 192 :540–542. [ PubMed : 14143329 ]
• Baker D, Pryce G, Giovannoni G, Thompson AJ. The therapeutic potential of cannabis. The Lancet Neurology. 2003; 2 :291–298. [ PubMed : 12849183 ]
• Belendiuk KA, Baldini LL, Bonn-Miller MO. Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders. Addiction Science & Clinical Practice. 2015; 10 :10. [ PMC free article : PMC4636852 ] [ PubMed : 25896576 ]
• Boehnke KF, Litinas E, Clauw DJ. Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. Journal of Pain. 2016; 17 (6):739–744. [ PubMed : 27001005 ]
• Bonn-Miller M. Study of four different potencies of smoked marijuana in 76 veterans with chronic, treatment-resistant PTSD. Bethesda, MD: National Library of Medicine; 2016. [September 28, 2016]. ClinicalTrials ​.gov . https://clinicaltrials.gov/ct2/show/NCT02759185 .
• Bradford AC, Bradford WD. Medical marijuana laws reduce prescription medication use in Medicare part D. Health Affairs. 2016; 35 (7):1230–1236. [ PubMed : 27385238 ]
• Budney AJ, Vandrey RG, Hughes JR, Moore BA, Bahrenburg B. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug and Alcohol Dependence. 2007; 86 (1):22–29. [ PubMed : 16769180 ]
• Bullock R, Chesnut R, Clifton GL, Ghajar J, Marion DW, Narayan RK, Newell DW, Pitts LH, Rosner MJ, Walters BC, Wilberger JE. Management and prognosis of severe traumatic brain injury. Journal of Neurotrauma. 2000; 17 :451–627.
• Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clinical Epidemiology. 2014; 6 :71–80. [ PMC free article : PMC3921083 ] [ PubMed : 24523597 ]
• Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, Parkin SG, Fox P, Wright D, Hobart J, Zajicek JP. Cannabis for dyskinesia in Parkinson disease: A randomized double-blind crossover study. Neurology. 2004; 63 (7):1245–1250. [ PubMed : 15477546 ]
• CDC (Centers for Disease Control and Prevention). Bleeding disorders glossary. 2015. [November 17, 2016]. https://www ​.cdc.gov/ncbddd ​/hemophilia/communitycounts ​/glossary.html .
• CDC. TBI: Get the facts. 2016. [November 17, 2016]. http://www ​.cdc.gov/traumaticbraininjury ​/get_the_facts.html .
• CDPHE (Colorado Department of Public Health and Environment). 2016 medical marijuana registry statistics. 2016. [October 28, 2016]. https://www ​.colorado ​.gov/pacific/cdphe/2016-medical-marijuana-registry-statistics .
• Chagas MHN, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, Dos Santos AC, Teixeira AL, Hallak JEC, Crippa JAS. Effects of cannabidiol in the treatment of patients with Parkinson's disease: An exploratory double-blind trial. Journal of Psychopharmacology. 2014; 28 (11):1088–1092. [ PubMed : 25237116 ]
• Colorado DOR (Department of Revenue). MED 2015 Annual Update. Denver: Colorado Department of Revenue; 2016. [December 7, 2016]. https://www ​.colorado ​.gov/pacific/sites/default ​/files/2015%20Annual ​%20Update%20FINAL%2009262016_1.pdf .
• Consroe P, Sandyk R, Sinder S. Open label evaluation of cannabidiol in dystonic movement disorders. International Journal of Neuroscience. 1986; 30 (4):277–282. [ PubMed : 3793381 ]
• Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R, Kennedy K, Schram K. Controlled clinical trial of cannabidiol in Huntington's disease. Pharmacology, Biochemistry, and Behavior. 1991; 40 (3):701–708. [ PubMed : 1839644 ]
• Cougle JR, Bonn-Miller MO, Vujanovic AA, Zvolensky MJ, Hawkins KA. Posttraumatic stress disorder and cannabis use in a nationally representative sample. Psychology of Addictive Behaviors. 2011; 25 (3):554–558. [ PubMed : 21480682 ]
• Curtis A, Mitchell I, Patel S, Ives N, Rickards H. A pilot study using nabilone for symptomatic treatment in Huntington's disease. Movement Disorders. 2009; 24 (15):2254–2259. [ PubMed : 19845035 ]
• Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014; 55 (6):791–802. [ PMC free article : PMC4707667 ] [ PubMed : 24854329 ]
• Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: An open-label interventional trial. The Lancet Neurology. 2016; 15 (3):270–278. [ PubMed : 26724101 ]
• Di Napoli M, Zha AM, Godoy DA, Masotti L, Schreuder FH, Popa-Wagner A, Behrouz R. Prior cannabis use is associated with outcome after intracerebral hemorrhage. Cerebrovascular Disease. 2016; 41 (5-6):248–255. [ PubMed : 26820826 ]
• Eades J. Evaluating safety and efficacy of cannabis in participants with chronic posttraumatic stress disorder. Bethesda, MD: National Library of Medicine; 2016. [September 28, 2016]. ClinicalTrials ​.gov . https://clinicaltrials.gov/ct2/show/NCT02517424 .
• Esfandyari T, Camilleri M, Ferber I, Burton D, Baxter K, Zinsmeister AR. Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: A randomized, placebo-controlled study. Neurogastroenterology & Motility. 2006; 18 (9):831–838. [ PubMed : 16918762 ]
• Fitzcharles MA, Ste-Marie PA, Hauser W, Clauw DJ, Jamal S, Karsh J, Landry T, LeClercq S, McDougall JJ, Shir Y, Shojania K, Walsh Z. Efficacy, tolerability, and safety of cannabinoid treatments in the rheumatic diseases: A systematic review of randomized controlled trials. Arthritis Care and Research. 2016; 68 (5):681–688. [ PubMed : 26548380 ]
• Foltin RW, Fischman MW, Byrne MF. Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite. 1988; 11 (1):1–14. [ PubMed : 3228283 ]
• Ford ES, Wheaton AG, Cunningham TJ, Giles WH, Chapman DP, Croft JB. Trends in outpatient visits for insomnia, sleep apnea, and prescriptions for sleep medications among US adults: Findings from the National Ambulatory Medical Care survey 1999-2010. Sleep. 2014; 37 (8):1283–1293. [ PMC free article : PMC4096197 ] [ PubMed : 25083008 ]
• Fox SH, Kellett M, Moore AP, Crossman AR, Brotchie JM. Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia. Movement Disorders. 2002; 17 (1):145–149. [ PubMed : 11835452 ]
• Garcia AN, Salloum IM. Polysomnograhic sleep disturbances in nicotine, caffeine, alcohol, cocaine, opioid, and cannabis use: A focused review. American Journal of Addiction. 2015; 24 (7):590–598. [ PubMed : 26346395 ]
• Gardner EL. Endocannabinoid signaling system and brain reward: Emphasis on dopamine. Pharmacology, Biochemistry & Behavior. 2005; 81 (2):263–284. [ PubMed : 15936806 ]
• Gelinas D, Miller RG, Abood M. A pilot study of safety and tolerability of delta 9-THC (Marinol) treatment for ALS. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders. 2002; 3 (Suppl 2):23–24.
• Gloss DS, Vickrey B. Cannabinoids for epilepsy. Cochrane Database of Systematic Reviews. 2014; 3 :CD009270. [ PMC free article : PMC7120304 ] [ PubMed : 24595491 ]
• Goetz CG, Stebbins GT, Shale HM, Lang AE, Chernik DA, Chmura TA, Ahlskog JE, Dorflinger EE. Utility of an objective dyskinesia rating scale for Parkinson's disease: Inter- and intrarater reliability assessment. Movement Disorders. 1994; 9 (4):390–394. [ PubMed : 7969204 ]
• Grotenhermen F, Müller-Vahl K. The therapeutic potential of cannabis and cannabinoids. Deutsches Ärzteblatt International. 2012; 109 (29-30):495–501. [ PMC free article : PMC3442177 ] [ PubMed : 23008748 ]
• Grundy RI. The therapeutic potential of the cannabinoids in neuroprotection. Expert Opinion on Investigational Drugs. 2002; 11 :1365–1374. [ PubMed : 12387700 ]
• GW Pharmaceuticals. Prescriber information. 2016. [November 15, 2016]. http://dev-gwpharma ​.pantheonsite ​.io/products-pipeline ​/sativex ​/prescriber-information-full .
• Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and delta-9-tetrahydrocannabinol are neuroprotective antioxidants. Proceedings of the National Academy of Sciences of the United States of America. 1998; 95 :8268–8273. [ PMC free article : PMC20965 ] [ PubMed : 9653176 ]
• Haney M, Hart CL, Vosburg SK, Nasser J, Bennett A, Zubaran C, Foltin RW. Marijuana withdrawal in humans: Effects of oral THC or divalproex. Neuropsychopharmacology. 2004; 29 (1):158–170. [ PubMed : 14560320 ]
• Heifets BD, Castillo PE. Endocannabinoid signaling and long-term synaptic plasticity. Annual Review of Physiology. 2009; 71 :283–306. [ PMC free article : PMC4454279 ] [ PubMed : 19575681 ]
• Hemming M, Yellowlees PM. Effective treatment of Tourette's syndrome with marijuana. Journal of Psychopharmacology. 1993; 7 :389–391. [ PubMed : 22291003 ]
• Ilgen MA, Bohnert K, Kleinberg F, Jannausch M, Bohnert AS, Walton M, Blow FC. Characteristics of adults seeking medical marijuana certification. Drug and Alcohol Dependence. 2013; 132 (3):654–659. [ PubMed : 23683791 ]
• IOM (Institute of Medicine). Marijuana and medicine: Assessing the science base. Washington, DC: National Academy Press; 1999. [ PubMed : 25101425 ]
• Jatoi A, Windschitl HE, Loprinzi CL, Sloan JA, Dakhil SR, Mailliard JA, Pundaleeka S, Kardinal CG, Fitch TR, Krook JE, Novotny PJ, Christensen B. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: A North Central Cancer Treatment Group study. Journal of Clinical Oncology. 2002; 20 (2):567–573. [ PubMed : 11786587 ]
• Jetly R, Heber A, Fraser G, Boisvert D. The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: A preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology. 2015; 51 :585–588. [ PubMed : 25467221 ]
• Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D. Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014; 82 (17):1556–1563. [ PMC free article : PMC4011465 ] [ PubMed : 24778283 ]
• Krishnan S, Cairns R, Howard R. Cannabinoids for the treatment of dementia. Cochrane Database of Systematic Reviews. 2009;(2):CD007204. [ PMC free article : PMC7197039 ] [ PubMed : 19370677 ]
• Leocani L, Nuara A, Houdayer E, Schiavetti I, Del Carro U, Amadio S, Straffi L, Rossi P, Martinelli V, Vila C, Sormani MP, Comi G. Sativex® and clinicalneurophysiological measures of spasticity in progressive multiple sclerosis. Journal of Neurology. 2015; 262 (11):2520–2527. [ PubMed : 26289497 ]
• Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV. Dronabinol for the treatment of cannabis dependence: A randomized, double-blind, placebo-controlled trial. Drug and Alcohol Dependence. 2011; 116 (1-3):142–150. [ PMC free article : PMC3154755 ] [ PubMed : 21310551 ]
• Light MK, Orens A, Lewandowski B, Pickton T. Market size and demand for marijuana in Colorado. The Marijuana Policy Group. 2014 [November 17, 2016]; https://www ​.colorado ​.gov/pacific/sites/default ​/files/Market%20Size ​%20and%20Demand ​%20Study,%20July%209,%202014%5B1%5D.pdf .
• Lotan I, Treves TA, Roditi Y, Djaldetti R. Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: An open-label observational study. Clinical Neuropharmacology. 2014; 37 (2):41–44. [ PubMed : 24614667 ]
• Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database of Systematic Reviews. 2013;(4):CD005175. [ PubMed : 23633327 ]
• Marshall K, Gowing L, Ali R, Le Foll B. Pharmacotherapies for cannabis dependence. Cochrane Database of Systematic Reviews. 2014; 12 CD008940. [ PMC free article : PMC4297244 ] [ PubMed : 25515775 ]
• Massot-Tarrús A, McLachlan RS. Marijuana use in adults admitted to a Canadian epilepsy monitoring unit. Epilepsy & Behavior. 2016; 63 :73–78. [ PubMed : 27568641 ]
• Mayo Clinic. Glaucoma. 2015. [December 1, 2016]. http://www ​.mayoclinic ​.org/diseases-conditions ​/glaucoma/basics ​/definition/con-20024042 .
• McLoughlin BC, Pushpa-Rajah JA, Gillies D, Rathbone J, Variend H, Kalakouti E, Kyprianou K. Cannabis and schizophrenia. Cochrane Database of Systematic Reviews. 2014;(10) CD004837. [ PMC free article : PMC10107010 ] [ PubMed : 25314586 ]
• Mechoulam R, Spatz M, Shohami E. Endocannabinoids and neuroprotection. Science's STKE. 2002;(129):re5. [ PubMed : 11972360 ]
• Meiri E, Jhangiani H, Vredenburgh JJ, Barbato LM, Carter FJ, Yang HM, Baranowski V. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Current Medical Research and Opinion. 2007; 23 (3):533–543. [ PubMed : 17355735 ]
• Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: Response to sequential treatment schedules. European Journal of Neurology. 2006; 13 (3):277–282. [ PubMed : 16618346 ]
• Morgan CJA, Das RK, Joye A, Curran HV, Kamboj SK. Cannabidiol reduces cigarette consumption in tobacco smokers: Preliminary findings. Addictive Behaviors. 2013; 38 (9):2433–2436. [ PubMed : 23685330 ]
• Müller-Vahl KR, Koblenz A, Jöbges M, Kolbe H, Emrich HM, Schneider U. Influence of treatment of Tourette syndrome with Δ 9 -tetrahydrocannabinol (Δ 9 -THC) on neuropsychological performance. Pharmacopsychiatry. 2001; 34 (1):19–24. [ PubMed : 11229617 ]
• Müller-Vahl KR, Schneider U, Koblenz A, Jöbges M, Kolbe H, Daldrup T, Emrich HM. Treatment of Tourette's syndrome with Δ 9 -tetrahydrocannabinol (THC): A randomized crossover trial. Pharmacopsychiatry. 2002; 35 (2):57–61. [ PubMed : 11951146 ]
• Müller-Vahl KR, Prevedel H, Theloe K, Kolbe H, Emrich HM, Schneider U. Treatment of Tourette syndrome with delta-9-tetrahydrocannabinol (Δ 9 -THC): No influence on neuropsychological performance. Neuropsychopharmacology. 2003a; 28 (2):384–388. [ PubMed : 12589392 ]
• Müller-Vahl KR, Schneider U, Prevedel H, Theloe K, Kolbe H, Daldrup T, Emrich HM. Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: A 6-week randomized trial. Journal of Clinical Psychiatry. 2003b; 64 (4):459–465. [ PubMed : 12716250 ]
• NCI (National Cancer Institute). What is cancer? 2015. [November 16, 2016]. https://www ​.cancer.gov ​/aboutcancer/understanding ​/what-is-cancer .
• NCI. Cancer statistics. 2016. [October 28, 2016]. https://www ​.cancer.gov ​/about-cancer/understanding/statistics .
• NCSL (National Conference of State Legislatures). State medical marijuana laws. 2016. [November 17, 2016]. http://www ​.ncsl.org/research ​/health/state-medical-marijuana-laws.aspx .
• NEI (National Eye Institute). What you should know. n.d. [November 17, 2016]. https://nei ​.nih.gov/glaucoma ​/content/english/know .
• Nguyen B, Kim D, Bricker S, Bongard F, Neville A, Putnam B, Smith J, Plurad D. Effects of marijuana use on outcomes in traumatic brain injury. American Surgeon. 2014; 80 (10):979–983. [ PubMed : 25264643 ]
• NIA (National Institute on Aging). About Alzheimer's disease: Other dementias. n.d. [December 22, 2016]. https://www ​.nia.nih.gov ​/alzheimers/topics/other-dementias .
• NIDA (National Institute on Drug Abuse). Research reports: Marijuana. 2015. [December 8, 2016]. https://www ​.drugabuse ​.gov/sites/default/files/mjrrs_4_15.pdf .
• NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases). Definition and facts for irritable bowel syndrome. 2015. [October 18, 2016]. www ​.niddk.nih.gov/health-information ​/health-topics ​/digestive-diseases ​/irritable-bowel-syndrome ​/pages/definition-facts ​.aspx .
• NIH (National Institues of Health). The dementias: Hope through research. 2013. [December 28, 2016]. file: ​///C:/Users/MMasiello ​/Downloads/the-dementias-hope-through-research.pdf .
• NIMH (National Institute of Mental Health). Schizophrenia. 2015. [October 28, 2016]. https://www ​.nimh.nih ​.gov/health/publications ​/schizophrenia-booklet-12-2015 ​/index.shtml .
• NIMH. Any mental illness (AMI) among U.S. adults. n.d. [November 17, 2016]. https://www ​.nimh.nih ​.gov/health/statistics ​/prevalence/any-mental-illness-ami-among-us-adults.shtml .
• NINDS (National Institute of Neurological Disorders and Stroke). Tourette syndrome fact sheet. 2014. [December 2, 2016]. http://www ​.ninds.nih ​.gov/disorders/tourette/detail_tourette ​.htm .
• NINDS. Parkinson's disease: Challenges, progress, and promise. 2015. [December 28, 2016]. https://catalog ​.ninds ​.nih.gov/pubstatic//15-5595/15-5595.pdf .
• NINDS. The epilepsies and seizures: Hope through research. 2016a. [November 16, 2016]. http://www ​.ninds.nih ​.gov/disorders/epilepsy/detail_epilepsy ​.htm .
• NINDS. Dystonias fact sheet. 2016b. [November 18, 2016]. http://www ​.ninds.nih ​.gov/disorders/dystonias ​/detail_dystonias.htm .
• NINDS. Traumatic brain injury: Hope through research. 2016c. [November 16, 2016]. http://www ​.ninds.nih ​.gov/disorders/tbi/detail_tbi.htm .
• OHA (Oregon Health Authority). Oregon medical marijuana program statistics. 2016. [October 28, 2016]. https://public ​.health ​.oregon.gov/DiseasesConditions ​/ChronicDisease ​/MedicalMarijuanaProgram ​/Pages/data.aspx .
• Pandyan AD, Johnson GR, Price CI, Curless RH, Barnes MP, Rodgers H. A review of the properties and limitations of the Ashworth and modified Ashworth scales as measures of spasticity. Clinical Rehabilitation. 1999; 13 (5):373–383. [ PubMed : 10498344 ]
• Pandyan AD, Gregoric M, Barnes MP, Wood DE, Wijck FV, Burridge JH, Hermens HJ, Johnson GR. Spasticity: Clinical perceptions, neurological realities and meaningful measurement. Disability and Rehabilitation. 2005; 27 (1-2):1–2. [ PubMed : 15799140 ]
• Pazos MR, Sagredo O, Fernandez-Ruiz J. The endocannabinoid system in Huntington's disease. Current Pharmaceutical Design. 2008; 14 (23):2317–2325. [ PubMed : 18781982 ]
• PDF (Parkinson's Disease Foundation). What is Parkinson's disease? 2016a. [October 18, 2016]. http://www ​.pdf.org/en/about_pd .
• PDF. Statistics on Parkinson's. 2016b. [October 18, 2016]. http://www ​.pdf.org/en ​/parkinson_statistics .
• Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: Pharmacological strategies and therapeutic possibilities. Philosophical Transactions of the Royal Society of London—Series B: Biological Sciences. 2012; 367 (1607):3353–3363. [ PMC free article : PMC3481523 ] [ PubMed : 23108552 ]
• Phillips RS, Friend AJ, Gibson F, Houghton E, Gopaul S, Craig JV, Pizer B. Antiemetic medication for prevention and treatment of chemotherapy-induced nausea and vomiting in childhood. Cochrane Database of Systematic Reviews. 2016;(2) CD007786. [ PMC free article : PMC7073407 ] [ PubMed : 26836199 ]
• Pinto L, Izzo AA, Cascio MG, Bisogno T, Hospodar-Scott K, Brown DR, Mascolo N, Di Marzo V, Capasso F. Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology. 2002; 123 :227–234. [ PubMed : 12105851 ]
• Prud'homme M, Cata R, Jutras-Aswad D. Cannabidiol as an intervention for addictive behaviors: A systematic review of the evidence. Substance Abuse: Research and Treatment. 2015; 9 :33–38. [ PMC free article : PMC4444130 ] [ PubMed : 26056464 ]
• Prum BE Jr, Rosenberg LF, Gedde SJ, Mansberger SL, Stein JD, Moroi SE, Herndon LW Jr., Lim MC, Williams RD. Primary open-angle glaucoma Preferred Practice Pattern® guidelines. Ophthalmology. 2016; 123 (1):P41–P111. [ PubMed : 26581556 ]
• Redler RL, Dokholyan NV. Progress in Molecular Biology and Translational Science. David BT, editor. Vol. 107. Cambridge, MA: Academic Press; 2012. pp. 215–262. (Chapter 7-The Complex Molecular Biology of Amyotrophic Lateral Sclerosis (ALS)). [ PMC free article : PMC3605887 ] [ PubMed : 22482452 ]
• Richards BL, Whittle SL, Van Der Heijde DM, Buchbinder R. Efficacy and safety of neuromodulators in inflammatory arthritis: A Cochrane systematic review. Journal of Rheumatology. 2012; 39 (Suppl 90):28–33. [ PubMed : 22942326 ]
• Rocha FCM, dos Santos JG Jr., Stefano SC, da Silveira DX. Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. Journal of Neuro-Oncology. 2014; 116 (1):11–24. [ PubMed : 24142199 ]
• Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and epilepsy. Neurotherapeutics. 2015; 12 (4):747–768. [ PMC free article : PMC4604191 ] [ PubMed : 26282273 ]
• Rossi S, Bernardi G, Centonze D. The endocannabinoid system in the inflammatory and neurodegenerative processes of multiple sclerosis and of amyotrophic lateral sclerosis. Experimental Neurology. 2010; 224 (1):92–102. [ PubMed : 20353778 ]
• Russo EB, Guy GW, Robson PJ. Cannabis, pain, and sleep: Lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chemistry & Biodiversity. 2007; 4 (8):1729–1743. [ PubMed : 17712817 ]
• Sandyk R, Awerbuch G. Marijuana and Tourette's syndrome. Journal of Clinical Psychopharmacology. 1988; 8 :444–445. [ PubMed : 3235704 ]
• Sateia MJ. International classification of sleep disorders, third edition: Highlights and modifications. Chest. 2014; 146 (5):1387–1394. [ PubMed : 25367475 ]
• Schauer GL, King BA, Bunnell RE, Promoff G, McAfee TA. Toking, vaping, and eating for health or fun: Marijuana use patterns in adults, U.S., 2014. American Journal of Preventive Medicine. 2016; 50 (1):1–8. [ PubMed : 26277652 ]
• Shen M, Thayer SA. Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Molecular Pharmacology. 1998; 54 :459–462. [ PubMed : 9730904 ]
• Sieradzan KA, Fox SH, Hill M, Dick JPR, Crossman AR, Brotchie JM. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: A pilot study. Neurology. 2001; 57 (11):2108–2111. [ PubMed : 11739835 ]
• Smith LA, Azariah F, Lavender TCV, Stoner NS, Bettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database of Systematic Reviews. 2015;(11) CD009464. [ PMC free article : PMC6931414 ] [ PubMed : 26561338 ]
• Snedecor SJ, Sudharshan L, Cappelleri JC, Sadosky A, Desai P, Jalundhwala YJ, Botteman M. Systematic review and comparison of pharmacologic therapies for neuropathic pain associated with spinal cord injury. Journal of Pain Research. 2013; 6 :539–547. [ PMC free article : PMC3712802 ] [ PubMed : 23874121 ]
• Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko YD, Schnelle M, Reif M, Cerny T. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: A multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the cannabis-in-cachexia-study-group. Journal of Clinical Oncology. 2006; 24 (21):3394–3400. [ PubMed : 16849753 ]
• Timpone JG, Wright DJ, Li N, Egorin MJ, Enama ME, Mayers J, Galetto G. The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. AIDS Research and Human Retroviruses. 1997; 13 (4):305–315. [ PubMed : 9071430 ]
• Todaro B. Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting. Journal of the National Comprehensive Cancer Network. 2012; 10 (4):487–492. [ PubMed : 22491047 ]
• Tomida I, Azuara-Blanco A, House H, Flint M, Pertwee R, Robson P. Effect of sublingual application of cannabinoids on intraocular pressure: A pilot study. Journal of Glaucoma. 2007; 15 (5):349–353. [ PubMed : 16988594 ]
• Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, Nissenkorn A, Yosef OB, Hyman E, Granot D, Dor M, Lerman-Sagie T, Ben-Zeev B. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016; 35 :41–44. [ PubMed : 26800377 ]
• Uribe Roca M, Micheli F, Viotti R. Cannabis sativa and dystonia secondary to Wilson's disease. Movement Disorders. 2005; 20 (1):113–115. [ PubMed : 15390041 ]
• van den Elsen GAH, Ahmed AIA, Lammers M, Kramers C, Verkes RJ, van der Marck MA, Olde Rikkert MGM. Efficacy and safety of medical cannabinoids in older subjects: A systematic review. Ageing Research Reviews. 2014; 14 (1):56–64. [ PubMed : 24509411 ]
• van den Elsen GAH, Ahmed AIA, Verkes RJ, Kramers C, Feuth T, Rosenberg PB, van der Marck MA, Olde Rikkert MGM. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial. Neurology. 2015; 84 (23):2338–2346. [ PMC free article : PMC4464746 ] [ PubMed : 25972490 ]
• van Laere K, Casteels C, Dhollander I, Goffin K, Grachev L, Bormans G, Vandenberghe W. Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. Journal of Nuclear Medicine. 2010; 51 (9):1413–1417. [ PubMed : 20720046 ]
• Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease. International Journal of Geriatric Psychiatry. 1997; 12 (9):913–919. [ PubMed : 9309469 ]
• Wade DT, Collin C, Stott C, Duncombe P. Meta-analysis of the efficacy and safety of sativex (nabiximols) on spasticity in people with multiple sclerosis. Multiple Sclerosis. 2010; 16 (6):707–714. [ PubMed : 20558502 ]
• Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. Journal of Pain. 2015; 16 (7):616–627. [ PMC free article : PMC5152762 ] [ PubMed : 25843054 ]
• Walther S, Mahlberg R, Eichmann U, Kunz D. Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology. 2006; 185 (4):524–528. [ PubMed : 16521031 ]
• Weber M, Goldman B, Truniger S. Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: A randomised, double-blind crossover trial. Journal of Neurology, Neurosurgery & Psychiatry. 2010; 81 (10):1135–1140. [ PubMed : 20498181 ]
• Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for medical use: A systematic review and meta-analysis. Journal of the American Medical Association. 2015; 313 (24):2456–2473. [ PubMed : 26103030 ]
• Wilsey BL, Deutsch R, Samara E, Marcotte TD, Barnes AJ, Huestis MA, Le D. A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis. Journal of Pain Research. 2016; 9 :587–598. [ PMC free article : PMC5012851 ] [ PubMed : 27621666 ]
• Wong BS, Camilleri M, Eckert D, Carlson P, Ryks M, Burton D, Zinsmeister AR. Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea. Neurogastroenterology & Motility. 2012; 24 (4):358–e169. [ PMC free article : PMC3775711 ] [ PubMed : 22288893 ]
• Wright K, Rooney N, Feeney M, Tate J, Robertson D, Welham M, Ward S. Differential expression of cannabinoid receptors in the human colon: Cannabinoids promote epithelial wound healing. Gastroenterology. 2005; 129 (2):437–453. [ PubMed : 16083701 ]
• Zadikoff C, Wadia P, Miyasaki J, Char R, Lang A, So J, Fox S. Cannabinoid, CB1 agonists in cervical dystonia: Failure in a phase IIa randomized controlled trial. Basal Ganglia. 2011; 1 (2):91–95.
• Zajicek J, Hobart J, Slade A, Mattison P. Multiple sclerosis and extract of cannabis: Results of the MUSEC trial. Journal of Neurology, Neurosurgery & Psychiatry. 2012; 83 (11):1125–1132. [ PubMed : 22791906 ]

ClinicalTrials ​.gov : NCT02447198 , NCT02926859 .

ClinicalTrials ​.gov : NCT01361607 .

Due to the lack of recent, high-quality reviews, the committee has identified that a research gap exists concerning the effectiveness of cannabis or cannabinoids in treating cancer in general.

Glioma is a type of tumor that originates in the central nervous system (i.e., the brain or spine) and arises from glial cells.

Key issues that led to high ROB ratings were: high (n = 1) or unclear (n = 3) ROB for allocation concealment; unclear ROB (n = 3) for blinded outcome assessments; high (n = 1) or unclear (n = 1) ROB for randomization.

BID is an abbreviation for the Latin phrase bis in die , which means twice per day.

ClinicalTrials ​.gov : NCT02224560 , NCT02224690 , NCT02091375 , NCT02324673 .

The Dyskinesia Disability Scale is a 0–4 scale (absent to most severe) measuring the severity of dyskinesia ( Goetz et al., 1994 ).

The modified Rankin Scale is a clinical assessment tool commonly used to measure the degree of disability following a stroke. Outcome scores from the scale range from 0 (no symptoms) to 6 (death) ( Di Napoli et al., 2016, p. 249 ).

Prud'homme (2015) is often categorized as a systematic review; however, the committee determined that the review lacks certain key elements of a systematic review, including a clearly stated research question, independent and duplicate data abstraction efforts, an assessment of the research quality and risk of bias, and a quantitative summary.

ClinicalTrials ​.gov : NCT02102230 , NCT02874898 , NCT02517424 , NCT02759185 .

• Cite this Page National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington (DC): National Academies Press (US); 2017 Jan 12. 4, Therapeutic Effects of Cannabis and Cannabinoids.
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March 1, 2024

Is Marijuana Bad for Health? Here’s What We Know So Far

Marijuana’s health impacts—good and bad—are coming into focus

By Jesse Greenspan

Cappi Thompson/Getty Images

With decades of legal and social opprobrium fading fast, marijuana has become an extremely popular commercial product with more than 48 million users across the U.S. Health concerns, once exaggerated, now often seem to be downplayed or overlooked. For example, pregnant patients “often tell me they had no idea there's any risk,” says University of Utah obstetrician Torri Metz, lead author of a recent paper in the Journal of the American Medical Association on cannabis and adverse pregnancy outcomes.

Fortunately, legal reforms are also gradually making it easier to study marijuana's health effects by giving U.S. scientists more access to the drug and a wider population of users to study. Although much research remains in “early stages,” the number of studies has finally been increasing, says Tiffany Sanchez, an environmental health scientist at Columbia University. As new results accumulate, they offer a long-overdue update on what science really knows about the drug.

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In addition to minor side effects that many users joke about—such as short-term memory loss—recent studies have linked marijuana to adverse health outcomes involving the lungs, heart, brain and gonads. For example, heavy marijuana consumption seems to increase the risk of clogged arteries and heart failure , and it may impact male fertility . Smoking weed likewise can lead to chronic bronchitis and other respiratory ailments (although, unlike tobacco, it hasn't been definitively tied to lung cancer). And cannabis plants hyperaccumulate metal pollutants, such as lead, which Sanchez found can enter users' bloodstreams .

Developing adolescent brains, particularly those predisposed to mental illness, may be most at risk from overconsumption. Although psychiatric effects are hotly debated , studies suggest that heavy weed use exacerbates—or may trigger— schizophrenia , psychosis and depression in youths and that it affects behavior and academic performance. “From a safety viewpoint, young people should definitely stay away from it,” says University of Ottawa psychiatrist Marco Solmi, lead author of a recent review of cannabis and health in the British Medical Journal .

24 states have legalized recreational marijuana, with 38 allowing medical use

Moreover, the drug can cross over to fetuses during pregnancy. Several studies have linked it to low birth weights , and researchers suspect it raises the likelihood of neonatal intensive care unit admissions and stillbirths . Some cannabis dispensaries have advertised their products as a cure for morning sickness, but Metz emphasizes that safer alternatives exist.

Of course, many adults use marijuana responsibly for pleasure and relaxation. Unlike with, say, opioids, there's effectively zero risk of life-threatening overdose. Plus, “people get addicted with tobacco way faster,” says Columbia University epidemiologist Silvia Martins, who studies substance use and related laws.

Cannabis, and its derivatives, also may help alleviate pain—although some researchers contend that it performs little better than a placebo . It may also decrease chemotherapy-induced nausea, calm epileptic seizures , ease the symptoms of multiple sclerosis and serve as a sleep aid .

Recent studies have hinted that the drug might slightly reduce opioid dependency rates, although this, too, is disputed . There's some evidence that weed users tend to be more empathetic , and researchers found that elderly mice get a mental boost from the drug. Still, experts caution against self-medicating: “You should ask your doctor,” Solmi says.

Some of the recent research into marijuana is more lighthearted. One study, for instance, found that, just like people, nematode worms dosed with cannabis get the munchies .

Read our research on: Gun Policy | International Conflict | Election 2024

Regions & Countries

Most americans favor legalizing marijuana for medical, recreational use, legalizing recreational marijuana viewed as good for local economies; mixed views of impact on drug use, community safety.

Pew Research Center conducted this study to understand the public’s views about the legalization of marijuana in the United States. For this analysis, we surveyed 5,140 adults from Jan. 16 to Jan. 21, 2024. Everyone who took part in this survey is a member of the Center’s American Trends Panel (ATP), an online survey panel that is recruited through national, random sampling of residential addresses. This way nearly all U.S. adults have a chance of selection. The survey is weighted to be representative of the U.S. adult population by gender, race, ethnicity, partisan affiliation, education and other categories. Read more about the ATP’s methodology .

Here are the questions used for the report and its methodology .

As more states pass laws legalizing marijuana for recreational use , Americans continue to favor legalization of both medical and recreational use of the drug.

An overwhelming share of U.S. adults (88%) say marijuana should be legal for medical or recreational use.

Nearly six-in-ten Americans (57%) say that marijuana should be legal for medical and recreational purposes, while roughly a third (32%) say that marijuana should be legal for medical use only.

Just 11% of Americans say that the drug should not be legal at all.

Opinions about marijuana legalization have changed little over the past five years, according to the Pew Research Center survey, conducted Jan. 16-21, 2024, among 5,14o adults.

The impact of legalizing marijuana for recreational use

While a majority of Americans continue to say marijuana should be legal , there are varying views about the impacts of recreational legalization.

About half of Americans (52%) say that legalizing the recreational use of marijuana is good for local economies; just 17% think it is bad and 29% say it has no impact.

More adults also say legalizing marijuana for recreational use makes the criminal justice system more fair (42%) than less fair (18%); 38% say it has no impact.

However, Americans have mixed views on the impact of legalizing marijuana for recreational use on:

• Use of other drugs: About as many say it increases (29%) as say it decreases (27%) the use of other drugs, like heroin, fentanyl and cocaine (42% say it has no impact).
• Community safety: More Americans say legalizing recreational marijuana makes communities less safe (34%) than say it makes them safer (21%); 44% say it has no impact.

Partisan differences on impact of recreational use of marijuana

There are deep partisan divisions regarding the impact of marijuana legalization for recreational use.

Majorities of Democrats and Democratic-leaning independents say legalizing recreational marijuana is good for local economies (64% say this) and makes the criminal justice system fairer (58%).

Fewer Republicans and Republican leaners say legalization for recreational use has a positive effect on local economies (41%) and the criminal justice system (27%).

Republicans are more likely than Democrats to cite downsides from legalizing recreational marijuana:

• 42% of Republicans say it increases the use of other drugs, like heroin, fentanyl and cocaine, compared with just 17% of Democrats.
• 48% of Republicans say it makes communities less safe, more than double the share of Democrats (21%) who say this.

Demographic, partisan differences in views of marijuana legalization

Sizable age and partisan differences persist on the issue of marijuana legalization though small shares of adults across demographic groups are completely opposed to it.

Older adults are far less likely than younger adults to favor marijuana legalization.

This is particularly the case among adults ages 75 and older: 31% say marijuana should be legal for both medical and recreational use.

By comparison, half of adults between the ages of 65 and 74 say marijuana should be legal for medical and recreational use, and larger shares in younger age groups say the same.

Republicans continue to be less supportive than Democrats of legalizing marijuana for both legal and recreational use: 42% of Republicans favor legalizing marijuana for both purposes, compared with 72% of Democrats.

There continue to be ideological differences within each party:

• 34% of conservative Republicans say marijuana should be legal for medical and recreational use, compared with a 57% majority of moderate and liberal Republicans.
• 62% of conservative and moderate Democrats say marijuana should be legal for medical and recreational use, while an overwhelming majority of liberal Democrats (84%) say this.

Views of marijuana legalization vary by age within both parties

Along with differences by party and age, there are also age differences within each party on the issue.

A 57% majority of Republicans ages 18 to 29 favor making marijuana legal for medical and recreational use, compared with 52% among those ages 30 to 49 and much smaller shares of older Republicans.

Still, wide majorities of Republicans in all age groups favor legalizing marijuana at least for medical use. Among those ages 65 and older, just 20% say marijuana should not be legal even for medical purposes.

While majorities of Democrats across all age groups support legalizing marijuana for medical and recreational use, older Democrats are less likely to say this.

About half of Democrats ages 75 and older (53%) say marijuana should be legal for both purposes, but much larger shares of younger Democrats say the same (including 81% of Democrats ages 18 to 29). Still, only 7% of Democrats ages 65 and older think marijuana should not be legalized even for medical use, similar to the share of all other Democrats who say this.

Views of the effects of legalizing recreational marijuana among racial and ethnic groups

Substantial shares of Americans across racial and ethnic groups say when marijuana is legal for recreational use, it has a more positive than negative impact on the economy and criminal justice system.

About half of White (52%), Black (53%) and Hispanic (51%) adults say legalizing recreational marijuana is good for local economies. A slightly smaller share of Asian adults (46%) say the same.

Criminal justice

Across racial and ethnic groups, about four-in-ten say that recreational marijuana being legal makes the criminal justice system fairer, with smaller shares saying it would make it less fair.

However, there are wider racial differences on questions regarding the impact of recreational marijuana on the use of other drugs and the safety of communities.

Use of other drugs

Nearly half of Black adults (48%) say recreational marijuana legalization doesn’t have an effect on the use of drugs like heroin, fentanyl and cocaine. Another 32% in this group say it decreases the use of these drugs and 18% say it increases their use.

In contrast, Hispanic adults are slightly more likely to say legal marijuana increases the use of these other drugs (39%) than to say it decreases this use (30%); 29% say it has no impact.

Among White adults, the balance of opinion is mixed: 28% say marijuana legalization increases the use of other drugs and 25% say it decreases their use (45% say it has no impact). Views among Asian adults are also mixed, though a smaller share (31%) say legalization has no impact on the use of other drugs.

Community safety

Hispanic and Asian adults also are more likely to say marijuana’s legalization makes communities less safe: 41% of Hispanic adults and 46% of Asian adults say this, compared with 34% of White adults and 24% of Black adults.

Wide age gap on views of impact of legalizing recreational marijuana

Young Americans view the legalization of marijuana for recreational use in more positive terms compared with their older counterparts.

Clear majorities of adults under 30 say it is good for local economies (71%) and that it makes the criminal justice system fairer (59%).

By comparison, a third of Americans ages 65 and older say legalizing the recreational use of marijuana is good for local economies; about as many (32%) say it makes the criminal justice system more fair.

There also are sizable differences in opinion by age about how legalizing recreational marijuana affects the use of other drugs and the safety of communities.

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Table of contents, most americans now live in a legal marijuana state – and most have at least one dispensary in their county, 7 facts about americans and marijuana, americans overwhelmingly say marijuana should be legal for medical or recreational use, clear majorities of black americans favor marijuana legalization, easing of criminal penalties, religious americans are less likely to endorse legal marijuana for recreational use, most popular.

About Pew Research Center Pew Research Center is a nonpartisan fact tank that informs the public about the issues, attitudes and trends shaping the world. It conducts public opinion polling, demographic research, media content analysis and other empirical social science research. Pew Research Center does not take policy positions. It is a subsidiary of The Pew Charitable Trusts .

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An Open Comparative Study of the Effectiveness and Incomparable Study of the Immunogenicity and Safety of the Vaccine (CoviVac) for Adults Aged 60 Years and Older

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