medicinal research articles

Editor's Choice: How AI Will Enhance Imaging Access and Analysis

• Kidney Donor and Recipient Outcomes May 23, 2024 Original Investigation Hypertension and Kidney Function After Living Kidney Donation Amit X. Garg, MD, PhD; Jennifer B. Arnold, BSc; Meaghan S. Cuerden, PhD; et al Editorial Prospectively Examining Outcomes After Living Kidney Donation: Informing the Altruist Elizabeth C. Lorenz, MD; Wolfgang C. Winkelmayer, MD, MPH, ScD
• Original Investigation Kidney Transplant Outcomes From Deceased Donors Who Received Dialysis Yumeng Wen, MD, PhD; Sherry G. Mansour, MD, MSc; Nityasree Srialluri, MD, MS, MHS; et al Editorial Expanding the Overton Window in Deceased Kidney Donor Eligibility—Enough to Make a Difference? Xingxing S. Cheng, MD, MS; Colin R. Lenihan, MB BCh BAO, PhD
• Audio Outcomes After Living Kidney Donation Amit X. Garg, MD, PhD, and Elizabeth C. Lorenz, MD, with host JAMA Associate Editor Wolfgang C. Winkelmayer, MD, MPH, ScD

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Research articles

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma, epidural analgesia during labour and severe maternal morbidity, exposure to antibiotics during pregnancy or early infancy and risk of neurodevelopmental disorders, clinical and healthcare use outcomes after cessation of long term opioid treatment due to prescriber workforce exit, effect of the hpv vaccination programme on incidence of cervical cancer by socioeconomic deprivation in england, long acting progestogens vs combined oral contraceptive pill for preventing recurrence of endometriosis related pain, ultra-processed food consumption and all cause and cause specific mortality, comparative effectiveness of second line oral antidiabetic treatments among people with type 2 diabetes mellitus, efficacy of psilocybin for treating symptoms of depression, reverse total shoulder replacement versus anatomical total shoulder replacement for osteoarthritis, effect of combination treatment with glp-1 receptor agonists and sglt-2 inhibitors on incidence of cardiovascular and serious renal events, prenatal opioid exposure and risk of neuropsychiatric disorders in children, temporal trends in lifetime risks of atrial fibrillation and its complications, antipsychotic use in people with dementia, predicting the risks of kidney failure and death in adults with moderate to severe chronic kidney disease, impact of large scale, multicomponent intervention to reduce proton pump inhibitor overuse, esketamine after childbirth for mothers with prenatal depression, glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer, use of progestogens and the risk of intracranial meningioma, delirium and incident dementia in hospital patients, derivation and external validation of a simple risk score for predicting severe acute kidney injury after intravenous cisplatin, quality and safety of artificial intelligence generated health information, large language models and the generation of health disinformation, 25 year trends in cancer incidence and mortality among adults in the uk, cervical pessary versus vaginal progesterone in women with a singleton pregnancy, comparison of prior authorization across insurers, diagnostic accuracy of magnetically guided capsule endoscopy with a detachable string for detecting oesophagogastric varices in adults with cirrhosis, ultra-processed food exposure and adverse health outcomes, added benefit and revenues of oncology drugs approved by the ema, exposure to air pollution and hospital admission for cardiovascular diseases, short term exposure to low level ambient fine particulate matter and natural cause, cardiovascular, and respiratory morbidity, optimal timing of influenza vaccination in young children, effect of exercise for depression, association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes, duration of cpr and outcomes for adults with in-hospital cardiac arrest, clinical effectiveness of an online physical and mental health rehabilitation programme for post-covid-19 condition, atypia detected during breast screening and subsequent development of cancer, publishers’ and journals’ instructions to authors on use of generative ai in academic and scientific publishing, effectiveness of glp-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes, neurological development in children born moderately or late preterm, invasive breast cancer and breast cancer death after non-screen detected ductal carcinoma in situ, all cause and cause specific mortality in obsessive-compulsive disorder, acute rehabilitation following traumatic anterior shoulder dislocation, perinatal depression and risk of mortality, undisclosed financial conflicts of interest in dsm-5-tr, effect of risk mitigation guidance opioid and stimulant dispensations on mortality and acute care visits, update to living systematic review on sars-cov-2 positivity in offspring and timing of mother-to-child transmission, perinatal depression and its health impact, christmas 2023: common healthcare related instruments subjected to magnetic attraction study, using autoregressive integrated moving average models for time series analysis of observational data, demand for morning after pill following new year holiday, christmas 2023: christmas recipes from the great british bake off, effect of a doctor working during the festive period on population health: experiment using doctor who episodes, christmas 2023: analysis of barbie medical and science career dolls, christmas 2023: effect of chair placement on physicians’ behavior and patients’ satisfaction, management of chronic pain secondary to temporomandibular disorders, christmas 2023: projecting complete redaction of clinical trial protocols, christmas 2023: a drug target for erectile dysfunction to help improve fertility, sexual activity, and wellbeing, christmas 2023: efficacy of cola ingestion for oesophageal food bolus impaction, conservative management versus laparoscopic cholecystectomy in adults with gallstone disease, social media use and health risk behaviours in young people, untreated cervical intraepithelial neoplasia grade 2 and cervical cancer, air pollution deaths attributable to fossil fuels, implementation of a high sensitivity cardiac troponin i assay and risk of myocardial infarction or death at five years, covid-19 vaccine effectiveness against post-covid-19 condition, association between patient-surgeon gender concordance and mortality after surgery, intravascular imaging guided versus coronary angiography guided percutaneous coronary intervention, treatment of lower urinary tract symptoms in men in primary care using a conservative intervention, autism intervention meta-analysis of early childhood studies, effectiveness of the live zoster vaccine during the 10 years following vaccination, effects of a multimodal intervention in primary care to reduce second line antibiotic prescriptions for urinary tract infections in women, pyrotinib versus placebo in combination with trastuzumab and docetaxel in patients with her2 positive metastatic breast cancer, association of dcis size and margin status with risk of developing breast cancer post-treatment, racial differences in low value care among older patients in the us, pharmaceutical industry payments and delivery of low value cancer drugs, rosuvastatin versus atorvastatin in adults with coronary artery disease, clinical effectiveness of septoplasty versus medical management for nasal airways obstruction, ultrasound guided lavage with corticosteroid injection versus sham lavage with and without corticosteroid injection for calcific tendinopathy of shoulder, early versus delayed antihypertensive treatment in patients with acute ischaemic stroke, mortality risks associated with floods in 761 communities worldwide, interactive effects of ambient fine particulate matter and ozone on daily mortality in 372 cities, association between changes in carbohydrate intake and long term weight changes, future-case control crossover analysis for adjusting bias in case crossover studies, association between recently raised anticholinergic burden and risk of acute cardiovascular events, suboptimal gestational weight gain and neonatal outcomes in low and middle income countries: individual participant data meta-analysis, efficacy and safety of an inactivated virus-particle vaccine for sars-cov-2, effect of invitation letter in language of origin on screening attendance: randomised controlled trial in breastscreen norway, visits by nurse practitioners and physician assistants in the usa, non-erosive gastro-oesophageal reflux disease and oesophageal adenocarcinoma, venous thromboembolism with use of hormonal contraception and nsaids, food additive emulsifiers and risk of cardiovascular disease, balancing risks and benefits of cannabis use, promoting activity, independence, and stability in early dementia and mild cognitive impairment, effect of home cook interventions for salt reduction in china, cancer mortality after low dose exposure to ionising radiation, effect of a smartphone intervention among university students with unhealthy alcohol use, long term risk of death and readmission after hospital admission with covid-19 among older adults, mortality rates among patients successfully treated for hepatitis c, association between antenatal corticosteroids and risk of serious infection in children, follow us on, content links.

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Page 1 of 87

Associations of prenatal blood pressure trajectory and variability with child neurodevelopment at 2 years old

The patterns of blood pressure (BP) change throughout the pregnancy were related to adverse birth outcomes. However, little is known about the long-term effect of BP change patterns on child neurodevelopment. ...

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Clustering care pathways of people with alcohol dependence using a data linkage of routine data in Bremen, Germany

Although many individuals with alcohol dependence (AD) are recognized in the German healthcare system, only a few utilize addiction-specific treatment services. Those who enter treatment are not well character...

Comparison of children and adults in deep brain stimulation for Tourette Syndrome: a large-scale multicenter study of 102 cases with long-term follow-up

Deep brain stimulation (DBS) is a promising therapy for refractory Gilles de la Tourette syndrome (GTS). However, its long-term efficacy, safety, and recommended surgical age remain controversial, requiring ev...

Personalized therapy in endometriosis — based on ERα or ERβ expression

The original article was published in BMC Medicine 2023 21 :460

Specification curve analysis to identify heterogeneity in risk factors for dementia: findings from the UK Biobank

In 2020, the Lancet Commission identified 12 risk factors as priorities for prevention of dementia, and other studies identified APOE e4/e4 genotype and family history of Alzheimer’s disease strongly associated w...

The efficacy and safety of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor, in patients with advanced head and neck mucosal melanoma harboring CDK4 amplification

Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HN...

Diabetes and further risk of cancer: a nationwide population-based study

Individuals with diabetes have a significantly higher risk of developing various forms of cancer, and the potential biological links between these two diseases are not completely understood.

Associations between vaping and self-reported respiratory symptoms in young people in Canada, England and the US

Prevalence of youth nicotine vaping has increased, heightening concerns around negative health effects. This study aimed to compare self-reported respiratory symptoms among youth by vaping behaviours.

Information technology-supported integrated health service for older adults in long-term care settings

To examine the effectiveness and safety of a data sharing and comprehensive management platform for institutionalized older patients.

The impact of major depressive disorder on glycaemic control in type 2 diabetes: a longitudinal cohort study using UK Biobank primary care records

This study evaluates longitudinal associations between glycaemic control, measured by mean and within-patient variability of glycated haemaglobin (HbA1c) levels, and major depressive disorder (MDD) in individu...

Healthy lifestyle change and all-cause and cancer mortality in the European Prospective Investigation into Cancer and Nutrition cohort

Healthy lifestyles are inversely associated with the risk of noncommunicable diseases, which are leading causes of death. However, few studies have used longitudinal data to assess the impact of changing lifes...

Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study

TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in p...

Association of heavy menstrual bleeding with cardiovascular disease in US female hospitalizations

Heavy menstrual bleeding (HMB) is a common menstrual disorder associated with multiple risk factors of cardiovascular disease (CVD) in women. In addition, HMB is often present with irregular menstruation (IM) ...

IL-2-free tumor-infiltrating lymphocyte therapy with PD-1 blockade demonstrates potent efficacy in advanced gynecologic cancer

Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinica...

ABO and Rhesus blood groups and multiple health outcomes: an umbrella review of systematic reviews with meta-analyses of observational studies

Numerous studies have been conducted to investigate the relationship between ABO and Rhesus (Rh) blood groups and various health outcomes. However, a comprehensive evaluation of the robustness of these associa...

Effectiveness of genetic feedback on alcohol metabolism to reduce alcohol consumption in young adults: an open-label randomized controlled trial

It is unclear whether brief interventions using the combined classification of alcohol-metabolizing enzymes aldehyde dehydrogenase 2 ( ALDH2 ) and alcohol dehydrogenase 1B ( ADH1B ) together with behavioral changes i...

Ruxolitinib plus standard of care in severe hospitalized adults with severe fever with thrombocytopenia syndrome (SFTS): an exploratory, single-arm trial

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease, and its morbidity and mortality are increasing. At present, there is no specific therapy available. An exacerbat...

Association between being large for gestational age and cardiovascular metabolic health in children conceived from assisted reproductive technology: a prospective cohort study

To the best of our knowledge, no study has investigated the potential joint effect of large for gestational age (LGA) and assisted reproductive technology (ART) on the long-term health of children.

Learning from sotorasib: risk of bias in confirmatory clinical studies of accelerated approved drugs and resolution strategies

Association of genetic variants related to combined lipid-lowering and antihypertensive therapies with risk of cardiovascular disease: 2 × 2 factorial mendelian randomization analyses.

Lipid-lowering drugs and antihypertensive drugs are commonly combined for cardiovascular disease (CVD). However, the relationship of combined medications with CVD remains controversial. We aimed to explore the...

Single-cell and spatial transcriptomics reveal metastasis mechanism and microenvironment remodeling of lymph node in osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor and is highly prone to metastasis. OS can metastasize to the lymph node (LN) through the lymphatics, and the metastasis of tumor cells reestabl...

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer

The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients ...

Learning together for better health using an evidence-based Learning Health System framework: a case study in stroke

In the context of expanding digital health tools, the health system is ready for Learning Health System (LHS) models. These models, with proper governance and stakeholder engagement, enable the integration of ...

Rethinking causal assumptions about maternal BMI, gestational weight gain, and adverse pregnancy outcomes

The aim of this study was to evaluate commonly assumed causal relationships between body mass index (BMI), gestational weight gain (GWG), and adverse pregnancy outcomes, which have formed the basis of guidelin...

Impact of mHealth interventions on maternal, newborn, and child health from conception to 24 months postpartum in low- and middle-income countries: a systematic review

Mobile health (mHealth) technologies have been harnessed in low- and middle-income countries (LMICs) to address the intricate challenges confronting maternal, newborn, and child health (MNCH). This review aspi...

Prevalence of diabetic cardiomyopathy in patients with type 2 diabetes in a large academic medical center

Diabetic cardiomyopathy (DbCM) is characterized by asymptomatic stage B heart failure (SBHF) caused by diabetes-related metabolic alterations. DbCM is associated with an increased risk of progression to overt ...

Modifiable lifestyle factors and lifetime risk of atrial fibrillation: longitudinal data from the Korea NHIS-HealS and UK Biobank cohorts

The reason for higher incidence of atrial fibrillation (AF) in Europe compared with East Asia is unclear. We aimed to investigate the association between modifiable lifestyle factors and lifetime risk of AF in...

Deprescribing of antidepressants: development of indicators of high-risk and overprescribing using the RAND/UCLA Appropriateness Method

Antidepressants are first-line medications for many psychiatric disorders. However, their widespread long-term use in some indications (e.g., mild depression and insomnia) is concerning. Particularly in older ...

Peripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank

Peripheral glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are sensitive markers of neuroinflammation and neuronal damage. Previous studies with highly selected participants have sho...

The Healthy Start scheme in England “is a lifeline for families but many are missing out”: a rapid qualitative analysis

Healthy Start (HS) is a government scheme in England, Wales and Northern Ireland that offers a financial payment card and free vitamins to families experiencing low income. Pregnant women and families with chi...

Supplementation with selenium and coenzyme Q 10 in an elderly Swedish population low in selenium — positive effects on thyroid hormones, cardiovascular mortality, and quality of life

Selenium-dependent deiodinases play a central role in thyroid hormone regulation and metabolism. In many European countries, insufficient selenium intake may consequently lead to adverse effects on thyroid fun...

A proposed simplified definition of metabolic syndrome in children and adolescents: a global perspective

Metabolic syndrome (MetS) is becoming prevalent in the pediatric population. The existing pediatric MetS definitions (e.g., the International Diabetes Federation (IDF) definition and the modified National Chol...

Glucose competition between endothelial cells in the blood-spinal cord barrier and infiltrating regulatory T cells is linked to sleep restriction-induced hyperalgesia

Sleep loss is a common public health problem that causes hyperalgesia, especially that after surgery, which reduces the quality of life seriously.

Floods and cause-specific mortality in the UK: a nested case-control study

Floods are the most frequent weather-related disaster, causing significant health impacts worldwide. Limited studies have examined the long-term consequences of flooding exposure.

Histology-specific standardized incidence ratio improves the estimation of second primary lung cancer risk

Lung cancer (LC) survivors are at increased risk for developing a second primary cancer (SPC) compared to the general population. While this risk is particularly high for smoking-related SPCs, the published st...

Driving delivery and uptake of catch-up vaccination among adolescent and adult migrants in UK general practice: a mixed methods pilot study

Migrants in the UK and Europe face vulnerability to vaccine-preventable diseases (VPDs) due to missed childhood vaccines and doses and marginalisation from health systems. Ensuring migrants receive catch-up va...

A randomized controlled trial of an app-based intervention on physical activity and glycemic control in people with type 2 diabetes

We investigated the effects of a physical activity encouragement intervention based on a smartphone personal health record (PHR) application (app) on step count increases, glycemic control, and body weight in ...

The effectiveness of a standardized tobacco cessation program on psychophysiological parameters in patients with addiction undergoing long-term rehabilitation: a quasi-experimental pilot study

Although there is a very high comorbidity between tobacco dependence and other addictive disorders, there are only few studies examining the implementation and outcomes of a tobacco cessation program in patien...

Toward evidence-based communication on overweight body mass index and mortality

Reducing overweight and obesity has been a longstanding focus of public health messaging and physician–patient interactions. Clinical guidelines by major public health organizations describe both overweight an...

Colon impairments and inflammation driven by an altered gut microbiota leads to social behavior deficits rescued by hyaluronic acid and celecoxib

The exact mechanisms linking the gut microbiota and social behavior are still under investigation. We aimed to explore the role of the gut microbiota in shaping social behavior deficits using selectively bred ...

First-trimester fetal size, accelerated growth in utero, and child neurodevelopment in a cohort study

Early pregnancy is a critical window for neural system programming; however, the association of first-trimester fetal size with children’s neurodevelopment remains to be assessed. This study aimed to explore t...

Suicide mortality following the implementation of tobacco packaging and pricing policies in Korea: an interrupted time-series analysis

To prevent tobacco use in Korea, the national quitline number was added to tobacco packages in December 2012, tobacco prices were raised by 80% in January 2015, and graphic health warning labels were placed on...

Correction: Identification of a novel bile marker clusterin and a public online prediction platform based on deep learning for cholangiocarcinoma

The original article was published in BMC Medicine 2023 21 :294

Correction: Autotaxin inhibition attenuates the aortic valve calcification by suppressing inflammation-driven fibro-calcific remodeling of valvular interstitial cells

The original article was published in BMC Medicine 2024 22 :122

Mini-dose methotrexate combined with methylprednisolone for the initial treatment of acute GVHD: a multicentre, randomized trial

There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cel...

Long-term assessment of the NHS hybrid closed-loop real-world study on glycaemic outcomes, time-in-range, and quality of life in children and young people with type 1 diabetes

Hybrid closed-loop (HCL) systems seamlessly interface continuous glucose monitoring (CGM) with insulin pumps, employing specialised algorithms and user-initiated automated insulin delivery. This study aimed to...

Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer

Osimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the inter...

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial

Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety ...

Impact of perioperative low-molecular-weight heparin therapy on clinical events of elderly patients with prior coronary stents implanted > 12 months undergoing non-cardiac surgery: a randomized, placebo-controlled trial

Little is known about the safety and efficacy of discontinuing antiplatelet therapy via LMWH bridging therapy in elderly patients with coronary stents implanted for > 12 months undergoing non-cardiac surgery. ...

A Pfs48/45-based vaccine to block Plasmodium falciparum transmission: phase 1, open-label, clinical trial

The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines. Transmission-blocking vaccines aim to induce human antibod...

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Design and synthesis of novel factor XIa Inhibitors with bicyclic isoquinoline and naphthalene fragments

A study of alkene disulfonoxylation

• Shyam Sathyamoorthi
• Steven P. Kelley

Exploring nucleoside analogs: key targets in the viral life cycle - advancing strategies against SARS-CoV-2

• Roopal Garg
• Raveen Kumar
• Richa Srivastava

Design and synthesis of benzo[ d ]imidazo-6,7-dihydrobenzo[ d ] imidazo[2,1- b ]thiazol-8(5 H )-ones as potent anti-infective agents

• Rakesh K. Bollikanda
• Yana L. Esaulkova
• Srinivas Kantevari

Design and synthesis of indole-based elipticine analogues as topoisomerase IIβ inhibitors

• Mardia T. El Sayed
• Alaadin E. Sarhan
• Mamdouh M. Ali

Discovery of cytotoxic truncated vitamin D derivatives against both bortezomib‐sensitive and bortezomib‐resistant multiple myeloma phenotypes

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• Mikako Fujita

Correction: Bioassay-guided fractionations of Cannabis sativa extract and HPLC-assisted purifications of anti-proliferative active fractions lead to the isolation of 16 known and one new phytomolecule and their in-silico analysis

• Yedukondalu Nalli
• Sahil Bharti
• Mahendra Kumar Verma

Structural simplification and ester bond flipping lead to bis-benzodioxole derivatives as potential hypolipidemic and hepatoprotective agent

• Yundong Xie

Morpholinated curcuminoids against urinary bladder cancer cells: synthesis and anticancer evaluation

• Pawel Bakun
• Malgorzata Kucinska
• Tomasz Goslinski

Synthesis and in vitro biological activity of chalcone derivatives as potential antiparasitic agents

• Koketso J. Setshedi
• Richard M. Beteck
• Lesetja J. Legoabe

Discovery of HNPC-A188: a novel acaricide containing trifluoroethyl thioether and pyrimidin-4-amine

• Weidong Liu

The emergence of sulfo-click amidation in kinetic target-guided synthesis

• Prakash T. Parvatkar
• Roman Manetsch

Development of semisynthetic saponin immunostimulants

• Hyunjung Kim
• Pengfei Wang

A very promising antibiofilm activity against Candida albicans from an in vitro screening for antimicrobial, antibiofilm and antiproliferative activity of new synthesized 4-cinnamamido- and 2-phenoxyacedamido-1H-pyrazol-5-yl)benzamides

• Fabiana Plescia
• Valentina Catania
• Domenico Schillaci

Candida albicans ergosterol disorders as a consequence of the new sulfone derivative action mode

• Monika Staniszewska
• Michalina Kazek
• Zbigniew Ochal

Naturally occurring and artificially designed antimicrobial peptides: a comparative study of Mastoparan C and BP52

• Hai Bui Thi Phuong
• Huy Luong Xuan

Recent pharmacological insights about imidazole hybrids: a comprehensive review

• Samet Poyraz
• Metin Yıldırım
• Mehmet Ersatir

Synthesis of novel benzothieno-[3,2’- f ][1,3] oxazepines and their isomeric 2-oxo-2 H -spiro[benzothiophene-3,3’-pyrrolines] via 1,4-dipolar cycloaddition reaction and their evaluation as cytotoxic anticancer leads

• Mohammed M. Al-Mahadeen
• Areej M. Jaber
• Mutasem O. Taha

Folate-conjugated organic CO prodrugs: Synthesis and CO release kinetic studies

• Shameer M. Kondengadan
• Shubham Bansal
• Binghe Wang

Structure-activity relationships and pharmacokinetic evaluation of L-cystine diamides as L-cystine crystallization inhibitors for cystinuria

• Haifa Albanyan
• Amrik Sahota

Molecular hybridization method for obtaining paeonol-based fibrate derivatives with potent lipid-lowering and hepatoprotective activity

Role of natural secondary metabolites as HIF-1 inhibitors in cancer therapy

• Prem Shankar Mishra
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• Samiksha Dewangan

Characterization of the CO release properties of a common CO donor, CORM-401, in the context of its application in studying CO biology

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Antitumor studies on celastrol and its derivatives as RORα agonists and RORγ inhibitors based on Alphafold reverse docking strategy

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Scientists develop visual tool to help people group foods based on their levels of processing

Fralin Biomedical Research Institute at VTC scientists studying ultra-processed foods have created a new tool for assessing the rewarding and reinforcing properties of foods that make up 58 percent of calories consumed in the United States. The foods have been linked to a wide range of negative health outcomes.

The research, which was published in April in the journal Appetite , provides a collection of carefully curated images of minimally processed and ultra-processed foods matched on 26 characteristics, including macronutrients, sodium, dietary fiber, calories, price, and visual characteristics such as a color and portion size.

The work was based on the NOVA classification system -- "nova" means new in Portuguese -- which groups foods into four categories based on their level of processing. Nutrition researchers at the University of São Paulo in Brazil developed the scale while studying the country's sharp increase in obesity rates.

The scale has its detractors.

"A major criticism of the NOVA scale is that it's difficult to use or that foods are classified differently by different people," said Alexandra DiFeliceantonio, corresponding author and assistant professor at the Fralin Biomedical Research Institute. "We found that people with education in nutrition generally agreed on the food classifications, providing some data that it might not be a valid criticism."

What they did

The NOVA system assigns food to four categories: unprocessed or minimally processed, such as fresh fruit, legumes, or plain yogurt; processed culinary ingredients, such as cooking oils, butter, and salt; processed foods, which combine the two above through simple methods suc as cheese, canned vegetables, or freshly baked bread; and ultra-processed foods, such as soft drinks, flavored yogurt, processed meat, and most packaged breads, made through industrial processing and additives rarely found in a home pantry.

To develop the picture set, a team of psychologists, neuroscientists, and registered dietitians selected foods to represent either minimally processed or ultra-processed foods.

The foods were prepared in a lab, visually represented through professional photography, and controlled for consistency. Researchers also gathered price, food weights, and nutritional information -- calories, macronutrients, sodium, and dietary fiber -- for the food in each image.

Study participants rated images across a range of qualities to generate a final set of 28 pictures matched across 26 characteristics. To objectively measure NOVA classification, researchers recruited 67 nutrition professionals and asked them to classify the foods as minimally or ultra-processed.

"With this food picture set we can start to infer that any differences between food pictures is due to the degree of food processing, and not all these other factors that we know are potentially impactful," said Zach Hutelin, the study's lead author and a Fralin Biomedical Research Institute-based graduate student in the translational biology, medicine and health Ph.D. program.

Why this matters

Ultra-processed foods are linked with increased risk of developing obesity, Type 2 diabetes, heart disease, and cancer. They represent more than half of calories consumed in the United States, Canada, and the United Kingdom and have been identified as a global threat to public health.

"There is very little experimental research on ultra-processed foods, and part of what's been holding us back is better tools for measuring and assessing their effects," said DiFeliceantonio, who is also associate director of the Fralin Biomedical Research Institute's Center for Health Behaviors Research. "The more tools we can provide, the more we can learn."

The Virginia Tech team is making the pictures and associated data accessible through the Virginia Tech Data Repository of the Virginia Tech University Libraries. This will allow scientists to test hypotheses in behavioral economic and neuroimaging studies.

In the DiFeliceantonio lab, the photos are being used with functional MRI to reveal associated brain activity, with the images isolating the effects of food processing from other characteristics.

The study was funded by a National Science Foundation graduate research fellowship, the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and a grant from the Seale Innovation Fund, which supports innovative pilot research projects at the Fralin Biomedical Research Institute. DiFeliceantonio received a grant from the fund to investigate metabolic, neural, and behavioral data to better understand how our brains process nutrient availability and food preference.

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Materials provided by Virginia Tech . Original written by Leigh Anne Kelley. Note: Content may be edited for style and length.

Journal Reference :

• Zach Hutelin, Monica Ahrens, Mary Elizabeth Baugh, Mary E. Oster, Alexandra L. Hanlon, Alexandra G. DiFeliceantonio. Creation and validation of a NOVA scored picture set to evaluate ultra-processed foods. . Appetite , 2024; 198: 107358 DOI: 10.1016/j.appet.2024.107358

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Plastic junk? Researchers find tiny particles in men's testicles

Researchers have detected microplastics in human testicles. Volodymyr Zakharov/Getty Images hide caption

Researchers have detected microplastics in human testicles.

Whether it's our bloodstream, brain, or lungs, microscopic fragments of plastic seem to turn up every time scientists scour a new corner of the human body.

The male reproductive organs are no exception.

New research published this month finds microplastics can build up in the testicles of humans and dogs — raising more questions about the potential health impacts of these particles.

Animal studies have shown exposure to microplastics can impact sperm quality and male fertility, but scientists are still in the early stages of translating this work to human health.

"Microplastics are everywhere," says Dr. John Yu , a toxicologist in the College of Nursing at the University of New Mexico and lead author of the study. "The quantification of those microplastics in humans is the first step to understanding its potential adverse effects."

For the first time, researchers find microplastics deep in the lungs of living people

When he set out to do the study, Yu didn't expect microplastics would have penetrated the male reproductive system so extensively, given the tight blood-tissue barrier around those organs. To his surprise, the research team unearthed a wide range and heavy concentration of microplastics in the testicles of about two dozen men and close to 50 dogs.

The results may also be relevant to a well-documented global decline in sperm count and other problems related to male fertility. This trend has been linked to a host of environmental and lifestyle factors, including certain endocrine-disrupting chemicals found in plastics.

The growing numbers of studies like this one are "compelling and should be a wake up call for policymakers," says Tracey Woodruff , director of the Environmental Research and Translation for Health Center at the University of California, San Francisco.

How much and what kind of plastics were in the testicles?

This is the largest study to measure how much of these microplastics that permeate the water, food and even air end up in the most intimate recesses of male reproductive anatomy.

It follows a smaller analysis, published last year by a team in China, that detected microplastics in about half a dozen human testicles and in semen.

For the current study, researchers at the University of New Mexico collected the testicles from autopsies of people ranging in age from 16 to 88 and from nearly 50 dogs after they were neutered at local veterinary clinics.

Dogs can function as "sentinel" animals for disease and harmful chemical exposure because they're so embedded in the human environment, plus canine spermatogenesis is more similar to the human process of producing sperm than lab rats, says Yu.

Researchers find a massive number of plastic particles in bottled water

Instead of trying to count each microplastic particle, the researchers were able to quantify the total amount of plastic by dissolving all the biological tissue and separating out the solids.

About 75% of what remained was plastic.

Polyethylene , or PE, made up a large portion of that. It's the most widely used plastic in the world, showing up in packaging, bags and any number of products.

Matthew Campen , who has examined these tiny particles up close, describes them as "shard-like, stabby bits" because of the way they've become "old and brittle and fragmented."

"What they do in the body, we don't know," says Campen, a professor at the UNM College of Pharmacy and one of the authors of the study, "Obviously, little tiny particles can disrupt the way cells behave."

Polyvinyl chloride — what's in PVC piping — emerged as another prominent culprit and was the second most common in the dog testicles. Vinyl chloride is classified as a carcinogen and long-term exposure, for example in drinking water, can increase the risk of cancer.

What's more, Yu and his team found a correlation between lower sperm count in the dog testicles and the presence of PVC (the analysis couldn't be done on the human samples because of how they had been stored).

There was also an association between greater levels of PVC and decreased weight of the testicles. The same was seen with Polyethylene terephthalate , or PET, another common source of plastic, which recent research suggests may be harmful.

Woodruff says weight is a somewhat "crude" marker for the effects on testicular health, although it's frequently used by regulatory agencies to evaluate the impacts of chemicals.

Implications?

The research comes with many caveats and cannot prove microplastics directly cause problems with male fertility. Nonetheless, Yu says the results are "concerning" and lay the foundation for more targeted studies on the "relationship between microplastic exposure and its potential impact on sperm."

An emerging body of evidence suggests microplastics can have toxic effects on reproductive health .

In a 2022 review of the evidence for the state of California, Woodruff and her colleagues concluded that microplastics were "suspected" to harm sperm quality and testicular health, but she says that may soon tip over from "suspected" to "likely" because more high-quality studies are being published.

"In the history of looking at chemical or environmental health issues, at the beginning you see these indicators of health harms and then those that have some type of evidence behind them just tend to grow," says Woodruff, "I anticipate we're just going to see more health harms from these microplastics."

In the University of New Mexico study, the concentration of microplastics in human testicles was on average three times higher than in dogs.

Campen says there are still many unknowns, like what specific concentration would pose a threat to health, or how that might vary depending on the kind of microplastic or where they accumulate in the body.

"We're just at the tip of the iceberg," says Campen, who has used this same technique to quantify the levels of microplastics in other tissues and organs.

The amount in the testicles is considerably higher than what was discovered in placenta, and second to what they observed in the brain, says Yu.

Exactly how the microplastics are making their way into the testicles requires further study. Campen suspects they could be "hitchhiking" through the gut via tiny fat particles that get metabolized and then fan out across the body.

It's plausible the build-up of microplastics in the testicles could affect reproductive health in any number of ways. Yu says microplastics could physically disrupt spermatogenesis, mess with the barrier between the testicles, or be a vehicle for harmful chemicals.

They could lead to inflammation and cause oxidative stress, which down the road might affect fertility, says Dr. Sarah Krzastek , a urologist at Virginia Commonwealth University.

"It's probably one more piece of the puzzle of things that are contributing to declines in male fertility over the years as these environmental exposures keep accumulating," she says, "We don't know the clinical ramifications of that yet."

Richard Lea , a reproductive biologist at the University of Nottingham, calls the findings "alarming."

"Having something unnatural like that in the testes is not particularly good news for good reproductive health," says Lea.

In his lab, Lea has found that exposure to phthalates , which are chemicals that can leach from plastics, can reduce the ability of sperm to swim and increase the fragmentation of DNA in the sperm head. This is one likely contributor to the decline in sperm quality in household dogs over the last several decades, a trend that mirrors what's seen in humans.

Of course, the testicles are just one part of the male reproductive system.

Lea says there's now research showing these chemical contaminants can affect the hormonal control of reproduction, at different levels in the body, including in the brain.

How to study a substance that is ubiquitous

Dr. Shanna Swan , a reproductive epidemiologist who has documented the global decline in sperm count, says she's concerned about the accumulation of microplastics. But it's not yet clear finding them in the testicles rather than other parts of the body is more worrisome from the standpoint of reproductive health.

For example in her work, she's looked at how prenatal exposure to endocrine-disrupting chemicals like phthalates can affect male reproductive function and "lead to lifetime of reproductive damage."

Swan says a limitation running through many of the recent studies on microplastics is that the samples may be inadvertently exposed to microplastics in the environment and that leads to skewed impressions of what was actually present in the person.

She notes there were similar quality control issues nearly a quarter century ago when scientists first started measuring phthalates in human tissues.

"I think there have to be a lot of caveats saying this is really the beginning," says Swan, a professor at the Icahn School of Medicine at Mount Sinai, "It's suggestive, it's important, and it's preliminary."

The University of New Mexico researchers developed a quality control process to protect the samples from being accidentally exposed to microplastics as much as possible. Campen says there's so much plastic in the human body, the amount that might contaminate the samples is "trivial."

More broadly, though, he acknowledges the field faces some huge challenges moving forward — especially as they try to draw a stronger link between these tiny particles and a decline in reproductive health or disease.

"A lot of the problem is they're so ubiquitous. There are no proper controls anymore. Right? Everybody's exposed," he says.

• men's reproductive health
• plastic pollution
• microplastics
• reproductive health
• endocrine disrupters

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2024 Top Research Awards Announced

Yale School of Public Health (YSPH) Associate Dean of Research Melinda Irwin Wednesday announced the recipients of this year’s top research awards.

“Congratulations to the YSPH faculty who were awarded YSPH Research Prizes for manuscripts published in 2023,” said Irwin, Susan Dwight Bliss Professor of Epidemiology (Chronic Diseases). “YSPH faculty published more than 1,100 papers in 2023, and these six papers were recognized for their novel approaches and significant findings, focused on critically important public health issues (e.g., opioid use disorder, environmental carcinogens, breastfeeding) using novel methods and approaches such as electronic medical record data of health outcomes linked to residential addresses’ drinking water supplies and incubating colorectal cancer organoids with PFAS resulting in expression of metastasis-related proteins. “

Here is a list of this year’s award winners:

YSPH Early Career Investigator Research Prize

Liew, Z., Meng, Q., Yan, Q., Schullehner, J., Hansen, B., Kristiansen, S. M., Voutchkova, D. D., Olsen, J., Ersbøll, A. K., Ketzel, M., Raaschou-Nielsen, O., & Ritz, B. R. (2023). Association Between Estimated Geocoded Residential Maternal Exposure to Lithium in Drinking Water and Risk for Autism Spectrum Disorder in Offspring in Denmark. JAMA Pediatrics .

Dr. Liew and his team conducted a nationwide nested case-control study using medical records to capture ASD diagnoses in Denmark, and then created a model to estimate lithium levels in drinking water supplies linked to every residential address in Denmark. They are the first to report a novel association between maternal exposure to lithium in drinking water and child ASD. The study findings have been widely reported in the media, including the New York Times, CNN, and NBC.

YSPH Investigator Research Prize

Yize Zhao, Changgee Chang, Jingwen Zhang & Zhengwu Zhang. Genetic Underpinnings of Brain Structural Connectome for Young Adults . Journal of the American Statistical Association .

With the primary goal of her paper to uncover genetic underpinnings to brain structural connectome variations among young adult populations, Dr. Zhao developed an innovative Bayesian analytical framework and identified genetic biomarkers and validated the reliability of these scientific findings with an external database. The developed methods are readily applicable for use in biobanks and brain imaging genetic landmark studies, which offers a great potential for understanding the genetic bases and directing intervention targets for neurological and psychiatric research for public health outcomes.

YSPH Team Science Prize

Robert Heimer and Lauretta Grau from YSPH

Receipt of opioid use disorder treatments prior to fatal overdoses and comparison to no treatment in Connecticut, 2016–17 . Heimer R, Black AC, Lin H, Grau LE, Fiellin DA, Howell BA, Hawk K, D’Onofrio G, Becker WC. Drug and Alcohol Dependence .

Dr. Heimer and team compiled and merged state agency data on opioid overdose deaths and exposures to opioid use disorder treatment to determine incidence rates following exposure to different treatment modalities. Exposure to treatment reduced the relative risk by 38% compared to non-medication treatment. These findings have been presented to statewide advisory boards, and in February Dr. Heimer presented the results at the federal level to an interagency group convened by the Office of National Drug Control Policy, with the goal of expanding access to OUD treatment.

Caroline Johnson and other YSPH faculty members Krystal Pollitt and Lingeng Lu

Zheng, J., Sun, B., Berardi, D., Lu, L., Yan, H., Zheng, S., Aladelokun, O., Xie, Y., Cai, Y., Godri Pollitt, K. J., Khan, S. A., & Johnson, C. H. (2023). Perfluorooctanesulfonic Acid and Perfluorooctanoic Acid Promote Migration of Three-Dimensional Colorectal Cancer Spheroids . Environmental Science & Technology .

PFAS are widespread environmental contaminants that accumulate in the environment and body, and are found in man-made products such as cosmetics, cookware, food packaging, and carpets. Even though PFAS have been linked to cancer, and recently classified as Group 1 carcinogens, there has been limited research on the effects of these chemicals in colorectal cancer (CRC). Dr. Caroline Johnson and her team found that when CRC human organoids are incubated with occupational exposure levels of PFOS, they exhibit increased motility and expression of metastasis-related proteins. Their study was the first to show that PFAS can elicit a metastatic phenotype in CRC cells when PFAS were at levels comparable to those seen in the blood of those occupationally exposed, such as firefighters.

YSPH Impact Research Prize

Rafael Pérez-Escamilla

Rafael Pérez-Escamilla, Cecília Tomori, Sonia Hernández-Cordero, Phillip Baker, Aluisio J D Barros, France Bégin, Donna J Chapman, Laurence M Grummer-Strawn, David McCoy, Purnima Menon, Paulo Augusto Ribeiro Neves, Ellen Piwoz, Nigel Rollins, Cesar G Victora, Linda Richter, on behalf of the 2023 Lancet Breastfeeding Series Group* Breastfeeding: crucially important, but increasingly challenged in a market-driven world . Lancet .

This article has been cited over 140 times since it was published in February 2023. The article involved scholars from around the world working together for over two years updating the evidence on breastfeeding benefits, and evidence-based approaches to protect, promote, and support breastfeeding on a large scale, heavily considering the economic, social, political, and commercial determinants of infant feeding. The article is based on a strong and innovative conceptual framework and is informed by original data analyses of large epidemiological studies, as well as eight systematic reviews and one meta-analysis commissioned by the World Health Organization. This work is already having a strong impact in reshaping breastfeeding initiatives, policies, and programs across the globe.

David Paltiel and Gregg Gonsalves

Paltiel AD, Ahmed AR, Jin EY, McNamara M, Freedberg KA, Neilan AM, and Gonsalves GS. Increased HIV transmissions with reduced insurance coverage for HIV pre-exposure prophylaxis: Potential consequences of Braidwood Management v. Becerra . Open Forum Infectious Diseases

This study evaluates the potential public health consequences of a recent U.S. federal court ruling that deemed it unconstitutional for the Affordable Care Act to require employers to cover HIV prevention with pre-exposure prophylaxis (PrEP). The authors found that this ruling could result in more than 2,000 preventable HIV infections in the coming year alone. In the 24 hours following publication, the paper achieved an Altimetric score of 149. It received widespread national attention, including coverage in the New York Times, the Boston Globe, and the American Journal of Managed Care. The paper was selected as a Best of 2023 by the editors-in-chief of the journals of the Infectious Disease Society of America. Their paper was the central analytic element of several friend-of-the-court (amicus) briefs filed with the U.S. Court of Appeals for the Fifth Circuit, urging reversal of the lower court ruling, including the HIV Medicine Association and National Alliance of State and Territorial AIDS Directors, the American Public Health Association, the Yale Law School, and others.

• Recognitions

Featured in this article

• Melinda Irwin, PhD, MPH Associate Dean of Research and Susan Dwight Bliss Professor of Epidemiology (Chronic Diseases); Deputy Director (Public Health), Yale Center for Clinical Investigation; Deputy Director, Yale Cancer Center
• Zeyan Liew, PhD, MPH Assistant Professor of Epidemiology (Environmental Health)
• Yize Zhao, PhD Associate Professor of Biostatistics
• Robert Heimer, PhD Professor of Epidemiology (Microbial Diseases) and of Pharmacology; Affiliated Faculty, Yale Institute for Global Health
• Lauretta Grau, PhD Research Scientist in Epidemiology (Microbial Diseases)
• Caroline Helen Johnson, PhD Associate Professor of Epidemiology (Environmental Health Sciences)
• Krystal Pollitt, PhD, P.Eng. Associate Professor of Epidemiology (Environmental Health); Affiliated Faculty, Yale Institute for Global Health
• Lingeng Lu, MD, PhD Research Scientist in Epidemiology (Chronic Diseases)
• Rafael Pérez-Escamilla, PhD Professor of Public Health (Social and Behavioral Sciences); Director, Office of Public Health Practice; Affiliated Faculty, Yale Institute for Global Health; Director, YSPH Global Health Concentration; Director, Maternal and Child Health Promotion (MCHP) Program
• A. David Paltiel, MBA, PhD Professor of Public Health (Health Policy), Professor of Management, and Professor in the Institution for Social and Policy Studies; Co-director, Public Health Modeling Concentration; Affiliated Faculty, Yale Institute for Global Health
• Gregg Gonsalves, PhD Associate Professor of Epidemiology (Microbial Diseases); Associate (Adjunct) Professor of Law, Yale Law School; Affiliated Faculty, Program in Addiction Medicine; Co-Director, Global Health Justice Partnership; Affiliated Faculty, Yale Institute for Global Health

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Cannabis Tops Alcohol as Americans’ Daily Drug of Choice

A new study shows a growing number of people are regularly using cannabis, while frequent alcohol consumption has remained stable.

By Christina Caron

For the first time on record, cannabis has outpaced alcohol as the daily drug of choice for Americans.

In 2022 there were 17.7 million people who reported using cannabis either every day or nearly every day, compared with 14.7 million who reported using alcohol with the same frequency, according to a study, published on Wednesday in the journal Addiction that analyzed data from the U.S. National Survey on Drug Use and Health.

While far more people drink than use cannabis, drinking frequently has become slightly less common than it was around 15 years ago, the study found. But the proportion of people in the U.S. who use cannabis frequently has increased 15-fold in the three decades since 1992, when daily cannabis use hit a low point.

Cannabis legalization has also rapidly accelerated since the ’90s. The drug is now legal for recreational use in 24 states and Washington, D.C. , and for medical use in 38 states and D.C.

The sharp increase in the prevalence of high-frequency cannabis use over the last three decades might partly be attributed to a growing acceptance of the drug, said Jonathan P. Caulkins, a professor of public policy at Heinz College at Carnegie Mellon University. And because the survey data was self-reported, people may now feel more comfortable disclosing how often they use it.

Even so, “I don’t think that for most daily or near-daily users it is a health-promoting activity,” he added. “For some, it’s truly harmful.”

Several experts who were not involved in the research said the study’s findings were concerning. Those in favor of legalizing cannabis have argued that making the drug widely available would draw people away from the harms of alcohol, said Beatriz Carlini, a research associate professor in the psychiatry department of the University of Washington in Seattle.

But the study’s data, which shows only a slight decline in frequent alcohol use, suggests this has not been the case.

“It is disheartening,” she said.

Dr. Carlini and others noted that the concentrations of THC, the psychoactive component in marijuana, have increased dramatically over the years.

In 1995, the concentration of THC in cannabis samples seized by the Drug Enforcement Administration was about 4 percent. By 2021, it was about 15 percent . And now cannabis manufacturers are extracting THC to make oils, edibles, wax, sugar-size crystals and glass-like products called shatter with THC levels that can exceed 95 percent.

In the last decade , research has shown that frequent cannabis use — and particularly the use of high-potency products with levels of THC greater than 10 percent — is a risk factor for the onset of schizophrenia and other psychotic disorders.

“But that isn’t to say that use less frequent — monthly or yearly — is necessarily safe,” said Dr. Michael Murphy, an assistant professor of psychiatry at Harvard Medical School and a psychiatrist at McLean Hospital in Belmont, Mass.

“As we see higher rates of cannabis use in young people, I expect to see higher rates of psychotic disorders,” he said.

The risks of developing psychotic symptoms are higher for those who use cannabis before age 25, people who use it frequently, those with a genetic predisposition (for example, a parent or sibling with a psychotic disorder) or individuals who experienced stressful events like abuse, poverty or neglect during childhood.

In states that have legalized cannabis for recreational use, anyone 21 and over can purchase it.

Those who use cannabis frequently are also at risk of developing cannabis addiction as well as cannabinoid hyperemesis syndrome, a condition that causes recurrent vomiting, the experts said.

This latest study arrives on the heels of the Biden administration’s move last week to downgrade marijuana from the most restrictive category of drugs, known as Schedule I, to Schedule III, which includes drugs thought to have a low-to-moderate risk of abuse.

The survey did not collect information about the concentrations of THC in the products purchased by frequent users or note how often the respondents used cannabis each day.

“A lot of people go home and have a vape after work or take a gummy to go to sleep at night,” said Aaron Smith, the co-founder and chief executive of the National Cannabis Industry Association. He didn’t see that kind of casual daily use as a problem, he added.

At the same time, there may be young people who are using throughout the day “and are exposing themselves to a lot more THC than those people who are just taking a puff a day,” said Ziva D. Cooper, the director of the Center for Cannabis and Cannabinoids at the University of California, Los Angeles. “The mental health and the physical health outcomes are probably going to vary drastically when you look at those different groups of people.”

Christina Caron is a Times reporter covering mental health. More about Christina Caron

U.S. Girls Are Beginning Periods Earlier

By Dennis Thompson HealthDay Reporter

WEDNESDAY, May 29, 2024 (HealthDay News) -- U.S. girls are getting their periods at younger ages, a new study has found.

Girls born between 2000 and 2005 started their periods at an average age of 11.9 years -- a half year earlier than the average age of 12.5 years for girls born between 1950 and 1969, researchers reported May 29 in the journal JAMA Network Open .

The latest generation was also more likely to start menstruation early (15.5% versus 8.6%) and very early (1.4% versus 0.6%), results show.

Early onset of menstruation “is associated with higher risk of adverse health outcomes, such as cardiovascular disease and cancer,” said researcher Zifan Wang , a postdoctoral research fellow with the Harvard T.H. Chan School of Public Health in Boston.

U.S. Cities With the Most Homelessness

The researchers found that all women are experiencing earlier menstruation, but that those who are poor or a racial minority were even more likely to start their periods at a younger age.

“To address these health concerns -- which our findings suggest may begin to impact more people, with disproportionate impact on already disadvantaged populations -- we need much more investment in menstrual health research,” Wang said.

For the study, researchers analyzed data on more than 71,000 women participating in a large-scale health study. The researchers divided the women into five age brackets: born between 1950-1969, 1970-1979, 1980-1989, 1990-1999 and 2000-2005.

A girl’s first menstrual period was defined as early if it occurred before age 11, very early if it occurred younger than age 9 and late if it came at age 16 or older.

Researchers found that as birth year increased, the average age of a girl’s first period decreased.

They also found it is taking girls longer for their menstrual cycle to become regular.

A girl’s weight appears to partially explain why periods are starting earlier, researchers said. In other words, childhood obesity -- already known to be a risk factor for early puberty -- could be contributing to earlier menstruation.

Other possible explanations include dietary patterns, stress, adverse childhood experiences and environmental factors like air pollution and chemicals that disrupt hormones.

More information

The Office on Women’s Health has more about menstrual cycles .

SOURCE: Harvard T.H. Chan School of Public Health, news release, May 29, 2024

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Benefits and harms of medical cannabis: a scoping review of systematic reviews

Misty pratt.

1 Knowledge Synthesis Group, Ottawa Methods Centre, Ottawa Hospital Research Institute, The Ottawa Hospital, General Campus, 501 Smyth Road, Ottawa, Ontario K1H 8 L6 Canada

Adrienne Stevens

2 TRIBE Graduate Program, University of Split School of Medicine, Split, Croatia

Micere Thuku

Claire butler.

3 Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3A 2B4 Canada

Becky Skidmore

4 Ottawa, Canada

L. Susan Wieland

5 Center for Integrative Medicine, University of Maryland School of Medicine, Baltimore, MD USA

Mark Clemons

6 School of Epidemiology and Public Health, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8 M5 Canada

7 Division of Medical Oncology and Department of Medicine, University of Ottawa, Ottawa, Canada

Salmaan Kanji

8 Department of Pharmacy, The Ottawa Hospital, Ottawa, Canada

9 Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada

Brian Hutton

Associated data.

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

There has been increased interest in the role of cannabis for treating medical conditions. The availability of different cannabis-based products can make the side effects of exposure unpredictable. We sought to conduct a scoping review of systematic reviews assessing benefits and harms of cannabis-based medicines for any condition.

A protocol was followed throughout the conduct of this scoping review. A protocol-guided scoping review conduct. Searches of bibliographic databases (e.g., MEDLINE®, Embase, PsycINFO, the Cochrane Library) and gray literature were performed. Two people selected and charted data from systematic reviews. Categorizations emerged during data synthesis. The reporting of results from systematic reviews was performed at a high level appropriate for a scoping review.

After screening 1975 citations, 72 systematic reviews were included. The reviews covered many conditions, the most common being pain management. Several reviews focused on management of pain as a symptom of conditions such as multiple sclerosis (MS), injury, and cancer. After pain, the most common symptoms treated were spasticity in MS, movement disturbances, nausea/vomiting, and mental health symptoms. An assessment of review findings lends to the understanding that, although in a small number of reviews results showed a benefit for reducing pain, the analysis approach and reporting in other reviews was sub-optimal, making it difficult to know how consistent findings are when considering pain in general. Adverse effects were reported in most reviews comparing cannabis with placebo (49/59, 83%) and in 20/24 (83%) of the reviews comparing cannabis to active drugs. Minor adverse effects (e.g., drowsiness, dizziness) were common and reported in over half of the reviews. Serious harms were not as common, but were reported in 21/59 (36%) reviews that reported on adverse effects. Overall, safety data was generally reported study-by-study, with few reviews synthesizing data. Only one review was rated as high quality, while the remaining were rated of moderate ( n = 36) or low/critically low ( n = 35) quality.

Conclusions

Results from the included reviews were mixed, with most reporting an inability to draw conclusions due to inconsistent findings and a lack of rigorous evidence. Mild harms were frequently reported, and it is possible the harms of cannabis-based medicines may outweigh benefits.

Systematic review registration

The protocol for this scoping review was posted in the Open Access ( https://ruor.uottawa.ca/handle/10393/37247 ).

Interest in medical applications of marijuana ( Cannabis sativa ) has increased dramatically during the past 20 years. A 1999 report from the National Academies of Sciences, Engineering, and Medicine supported the use of marijuana in medicine, leading to a number of regulatory medical colleges providing recommendations for its prescription to patients [ 1 ]. An updated report in 2017 called for a national research agenda, improvement of research quality, improvement in data collection and surveillance efforts, and strategies for addressing barriers in advancing the cannabis agenda [ 2 ].

Proponents of medical cannabis support its use for a highly varied range of medical conditions, most notably in the fields of pain management [ 3 ] and multiple sclerosis [ 4 ]. Marijuana can be consumed by patients in a variety of ways including smoking, vaporizing, ingesting, or administering sublingually or rectally. The plant consists of more than 100 known cannabinoids, the main ones of relevance to medical applications being tetrahydrocannabinol (THC) and cannabidiol (CBD) [ 5 ]. Synthetic forms of marijuana such as dronabinol and nabilone are also available as prescriptions in the USA and Canada [ 6 ].

Over the last decade, there has been an increased interest in the use of medical cannabis products in North America. It is estimated that over 3.5 million people in the USA are legally using medical marijuana, and a total of USD$6.7 billion was spent in North America on legal marijuana in 2016 [ 7 ]. The number of Canadian residents with prescriptions to purchase medical marijuana from Health Canada–approved growers tripled from 30,537 in 2015 to near 100,000 in 2016 [ 8 ]. With the legalization of recreational-use marijuana in parts of the USA and in Canada in October 2018, the number of patients using marijuana for therapeutic purposes may become more difficult to track. The likely increase in the numbers of individuals consuming cannabis also necessitates a greater awareness of its potential benefits and harms.

Plant-based and plant-derived cannabis products are not monitored as more traditional medicines are, thereby increasing the uncertainty regarding its potential health risks to patients [ 3 ]. While synthetic forms of cannabis are available by prescription, different cannabis plants and products contain varied concentrations of THC and CBD, making the effects of exposure unpredictable [ 9 ]. While short-lasting side effects including drowsiness, loss of short-term memory, and dizziness are relatively well known and may be considered minor, other possible effects (e.g., psychosis, paranoia, anxiety, infection, withdrawal) may be more harmful to patients.

There remains a considerable degree of clinical equipoise as to the benefits and harms of marijuana use for medical purposes [ 10 – 13 ]. To understand the extent of synthesized evidence underlying this issue, we conducted a scoping review [ 14 ] of systematic reviews evaluating the benefits and/or harms of cannabis (plant-based, plant-derived, and synthetic forms) for any medical condition. We located and mapped systematic reviews to summarize research that is available for consideration for practice or policy questions in relation to medical marijuana.

A scoping review protocol was prepared and posted to the University of Ottawa Health Sciences Library’s online repository ( https://ruor.uottawa.ca/handle/10393/37247 ). We used the PRISMA for Scoping Reviews checklist to guide the reporting of this report (see Additional file 1 ) [ 15 ].

Literature search and process of study selection

An experienced medical information specialist developed and tested the search strategy using an iterative process in consultation with the review team. Another senior information specialist peer-reviewed the strategy prior to execution using the PRESS Checklist [ 16 ]. We searched seven Ovid databases: MEDLINE®, including Epub Ahead of Print and In-Process & Other Non-Indexed Citations, Embase, Allied and Complementary Medicine Database, PsycINFO, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, and the Health Technology Assessment Database. The final peer-reviewed search strategy for MEDLINE was translated to the other databases (see Additional file 2 ). We performed the searches on November 3, 2017.

The search strategy incorporated controlled vocabulary (e.g., “Cannabis,” “Cannabinoids,” “Medical Marijuana”) and keywords (e.g., “marijuana,” “hashish,” “tetrahydrocannabinol”) and applied a broad systematic review filter where applicable. Vocabulary and syntax were adjusted across the databases and where possible animal-only and opinion pieces were removed, from the search results.

Gray literature searching was limited to relevant drug and mental health databases, as well as HTA (Health Technology Assessment) and systematic review databases. Searching was guided by the Canadian Agency for Drugs and Technologies in Health’s (CADTH) checklist for health-related gray literature (see Additional file 3 ). We performed searches between January and February 2018. Reference lists of overviews were searched for relevant systematic reviews, and we searched for full-text publications of abstracts or protocols.

Management of all screening was performed using Distiller SR Software ® (Evidence Partners Inc., Ottawa, Canada). Citations from the literature search were collated and de-duplicated in Reference Manager (Thomson Reuters: Reference Manager 12 [Computer Program]. New York: Thomson Reuters 2011), and then uploaded to Distiller. The review team used Distiller for Levels 1 (titles and abstracts) and 2 (full-text) screening. Pilot testing of screening questions for both levels were completed prior to implementation. All titles and abstracts were screened in duplicate by two independent reviewers (MT and MP) using the liberal accelerated method [ 17 ]. This method requires only one reviewer to assess an abstract as eligible for full-text screening, and requires two reviewers to deem the abstract irrelevant. Two independent reviewers (MT and MP) assessed full-text reports for eligibility. Disagreements during full-text screening were resolved through consensus, or by a third team member (AS). The process of review selection was summarized using a PRISMA flow diagram (Fig. ​ (Fig.1) 1 ) [ 18 ].

PRISMA-style flow diagram of the review selection process

Review selection criteria

English-language systematic reviews were included if they reported that they investigated harms and/or benefits of medical or therapeutic use of cannabis for adults and children for any indication. Definitions related to medical cannabis/marijuana are provided in Table ​ Table1. 1 . We also included synthetic cannabis products, which are prescribed medicines with specified doses of THC and CBD. Reviews of solely observational designs were included only in relation to adverse effects data, in order to focus on the most robust evidence available. We considered studies to be systematic reviews if at least one database was searched with search dates reported, at least one eligibility criterion was reported, the authors had assessed the quality of included studies, and there was a narrative or quantitative synthesis of the evidence. Reviews assessing multiple interventions (both pharmacological and complementary and alternative medicine (CAM) interventions) were included if the data for marijuana studies was reported separately. Published and unpublished guidelines were included if they conducted a systematic review encompassing the criteria listed above.

Context for the use of cannabis-related terms during the review selection process

We excluded overviews of systematic reviews, reviews in abstract form only, and review protocols. We further excluded systematic reviews focusing on recreational, accidental, acute, or general cannabis use/abuse and interventions such as synthetic cannabinoids not approved for therapeutic use (e.g., K2 or Spice).

Data collection and quality assessment

All data were collected electronically in a pre-developed form using Microsoft Excel software (Microsoft Corporation, Seattle, USA). The form was pilot tested on three included reviews by three people. One reviewer (MP or CB) independently extracted all data, and a second reviewer (MT) verified all of the items collected and checked for any omitted data. Disagreements were resolved by consensus and consultation with a third reviewer if necessary. A data extraction form with the list of included variables is provided in Additional file 4 . All collected data has also been made available in the online supplemental materials associated with this report.

Quality assessment of systematic reviews was performed using the AMSTAR-2 [ 20 ] tool. One reviewer (MP or CB) independently assessed quality, while a second reviewer (MT) verified the assessments. Disagreements were resolved by consensus and consultation with a third reviewer if necessary. The tool consists of 16 items in total, with four critical domains and 12 non-critical domains. The AMSTAR-2 tool is not intended to generate an overall score, and instead allows for an overall rating based on weaknesses in critical domains. Reviews were rated as high (no critical flaws with zero or one non-critical flaw), moderate (no critical flaws with ≥ 1 non-critical flaw), low (one critical flaw with/without non-critical weakness), or critically low (> 1 critical flaw with/without non-critical weakness) quality.

Evidence synthesis

We used a directed content analytic approach [ 21 ] with an initial deductive framework [ 22 ] that allowed flexibility for inductive analysis if refinement or development of new categorization was needed. The framework used to categorize outcome data results is outlined in Table ​ Table2. 2 . Where reviews had a mix of narrative and quantitative data, results from meta-analyses were prioritized over count data or study-by-study data. The extraction and reporting of data results was performed at a high level and did not involve an in-depth evaluation, which is appropriate for a scoping review [ 14 ]. Review authors’ conclusions and/or recommendations were extracted and reported narratively.

Outcome result categorization

Changes from the study protocol

For feasibility, we decided to limit the inclusion of systematic reviews of only observational study designs to those that addressed adverse events data. All other steps of the review were performed as planned.

Search findings

The PRISMA flow diagram describing the process of review selection is presented in Fig. ​ Fig.1. 1 . After duplicates were removed, the search identified a total of 1925 titles and abstracts, of which 47 references were located through the gray literature search. Of the total 1925 citations assessed during Level 1 screening, 1285 were deemed irrelevant. We reviewed full-text reports for the 640 reviews of potential relevance, and of these, 567 were subsequently excluded, leaving a total of 72 systematic reviews that were included; the associated data collected are provided in Additional file 5 . A listing of the reports excluded during full-text review is provided in Additional file 6 .

Characteristics of included reviews

There were 63 systematic reviews [ 4 , 19 , 23 – 83 ] and nine guidelines with systematic reviews [ 84 – 92 ]. Overall, 27 reviews were performed by researchers in Europe, 16 in the USA, 15 in Canada, eight in Australia, two in Brazil, and one each in Israel, Singapore, South Africa, and China. Funding was not reported in 29 (40%) of the reviews, and the remaining reviews received funding from non-profit or academic ( n = 20; 28%), government ( n = 14; 19%), industry ( n = 3; 4%), and mixed ( n = 1; 1%) sources. Five reviews reported that they did not receive any funding for the systematic review. Tables ​ Tables3, 3 , ​ ,4, 4 , ​ ,5, 5 , ​ ,6, 6 , ​ ,7, 7 , ​ ,8, 8 , ​ ,9, 9 , ​ ,10, 10 , ​ ,11, 11 , ​ ,12, 12 , and ​ and13 13 provide an overview of the characteristics of the 72 included systematic reviews.

Multiple sclerosis

MS multiple sclerosis, NICE National Institute for Health and Care Excellence, No . number, NR not reported, NRS numerical rating scale, QoL quality of life, RMI Rivermead Mobility Index, SBS study-by-study, VAS visual analog scale

*A colon indicates that there were separate analyses for each comparator

Movement disorders

HD Huntington’s disease, MS multiple sclerosis, NR not reported, PD Parkinson’s disease, SBS study-by-study, SCL-90R Symptoms Checklist-90 Revised, QoL quality of life, STSSS Shapiro Tourette Syndrome Severity Scale, THC tetrahydrocannabinol, TS-CGI Tourette Syndrome Clinical Global Impressions, TSSL Tourette’s Syndrome Symptom List (patient rated), VAS visual analog scale, YGTSS Yale Global Tic Severity Scale

AE : adverse effect, NICE National Institute for Health and Care Excellence, NNT numbers needed to treat, NP neuropathic pain, NR not reported, QoL quality of life, QST quantitative sensory testing, SBS study-by-study, VAS visual analog scale

*A colon indicates that there were separate analyses for each comparator; a “+” sign indicates placebo was combined with another comparator

AE adverse effect, NP neuropathic pain, NR not reported, NRS numerical rating scale, QoL quality of life, THC tetrahydrocannabinol, SIGN Scottish Intercollegiate Guidelines Network, SBS study-by-study

Rheumatic disease

AE adverse event, FM fibromyalgia, NR not reported, NRS numerical rating scale, OA osteoarthritis, RA rheumatoid arthritis, SBS study-by-study

NP neuropathic pain, NR not reported, QoL quality of life, SBS study-by-study

Mental health

PTSD posttraumatic stress disorder, SBS study-by-study

NP neuropathic pain, NR not reported, SBS study-by-study

Neurological conditions

AE adverse effect, ALS amyotrophic lateral sclerosis, CADTH Canadian Agency for Drugs and Technologies in Health, NR not reported

Various conditions

AE adverse effect, AD Alzheimer’s disease, ALS amyotrophic lateral sclerosis, CADTH Canadian Agency for Drugs and Technologies in Health, CGI-C Clinical Global Impression of Change scale, COPD Chronic Obstructive Pulmonary Disease, FIQ fibromyalgia impact questionnaire, FM fibromyalgia, HD Huntington’s disease, IBD inflammatory bowel disease, MS multiple sclerosis, NP neuropathic pain, NR not reported, PD Parkinson’s disease, PTSD posttraumatic stress disorder, RA rheumatoid arthritis, SBS study-by-study, SCI spinal cord injury

Other conditions

CADTH Canadian Agency for Drugs and Technologies in Health, IBS irritable bowel syndrome, NR not reported, QoL quality of life, SBS study-by-study, VAS visual analog scale

The reviews were published between 2000 and 2018 (median year 2014), and almost half (47%) were focused solely on medical cannabis. Four (6%) reviews covered both medical and other cannabis use (recreational and substance abuse), 19 (26%) reported multiple pharmaceutical interventions (cannabis being one), six (8%) reported various CAM interventions (cannabis being one), and nine (13%) were mixed pharmaceutical and CAM interventions (cannabis being one). Multiple databases were searched by almost all of the reviews (97%), with Medline/PubMed or Embase common to all.

Cannabis use

Figure ​ Figure2 2 illustrates the different cannabis-based interventions covered by the included reviews. Plant-based cannabis consists of whole plant products such as marijuana or hashish. Plant-derived cannabinoids are active constituents of the cannabis plant, such as tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination of THC:CBD (also called nabiximols, under the brand name Sativex) [ 3 ]. Synthetic cannabinoids are manufactured rather than extracted from the plant and include drugs such as nabilone and dronabinol.

Review coverage of the various cannabis-based interventions

Twenty-seven reviews included solely interventions from plant-derived cannabinoids, 10 studied solely synthetic cannabinoids, and eight included solely studies on plant-based cannabis products. Twenty-four reviews covered a combination of different types of cannabis, and the remaining three systematic reviews did not report which type of cannabinoid was administered in the included studies.

The systematic reviews covered a wide range of conditions and illnesses, the most notable being pain management. Seventeen reviews looked at specific types of pain including neuropathic [ 31 , 42 , 62 , 69 , 85 , 90 ], chronic [ 26 , 32 , 52 , 58 , 80 ], cancer [ 84 , 87 ], non-cancer [ 41 , 68 ], and acute [ 38 ] types of pain (one review covered all types of pain) [ 65 ]. Twenty-seven reviews (38%) also focused on management of pain as a symptom of conditions such as multiple sclerosis (MS) [ 6 , 23 , 27 , 43 , 46 , 52 , 63 , 85 , 92 ], injury [ 29 , 35 , 36 , 69 ], cancer [ 37 , 43 , 65 , 88 ], inflammatory bowel disease (IBD) [ 28 ], rheumatic disease (RD) [ 49 , 51 , 73 ], diabetes [ 68 – 70 ], and HIV [ 48 , 53 , 67 ]. In Fig. ​ Fig.3, 3 , the types of illnesses addressed by the set of included reviews are graphically represented, with overlap between various conditions and pain. Some systematic reviews covered multiple diseases, and therefore the total number of conditions represented in Fig. ​ Fig.3 3 is greater than the total number of included reviews.

Conditions or symptoms across reviews that were treated with cannabis. IBD inflammatory bowel disease, MS multiple sclerosis, RD rheumatic disease

One review included a pediatric-only population, in the evaluation of marijuana for nausea and vomiting following chemotherapy [ 54 ]. Although trials in both adult and child populations were eligible for thirteen (18%) reviews, only two additional reviews included studies in children; these reviews evaluated cannabis in cancer [ 60 ] and a variety of conditions [ 25 ]. Many of the reviews ( n = 25, 35%) included only adults ≥ 18 years of age. Almost half of the reviews ( n = 33, 46%) did not report a specific population for inclusion.

Cannabis was prescribed for a wide range of medical issues. The indication for cannabis use is illustrated in Fig. ​ Fig.4. 4 . Pain management ( n = 27) was the most common indication for cannabis use. A number of reviews sought to address multiple disease symptoms ( n = 12) or explored a more holistic treatment for the disease itself ( n = 11). After pain, the most common symptoms being treated with cannabis were spasticity in MS, movement disturbances (such as dyskinesia, tics, and spasms), weight or nausea/vomiting, and mental health symptoms.

Indications for cannabis use across included reviews

Figure ​ Figure5 5 summarizes the breadth of outcomes analyzed in the included reviews. The most commonly addressed outcomes were withdrawal due to adverse effects, “other pain,” neuropathic pain, spasticity, and the global impression of the change in clinical status. Many outcomes were reported using a variety of measures across reviews. For example, spasticity was measured both objectively (using the Ashworth scale) and subjectively (using a visual analog scale [VAS] or numerical rating scale [NRS]). Similarily, outcomes for pain included VAS or NRS scales, reduction in pain, pain relief, analgesia, pain intensity, and patient assessment of change in pain.

Quality of the systematic reviews

Quality assessments of the included reviews based upon AMSTAR-2 are detailed in Additional file 7 and Additional file 8 . Only one review was rated as high quality [ 45 ]. All other reviews were deemed to be of moderate ( n = 36) or low/critically low ( n = 35) methodological quality. Assessments for the domains deemed of critical importance for determining quality ratings are described below.

Only 20% of reviews used a comprehensive search strategy; another 47% were given a partial score because they had not searched the reference lists of the included reviews, trial registries, gray literature, and/or the search date was older than 2 years. The remaining reviews did not report a comprehensive search strategy.

Over half of the reviews (51%) used a satisfactory technique for assessing risk of bias (ROB) of the individual included studies, while 35% were partially satisfactory because they had not reported whether allocation sequence was truly random and/or they had not assessed selective reporting. The remaining reviews did not report a satisfactory technique for assessing ROB.

Most reviews (71%) could not be assessed for an appropriate statistical method for combining results in a meta-analysis, as they synthesized study data narratively. Approximately 19% of reviews used an appropriate meta-analytical approach, leaving 10% that used inappropriate methods.

The final critical domain for the AMSTAR-2 determines whether review authors accounted for ROB in individual studies when discussing or interpreting the results of the review. The majority of reviews (83%) did so in some capacity.

Mapping results of included systematic reviews

We mapped reviews according to authors’ comparisons, the conditions or symptoms they were evaluating, and the categorization of the results (see Table ​ Table2). 2 ). In some cases, reviews contributed to more than one comparison (e.g., cannabis versus placebo or active drug). As pain was the most commonly addressed outcome, we mapped this outcome separately from all other endpoints. This information is shown for all reviews and then restricted to reviews of moderate-to-high quality (as determined using the AMSTAR-2 criteria): cannabis versus placebo (Figs. ​ (Figs.6 6 and ​ and7), 7 ), cannabis versus active drugs (Figs. ​ (Figs.8 8 and ​ and9), 9 ), cannabis versus a combination of placebo and active drug (Figs. ​ (Figs.10 10 and ​ and11), 11 ), one cannabis formulation versus other (Figs. ​ (Figs.12 12 and ​ and13), 13 ), and cannabis analyzed against all other comparators (Fig. ​ (Fig.14). 14 ). Details on how to read the figures are provided in the corresponding figure legends. The median number of included studies across reviews was four, and ranged from one to seventy-nine (not shown in figures).

Cannabis vs. placebo. Authors’ presentations of the findings were mapped using the categorization shown in Table ​ Table2. 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

Cannabis vs. placebo, high and moderate quality reviews. Authors’ presentations of the findings were mapped using the categorizations shown in Table ​ Table2. 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

Cannabis vs. active drugs. Authors’ presentations of the findings were mapped using the categorizations shown in Table ​ Table2. 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

Cannabis vs. active drugs, high and moderate quality reviews. Authors’ presentations of the findings were mapped using the categorizations shown in Table ​ Table2. 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

Cannabis vs. placebo + active drug. Authors’ presentations of the findings were mapped using the categorizations shown in Table ​ Table2. 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

Cannabis vs. placebo + active drug, high and moderate quality reviews. Authors’ presentations of the findings were mapped using the categorizations shown in Table ​ Table2. 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

One cannabis formulation vs. other. Authors’ presentations of the findings were mapped using the categorizations shown in Table ​ Table2. 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

One cannabis formulation vs. other, high and moderate quality reviews. Authors’ presentations of the findings were mapped using the categorizations shown in Table ​ Table2. 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

Cannabis vs. all comparators combined. Authors’ presentations of the findings were mapped using the categorizations shown in Table ​ Table2. 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

Cannabis versus placebo

Most reviews (59/72, 82%) compared cannabis with placebo. Of these reviews, 34 (58%) addressed pain outcomes and 47 (80%) addressed non-pain outcomes, with most outcomes addressed by three reviews or fewer (Fig. ​ (Fig.6). 6 ). Some reviews had a mix of quantitative syntheses and study-by-study data reported (13/59, 22%), while another group of reviews (14/59, 24%) only reported results study-by-study. Overall, 24% (14/59) of the cannabis versus placebo reviews had only one included study.

• i. Reviews focused on addressing pain across conditions. In most cases, findings were discordant across reviews for the pain outcomes measured. For chronic non-cancer pain, however, two reviews favored cannabis over placebo for decreasing pain. One review assessing acute pain for postoperative pain relief found no difference between various cannabinoid medications and placebo. The distribution of findings was similar when restricting to moderate-to-high-quality reviews.
• ii. Reviews focused on treating a condition or family of related conditions . Various results were observed for pain. For MS and HIV/AIDS, one review each reported quantitative results favoring cannabis for decreased pain but with other reviews reporting results study-by-study, it is difficult to know, broadly, how consistent those findings are. For cancer, two reviews reported results favoring cannabis for decreased pain. For rheumatic disease, findings are discordant between two reviews, and another two reviews reported results study-by-study. One review that included studies of MS or paraplegia found no difference in pain between groups. For treating injury, one review showed that the placebo group had less pain and one review reported data study-by-study. No reviews addressed pain in movement disorders, neurological conditions, and IBD.

For those reviews assessing pain as part of a focus on treating a range of conditions, two showed cannabis reduced pain [ 43 , 52 ], but one showed mixed results depending on how pain was measured [ 43 ]. These reviews covered several different conditions, including injury, chronic pain, rheumatoid arthritis, osteoarthritis, fibromyalgia, HIV/AIDS, cancer, and MS or paraplegia.

When restricting to moderate-to-high-quality reviews, only one review each in multiple sclerosis and HIV/AIDS with a study-by-study analysis on pain remained. One review on cancer favored cannabis for pain reduction. Findings remained the same for MS or paraplegia and rheumatic disease. No review for injury and paint outcomes was of higher quality.

• 2. Non-pain outcomes

The types of non-pain outcomes included in the reviews varied by condition/illness. The most commonly reported outcomes (see Fig. ​ Fig.5 5 for overall outcomes) when comparing cannabis to placebo included muscle- or movement-related outcomes ( n = 20), quality of life ( n = 14), and sleep outcomes ( n = 10).

There was no consistent pattern for non-pain outcomes either within or across medical conditions. Many ( n = 24, 33%) reviews assessing non-pain outcomes reported the results of those analyses study-by-study. Conflicting results are observed in some cases due to the use of different measures, such as different ways of quantifying spasticity in patients with multiple sclerosis [ 56 , 91 ]. One review each addressing neurological conditions [ 50 ] (outcome: muscle cramps) and MS/paraplegia [ 27 ] (outcomes: spasticity, spasm, cognitive function, daily activities, motricity, and bladder function) showed no difference between groups.

• 3. Adverse effects

Adverse effects were reported in most reviews comparing cannabis with placebo (49/59, 83%). Most adverse events were reported study-by-study, with few reviews ( n = 16/59, 27%) conducting a narrative or quantitative synthesis. Serious adverse effects were reported in 21/59 (36%) reviews, and minor adverse effects were reported in 30/59 (51%) reviews. The remaining reviews did not define the difference between serious and minor adverse events. The most commonly reported serious adverse events included psychotic symptoms ( n = 6), severe dysphoric reactions ( n = 3), seizure ( n = 3), and urinary tract infection ( n = 2). The most commonly reported minor adverse events included somnolence/drowsiness ( n = 28), dizziness ( n = 27), dry mouth ( n = 20), and nausea ( n = 18). Many reviews ( n = 37/59, 63%) comparing cannabis to placebo reported both neurocognitive and non-cognitive adverse effects. Withdrawals due to adverse events were reported in 22 (37%) reviews.

Of the moderate-/high-quality reviews, adverse effect analyses were reported in reviews on pain, multiple sclerosis, cancer, HIV/AIDS, movement disorders, rheumatic disease, and several other conditions. Two reviews on pain showed fewer adverse events with cannabis for euphoria, events linked to alternations in perception, motor function, and cognitive function, withdrawal due to adverse events, sleep, and dizziness or vertigo [ 58 , 90 ]. One review on MS showed that there was no statistically significant difference between cannabis and placebo for adverse effects such as nausea, weakness, somnolence, and fatigue [ 91 ], while another review on MS/paraplegia reported fewer events in the placebo group for dizziness, somnolence, nausea, and dry mouth [ 27 ]. Within cancer reviews, one review found no statistically significant difference between cannabis and placebo for dysphoria or sedation but reported fewer events with placebo for “feeling high,” and fewer events with cannabis for withdrawal due to adverse effects [ 40 ]. In rheumatic disease, one review reported fewer total adverse events with cannabis and found no statistically significant difference between cannabis and placebo for withdrawal due to adverse events [ 51 ].

Cannabis versus other drugs

Relatively fewer reviews compared cannabis with active drugs ( n = 23/72, 32%) (Fig. ​ (Fig.8). 8 ). Many of the reviews did not synthesize studies quantitatively, and results were reported study-by-study. The most common conditions in reviews comparing cannabis to active drugs were pain, cancer, and rheumatic disease. Comparators included ibuprofen, codeine, diphenhydramine, amitriptyline, secobarbital, prochlorperazine, domperidone, metoclopramide, amisulpride, neuroleptics, isoproterenol, megestrol acetate, pregabalin, gabapentin, and opioids.

• i. Reviews focused on addressing pain across conditions. When comparing across reviews, a mix of results are observed (see Fig. ​ Fig.8), 8 ), and some were reported study-by-study. One review found no statistically significant difference between cannabinoids and codeine for nociceptive pain, postoperative pain, and cancer pain [ 65 ]. Another review favored “other drugs” (amitriptyline and pregabalin) over cannabinoids for neuropathic pain [ 90 ]. The distribution of findings was similar when restricting to moderate-to-high-quality reviews.
• ii. Reviews focused on treating a condition or family of related conditions. One review on cancer compared cannabinoids and codeine or secobarbital and reported pain results study-by-study. Another review on fibromyalgia comparing synthetic cannabinoids with amitriptyline also reported pain data study-by-study [ 39 ].
• Non-pain outcomes

Two reviews on cancer favored cannabinoids over active drugs (prochlorperazine, domperidone, metoclopramide, and neuroleptics) for patient preference and anti-emetic efficacy [ 40 , 60 ]. Non-pain outcomes were reported study-by-study for the outcome of sleep in neuropathic pain [ 90 ] and rheumatic disease [ 39 , 49 ]. In a review covering various conditions (pain, MS, anorexia, cancer, and immune deficiency), results were unclear or indeterminate for subjective measures of sleep [ 46 ].

Adverse effects were reported in 20/24 (83%) of the reviews comparing cannabis to active drugs, and only 6/20 (30%) reported a narrative or quantitative synthesis. Many reviews that reported narrative data did not specify whether adverse effects could be attributed to a placebo or active drug comparator.

Of the moderate-to-high-quality reviews, two pain reviews found no statistically significant difference for cannabis compared to codeine or amitriptyline for withdrawals due to adverse events [ 65 , 90 ]. Results from one cancer review were mixed, with fewer adverse events for cannabis (compared to prochlorperazine, domperidone, or metoclopramide) or no difference between groups, depending on the type of subgroup analysis that was conducted [ 40 ].

Cannabis + active drugs versus placebo + active drugs

Two reviews compared cannabis with placebo cannabis in combination with an active drug (opioids and gabapentin) (Figs. ​ (Figs.10 10 and ​ and11). 11 ). Both were scored to be of moderate quality. Although one review showed that cannabis plus opioids decreased chronic pain [ 80 ], another review on pain in MS included only a single study [ 81 ], precluding the ability to determine concordance of results. Cannabis displayed varied effects on non-pain outcomes, including superiority of placebo over cannabis for some outcomes. One review reported withdrawal due to adverse events study-by-study and also reported that side effects such as nausea, drowsiness, and dizziness were more frequent with higher doses of cannabinoids (data from two included studies) [ 80 ].

Cannabis versus other cannabis comparisons

Six (8%) reviews compared different cannabis formulations or doses (Figs. ​ (Figs.12 12 and ​ and13). 13 ). Almost all were reported as study-by-study results, with two reviews including only one RCT. One review for PTSD found only observational data [ 33 ] and another review on anxiety and depression combined data from one RCT with cross-sectional study data [ 19 ]. A single review on MS reported a narrative synthesis that found a benefit for spasticity. However, it was unclear if the comparator was placebo or THC alone [ 56 ]. Four reviews reported adverse effects study-by-study, with a single review comparing side effects from different dosages; in this review, combined extracts of THC and CBD were better tolerated than extracts of THC alone [ 56 ].

Cannabis versus all comparators

One review combined all comparators for the evaluation (Fig. ​ (Fig.14). 14 ). The review (combining non-users, placebo and ibuprofen) covered a range of medical conditions and was rated as low quality [ 30 ]. No adverse effects were evaluated for this comparison.

Mapping the use of quality assessment and frameworks to interpret the strength of evidence

Although 83% of reviews incorporated risk of bias assessments in their interpretation of the evidence, only 11 (15%) reviews used a framework such as GRADE to evaluate important domains other than risk of bias that would inform the strength of the evidence.

Mapping authors’ conclusions or recommendations

Most reviews (43/72 60%) indicated an inability to draw conclusions, whether due to uncertainty, inconsistent findings, lack of (high quality) evidence, or focusing their conclusion statement on the need for more research. Almost 15% of reviews (10/72) reported recommendations or conclusions that included some uncertainty. One review (1%) provided a statement of the extent of the strength of the evidence, which differed according to outcome.

Eleven reviews provided clearer conclusions (14%). Four indicated that cannabis was not effective or not cost-effective compared to placebo in relation to multiple sclerosis, acute pain, cancer, and injury. Three reviews addressing various conditions provided varying conclusions: one stated cannabis was not effective, one indicated it was modestly safe and effective, and one concluded that cannabis was safe and efficacious as short-term treatment; all reviews were of low quality. The three remaining reviews stated moderate or modest effects for improving chronic pain, compared with placebo or other analgesia; two of those reviews were of medium AMSTAR-2 quality, and one used the GRADE framework for interpreting the strength of the evidence.

The eight remaining included reviews (11%) did not provide a clear conclusion statement or reported only limitations.

Mapping authors’ limitations of the research

Several of the reviews indicated that few studies, small sample sizes, short duration of treatment, and issues related to outcomes (e.g., definition, timing, and types) were drawbacks to the literature. Some reviews noted methodological issues with and heterogeneity among studies as limitations. A few authors stated that restricting eligibility to randomized trials, English-language studies, or full publications may have affected their review results.

With the increasing use of medical cannabis, an understanding of the landscape of available evidence syntheses is needed to support evidence-informed decision-making, policy development, and to inform a research agenda. In this scoping review, we identified 72 systematic reviews evaluating medical cannabis for a range of conditions and illnesses. Half of the reviews were evaluated as being of moderate quality, with only one review scoring high on the AMSTAR-2 assessment tool.

There was disparity in the reported results across reviews, including non-synthesized (study-by-study) data, and many were unable to provide a definitive statement regarding the effectiveness of cannabis (as measured by pain reduction or other relevant outcomes), nor the extent of increased side effects and harms. This is consistent with the limitations declared in general across reviews, such as the small numbers of relevant studies, small sample sizes of individual studies, and methodological weaknesses of available studies. This common theme in review conclusions suggests that while systematic reviews may have been conducted with moderate or high methodological quality, the strength of their conclusions are driven by the availability and quality of the relevant underlying evidence, which was often found to be limited.

Relatively fewer reviews addressed adverse effects associated with cannabis, except to narratively summarize study level data. Although information was provided for placebo-controlled comparisons, none of the comparative effectiveness reviews quantitatively assessed adverse effects data. For the placebo-controlled data, although the majority of adverse effects were mild, the number of reviews reporting serious adverse effects such as psychotic symptoms [ 25 , 42 ] and suicidal ideation [ 68 , 85 ] warrants caution.

A mix of reviews supporting and not supporting the use of cannabis, according to authors’ conclusions, was identified. Readers may wish to consider the quality of the reviews, the use of differing quality assessment tools, additional considerations covered by the GRADE framework, and the potential for spin as possible reasons for these inconsistencies. It is also possible that cannabis has differing effects depending on its type (e.g., synthetic), dose, indication, the type of pain being evaluated (e.g., neuropathic), and the tools used for outcome assessment, which can be dependent on variations in condition. Of potential interest to readers may be a closer examination of the reviews evaluating chronic pain, in order to locate the source(s) of discordance. For example, one review was deemed of moderate quality, used the GRADE framework, and rated the quality of evidence for the effectiveness of cannabis for reducing neuropathic pain as moderate, suggesting that further investigation of cannabis for neuropathic pain may be warranted [ 80 ]. The exploration aspects outlined in this paragraph are beyond the purview of scoping review methodology; a detailed assessment of the reviews, including determining the overlap of included studies among similar reviews, potential reasons for the observed discordance of findings, what re-analysis of study-by-study analyses would yield, and an undertaking of missing GRADE assessments would fall outside the bounds of a scoping review and require the use of overview methodology [ 14 ].

Our findings are consistent with a recently published summary of cannabis-based medicines for chronic pain management [ 3 ]. This report found inconsistent results in systematic reviews of cannabis-based medicines compared to placebo for chronic neuropathic pain, pain management in rheumatic diseases and painful spasms in MS. The authors also concluded that cannabis was not superior to placebo in reducing cancer pain. Four out of eight included reviews scored high on the original AMSTAR tool. The variations between the two tools can be attributed to the differences in our overall assessments. Lastly, the summary report included two reviews that were not located in our original search due to language [ 93 ] and the full-text [ 94 ] of an abstract [ 95 ] that was not located in our search.

This scoping review has identified a plethora of synthesized evidence in relation to medical cannabis. For some conditions, the extent of review replication may be wasteful. Many reviews have stated that additional trials of methodologically robust design and, where possible, of sufficient sample size for precision, are needed to add to the evidence base. This undertaking may require the coordination of multi-center studies to ensure adequate power. Future trials may also help to elucidate the effect of cannabis on different outcomes.

Given authors’ reporting of issues in relation to outcomes, future prospective trials should be guided by a standardized, “core” set of outcomes to strive for consistency across studies and ensure relevance to patient-centered care. Development of those core outcomes should be developed using the Core Outcome Measures in Effectiveness Trials (COMET) methodology [ 96 ], and further consideration will need to be made in relation to what outcomes may be common across all cannabis research and which outcomes are condition-specific. With maturity of the evidence base, future systematic reviews should seek and include non-journal-published (gray literature) reports and ideally evaluate any non-English-language papers; authors should also adequately assess risk of bias and undertake appropriate syntheses of the literature.

The strengths of this scoping review include the use of an a priori protocol, peer-reviewed search strategies, a comprehensive search for reviews, and consideration of observational designs for adverse effects data. For feasibility, we restricted to English-language reviews, and it is unknown how many of the 39 reviews in other languages that we screened would have met our eligibility criteria. The decision to limit the inclusion of reviews of observational data to adverse effects data was made during the process of full-text screening and for pragmatic reasons. We also did not consider a search of the PROSPERO database for ongoing systematic reviews; however, in preparing this report, we performed a search and found that any completed reviews were already considered for eligibility or were not available at the time of our literature search. When charting results, we took a broad perspective, which may be different than if these reviews were more formally assessed during an overview of systematic reviews.

Cannabis-based medicine is a rapidly emerging field of study, with implications for both healthcare practitioners and patients. This scoping review is intended to map and collate evidence on the harms and benefits of medical cannabis. Many reviews were unable to provide firm conclusions on the effectiveness of medical cannabis, and results of reviews were mixed. Mild adverse effects were frequently but inconsistently reported, and it is possible that harms may outweigh benefits. Evidence from longer-term, adequately powered, and methodologically sound RCTs exploring different types of cannabis-based medicines is required for conclusive recommendations.

Supplementary information

Acknowledgements.

Not applicable.

Abbreviations

Authors’ contributions.

MP, AS, and BH drafted the initial version of the report. BS designed and implemented the literature search. MP, MT, and CB contributed to review of abstracts and full texts as well as data collection. MP, AS, and BH were responsible for analyses. All authors (MP, AS, MT, CB, BS, SW, MC, SK, BH) contributed to interpretation of findings and revision of drafts and approved the final version of the manuscript.

Research reported in this publication was supported by the National Center for Complementary and Integrative Health of the National Institutes of Health under award number R24AT001293. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Availability of data and materials

Ethics approval and consent to participate, consent for publication, competing interests.

BH has previously received honoraria from Cornerstone Research Group for provision of methodologic advice related to the conduct of systematic reviews and meta-analysis. All other authors declare that they have no conflicts of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Misty Pratt, Email: ac.irho@ttarpim .

Adrienne Stevens, Email: ac.irho@snevetsda .

Micere Thuku, Email: ac.irho@ukuhtm .

Claire Butler, Email: ac.irho@reltublc .

Becky Skidmore, Email: moc.sregor@eromdiksb .

L. Susan Wieland, Email: moc.liamg@dnaleiwsl .

Mark Clemons, Email: ac.hot@snomelcm .

Salmaan Kanji, Email: ac.hot@ijnaks .

Brian Hutton, Email: ac.irho@nottuhb .

Supplementary information accompanies this paper at 10.1186/s13643-019-1243-x.

How to make money from medical research and donations

• You can make thousands of dollars by donating some time or body parts to science.
• But these procedures are not all painless, and not everyone can participate.
• Below is a short list, though be warned: these strategies aren't all easy money.

Get dysentery. Play cards with someone who has the flu . Or, spend 45 days trapped in a tiny apartment with three total strangers.

These are just a few of the many ways you can get paid for helping out with scientific research. If you want to aid the science community and potentially save some lives while making a little extra cash, there are some unconventional options to consider.

Below is a short list, though be warned: these strategies aren't all exactly easy money.

Sell your blood plasma

Payout (per donation): around $50

Plasma is the largest component in human blood. It's a protein-rich liquid that contains mostly water but is also filled with enzymes, antibodies, and salts. This gooey, sticky yellow-ish stuff can be used to create therapies that treat people with blood clotting disorders, autoimmune diseases, and even burn victims. Donating plasma is often called "the gift of life" since treatments for some conditions can't be made synthetically and require this kind of human contribution.

During plasma donation, blood is drawn and an automated machine separates the plasma from other blood components, which are returned to the donor. Plasma donation pay varies from site to site, but the average payout is typically around $50 per donation. You can donate safely roughly once a month, according to the American Red Cross , and a typical session takes less than two hours. Find a licensed and certified plasma center near you.

Donate your sex cells

Payout for eggs (per donation): usually $10,000 to $12,000;

Payout for sperm (per donation): typically $35-$150

Egg and sperm donation can allow couples who have trouble conceiving naturally to become parents by using a donor's sex cells. But the time commitment and risk involved in a woman's egg donation is far steeper than what a man goes through donating his sperm.

In the United States, egg donors generally net around $10,000-$12,000. Weill Cornell outlines the standard steps for egg donation , which requires about a four-week time commitment.

During the egg donation cycle, patients are injected with fertility drugs so that the ovaries make more mature eggs than normal. (Eligible women are generally between the ages of 21 and 30). The egg retrieval procedure takes about 20 minutes but may require several days of recovery. Donors should be aware of the risks involved (largely related to the hormones used) before signing up.

Related stories

Men are generally paid anywhere from $35 to $150 per sperm donation, according to The Sperm Bank of California , but sperm donation can really start to add up if you regularly donate samples (many programs require a six-month or one-year donation commitment).

Donors should bear in mind that even if they choose to donate anonymously, sperm and egg donation is never really 100% incognito. Your DNA always knows who you are.

Spend 45 days on a fake spaceship

Payout: $160/day

NASA will pay you to spend 45 days traveling in space. Well, sort of.

You'll actually be on the ground the whole time in Houston, Texas, but you'll be locked inside a model space capsule (650 square feet) along with three strangers. This simulation is designed to study what being cooped up for a very long time inside a spaceship might do to a person, both physically and mentally. NASA wants to check this out thoroughly before they start sending astronauts on missions to Mars, or to explore faraway asteroids.

Participants in NASA's human research program share a capsule with each other that includes some workspace for doing lab experiments, a little kitchen table for eating meals that are just like what's served aboard the International Space Station, plus an exercise bike and some free weights. There's no internet, but you do get your own little cozy sleeping pod on the top floor.

The fake astronauts "on board" the capsule in May and June of 2024 include an aerospace engineering professor, a US Air Force Reserve member, a commercial pilot, and a biomedical engineer.

And that mission is nothing compared to NASA's CHAPEA Mars simulation , which keeps recruits in a simulated habitat of the red planet for 378 days. (NASA declined to comment on how much CHAPEA pays).

Take part in a clinical trial

Payout: Varies by program

The National Institutes of Health run a searchable database, ClincalTrials.gov , that rounds up human clinical studies ongoing around the world. Participants may be guinea pigs for new medical products, like drugs to treat high blood pressure, or they take part in observational research, like a study that records the effects of different lifestyles on heart health.

Subjects are generally paid to participate in such clinical trials, and most of the time, the bigger the risk, the bigger the reward. For example, a participant in one study in which participants were exposed to dysentery-causing bacteria was paid over $7,000, while a single blood draw or lab visit for a more straightforward study may only be worth $100 or so.

If you do decide to enroll in a study, choose wisely and carefully because not all of the studies on the site are regulated or evaluated for safety by the US Food and Drug Administration.

Enroll in a psychological study

Paid psychological studies, such as those that examine human behavior and brain function, may not generate as high of a return as clinical trials, but they are generally lower risk and require a shorter time commitment.

Most research universities keep an online database of studies so people can easily sign up. For example, here's a list of the most recent paid research studies offered by New York University . At NYU, you can make $12 an hour playing video games, and receive a $50 bonus if you're good at it.

Give your dead body to science

Payout: free cremation

This last idea is sort of morbid, but if you're worried about being a bother when you're dead, you can donate your body to science . This helps with various types of research and education.

Places like BioGift and Science Care will cover the costs of cremation, which can run upwards of $2,000.

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Medicinal chemistry articles within Nature Chemistry

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Anticancer platinum-based photo-oxidants in a new light

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A hydroxide lock for metallo-β-lactamases

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News & Views | 01 June 2021

Expanding the effectiveness of screening

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News & Views | 30 March 2021

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The liberating force of ultrasound

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• Roman Boulatov

Article | 21 December 2020

Selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells

A method to label membrane proteins with a DNA tag has been developed that enables the selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells. As a demonstration, a 30-million-compound DNA-encoded chemical library is screened against folate receptor, carbonic anhydrase 12 and epidermal growth factor receptor on live cells.

• , Ling Meng

News & Views | 23 September 2020

Protein targeting with SAF(er) electrophiles

Electrophilic groups that undergo sulfur-exchange chemistry with protein nucleophiles can serve as the functional basis of chemical proteomic probes. A new addition to this class, sulfuramidimidoyl fluoride (SAF), which can be included in an array of covalent small molecule probes, exhibits a unique reactivity profile with proteins.

• Thomas E. Speltz
•  &  Raymond E. Moellering

Article | 24 August 2020

Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold–small molecule interactions

A selection-based screen has now revealed preferences in small-molecule chemotypes that bind RNA as well as preferences in the RNA motifs that bind small molecules. Analysis of these data enabled the design of a small molecule that selectively binds a non-coding microRNA and upregulates expression of vascular endothelial growth factor A.

• Hafeez S. Haniff
• , Laurent Knerr
•  &  Matthew D. Disney

Comment | 10 July 2020

Harder, better, faster

The gap between fundamental academic research and the applied industrial research that is necessary to ensure real-world applications can be bridged by engaging in well-defined collaborative academia–industry projects and fostering better communication between the scientists involved in them.

• Danielle Schultz
•  &  Louis-Charles Campeau

Correspondence | 18 June 2020

Crowdsourcing drug discovery for pandemics

• John Chodera
• , Alpha A. Lee
•  &  Frank von Delft

Thesis | 13 March 2020

A chemist’s cup of tea

Michelle Francl dips into the science of making tea.

Article | 16 December 2019

Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus , persisters and biofilms

Screening commercial kinase inhibitors for antibacterial activity identified the anticancer drug sorafenib as a major hit. Subsequent structure–activity optimization created a new antibacterial analogue with high potency against methicillin-resistant Staphylococcus aureus , including challenging persisters and biofilms, as well as demonstrating efficacy in an in vivo mouse model. The mode of action involves stimulation of protein secretion and inhibition of menaquinone biosynthesis.

• , Elena Kunold
•  &  Stephan A. Sieber

Article | 28 October 2019

Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs

A set of enantioprobes—photoreactive, clickable fragment pairs differing only in absolute stereochemistry—have been used to provide a robust and streamlined chemical proteomic map of small-molecule/protein interactions in human cells. More than 170 stereoselective fragment–protein interactions were discovered and shown to occur at functional sites on proteins from diverse classes.

• , Melissa M. Dix
•  &  Benjamin F. Cravatt

Article | 23 September 2019

Targeted photoredox catalysis in cancer cells

Current photodynamic therapy photosensitizers require oxygen; however, tumours are often hypoxic. Now, an organoiridium complex with an unusually high redox potential, which is effective in normoxia and hypoxia, has been developed. The organoiridium complex kills cancer cells by an immunogenic apoptotic mechanism involving efficient photocatalytic oxidation of NADH to NAD radicals, and reduction of cytochrome c .

• Huaiyi Huang
• , Samya Banerjee
•  &  Peter J. Sadler

Fungal indole alkaloid biogenesis through evolution of a bifunctional reductase/Diels–Alderase

The complete biosynthesis of the fungal indole alkaloid malbrancheamide, which culminates in an intramolecular [4+2] hetero-Diels–Alder cyclization to produce the bicyclo[2.2.2]diazaoctane scaffold, has now been discovered. Chemical synthesis and protein structural analysis were used to provide mechanistic insight into this enzyme-dependent diastereo- and enantioselective cycloaddition.

• Qingyun Dan
• , Sean A. Newmister
•  &  Robert M. Williams

Perspective | 02 September 2019

Towards the online computer-aided design of catalytic pockets

The shape complementarity between the active site of a catalyst and a substrate influences how effectively a reaction can be catalysed. Computational tools can be used to visualize the shape around the active centre of a range of catalysts and the application of such approaches to rationalize the behaviour of known catalysts — and to design new ones — is discussed.

• Laura Falivene
•  &  Luigi Cavallo

News & Views | 13 May 2019

Diverse engineering

Methods for generating molecular diversity provide a route to screen a wider section of chemical space, to discover compounds with useful biological properties. Now, a complexity-to-diversity strategy has enabled the discovery of a multi-cyclic structure from a complex natural product that induces ferroptotic cell death in cancer cells.

• Tatiana Cañeque
•  &  Raphaël Rodriguez

Article | 13 May 2019

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis

A set of stereochemically complex and structurally diverse compounds were created from the diterpene natural product pleuromutilin using the complexity-to-diversity strategy. Phenotypic screening identified a compound that induces rapid ferroptotic death of cancer cells. Experiments to probe the mechanism revealed the compound to be an inhibitor of thioredoxin.

• Evijola Llabani
• , Robert W. Hicklin
•  &  Paul J. Hergenrother

Article | 10 December 2018

Rapamycin-inspired macrocycles with new target specificity

Rapamycin and FK506 are macrocycles that contain an FKBP-binding domain and an effector domain responsible for interacting with their respective targets, mTOR and calcineurin. Now, a 45,000-compound macrocycle library has been synthesized by fusing oligopeptides with synthetic FKBP-binding domains. Screening and subsequent optimization yielded a highly potent FKBP-dependent inhibitor of hENT1.

• , Sam Y. Hong
•  &  Jun O. Liu

Article | 08 October 2018

Inhibiting amyloid-β cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design

Inhibiting the interaction between amyloid-β (Aβ) and a neuronal cell surface receptor, LilrB2, could offer a potential route for treating Alzheimer’s disease. Now, binding sites between Aβ and LilrB2 have been discovered and computational selection has identified inhibitors that block this binding site. Cell-penetrating inhibitors were found to block the Aβ–LilrB2 interaction and limit Aβ-induced cytotoxicity.

• , Woo Shik Shin
•  &  Lin Jiang

News & Views | 20 September 2018

A positive positive to negative

The structure of an antibiotic that is effective against Gram-positive bacteria, but not against Gram-negative bacteria, has now been modified to improve its effectiveness against Gram-negative bacteria. The approach could help broaden the spectrum of activity of other antibiotics.

• Jed F. Fisher
•  &  Shahriar Mobashery

Article | 10 September 2018

Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and -3

New natural-product-inspired molecules are often limited by their only partial coverage of biologically relevant chemical space. Combining fragments of natural products has now been shown to yield pseudo natural products, which — while still being inspired by natural products — populate previously unexplored areas of chemical space and have novel biological activities.

• George Karageorgis
• , Elena S. Reckzeh
•  &  Herbert Waldmann

Editorial | 21 June 2018

Ring binders

Encoded chemical libraries can be used to screen a vast array of compounds against a protein target to identify potent binders. A collection of articles in this issue discuss different methods to increase the chemical space sampled by encoded macrocycle libraries and the advantages that such libraries offer for discovering new drug leads.

Browse broader subjects

• Drug discovery

Browse narrower subjects

• Chemical libraries
• Cheminformatics
• Computational chemistry
• Drug delivery
• Drug discovery and development
• Lead optimization
• Pharmacology
• Structure-based drug design
• Target identification
• Target validation

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