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• April 01, 2024 | VOL. 181, NO. 4 CURRENT ISSUE pp.255-346
• March 01, 2024 | VOL. 181, NO. 3 pp.171-254
• February 01, 2024 | VOL. 181, NO. 2 pp.83-170
• January 01, 2024 | VOL. 181, NO. 1 pp.1-82

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Substance Use Disorders and Addiction: Mechanisms, Trends, and Treatment Implications

• Ned H. Kalin , M.D.

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The numbers for substance use disorders are large, and we need to pay attention to them. Data from the 2018 National Survey on Drug Use and Health ( 1 ) suggest that, over the preceding year, 20.3 million people age 12 or older had substance use disorders, and 14.8 million of these cases were attributed to alcohol. When considering other substances, the report estimated that 4.4 million individuals had a marijuana use disorder and that 2 million people suffered from an opiate use disorder. It is well known that stress is associated with an increase in the use of alcohol and other substances, and this is particularly relevant today in relation to the chronic uncertainty and distress associated with the COVID-19 pandemic along with the traumatic effects of racism and social injustice. In part related to stress, substance use disorders are highly comorbid with other psychiatric illnesses: 9.2 million adults were estimated to have a 1-year prevalence of both a mental illness and at least one substance use disorder. Although they may not necessarily meet criteria for a substance use disorder, it is well known that psychiatric patients have increased usage of alcohol, cigarettes, and other illicit substances. As an example, the survey estimated that over the preceding month, 37.2% of individuals with serious mental illnesses were cigarette smokers, compared with 16.3% of individuals without mental illnesses. Substance use frequently accompanies suicide and suicide attempts, and substance use disorders are associated with a long-term increased risk of suicide.

Addiction is the key process that underlies substance use disorders, and research using animal models and humans has revealed important insights into the neural circuits and molecules that mediate addiction. More specifically, research has shed light onto mechanisms underlying the critical components of addiction and relapse: reinforcement and reward, tolerance, withdrawal, negative affect, craving, and stress sensitization. In addition, clinical research has been instrumental in developing an evidence base for the use of pharmacological agents in the treatment of substance use disorders, which, in combination with psychosocial approaches, can provide effective treatments. However, despite the existence of therapeutic tools, relapse is common, and substance use disorders remain grossly undertreated. For example, whether at an inpatient hospital treatment facility or at a drug or alcohol rehabilitation program, it was estimated that only 11% of individuals needing treatment for substance use received appropriate care in 2018. Additionally, it is worth emphasizing that current practice frequently does not effectively integrate dual diagnosis treatment approaches, which is important because psychiatric and substance use disorders are highly comorbid. The barriers to receiving treatment are numerous and directly interact with existing health care inequities. It is imperative that as a field we overcome the obstacles to treatment, including the lack of resources at the individual level, a dearth of trained providers and appropriate treatment facilities, racial biases, and the marked stigmatization that is focused on individuals with addictions.

This issue of the Journal is focused on understanding factors contributing to substance use disorders and their comorbidity with psychiatric disorders, the effects of prenatal alcohol use on preadolescents, and brain mechanisms that are associated with addiction and relapse. An important theme that emerges from this issue is the necessity for understanding maladaptive substance use and its treatment in relation to health care inequities. This highlights the imperative to focus resources and treatment efforts on underprivileged and marginalized populations. The centerpiece of this issue is an overview on addiction written by Dr. George Koob, the director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and coauthors Drs. Patricia Powell (NIAAA deputy director) and Aaron White ( 2 ). This outstanding article will serve as a foundational knowledge base for those interested in understanding the complex factors that mediate drug addiction. Of particular interest to the practice of psychiatry is the emphasis on the negative affect state “hyperkatifeia” as a major driver of addictive behavior and relapse. This places the dysphoria and psychological distress that are associated with prolonged withdrawal at the heart of treatment and underscores the importance of treating not only maladaptive drug-related behaviors but also the prolonged dysphoria and negative affect associated with addiction. It also speaks to why it is crucial to concurrently treat psychiatric comorbidities that commonly accompany substance use disorders.

Insights Into Mechanisms Related to Cocaine Addiction Using a Novel Imaging Method for Dopamine Neurons

Cassidy et al. ( 3 ) introduce a relatively new imaging technique that allows for an estimation of dopamine integrity and function in the substantia nigra, the site of origin of dopamine neurons that project to the striatum. Capitalizing on the high levels of neuromelanin that are found in substantia nigra dopamine neurons and the interaction between neuromelanin and intracellular iron, this MRI technique, termed neuromelanin-sensitive MRI (NM-MRI), shows promise in studying the involvement of substantia nigra dopamine neurons in neurodegenerative diseases and psychiatric illnesses. The authors used this technique to assess dopamine function in active cocaine users with the aim of exploring the hypothesis that cocaine use disorder is associated with blunted presynaptic striatal dopamine function that would be reflected in decreased “integrity” of the substantia nigra dopamine system. Surprisingly, NM-MRI revealed evidence for increased dopamine in the substantia nigra of individuals using cocaine. The authors suggest that this finding, in conjunction with prior work suggesting a blunted dopamine response, points to the possibility that cocaine use is associated with an altered intracellular distribution of dopamine. Specifically, the idea is that dopamine is shifted from being concentrated in releasable, functional vesicles at the synapse to a nonreleasable cytosolic pool. In addition to providing an intriguing alternative hypothesis underlying the cocaine-related alterations observed in substantia nigra dopamine function, this article highlights an innovative imaging method that can be used in further investigations involving the role of substantia nigra dopamine systems in neuropsychiatric disorders. Dr. Charles Bradberry, chief of the Preclinical Pharmacology Section at the National Institute on Drug Abuse, contributes an editorial that further explains the use of NM-MRI and discusses the theoretical implications of these unexpected findings in relation to cocaine use ( 4 ).

Treatment Implications of Understanding Brain Function During Early Abstinence in Patients With Alcohol Use Disorder

Developing a better understanding of the neural processes that are associated with substance use disorders is critical for conceptualizing improved treatment approaches. Blaine et al. ( 5 ) present neuroimaging data collected during early abstinence in patients with alcohol use disorder and link these data to relapses occurring during treatment. Of note, the findings from this study dovetail with the neural circuit schema Koob et al. provide in this issue’s overview on addiction ( 2 ). The first study in the Blaine et al. article uses 44 patients and 43 control subjects to demonstrate that patients with alcohol use disorder have a blunted neural response to the presentation of stress- and alcohol-related cues. This blunting was observed mainly in the ventromedial prefrontal cortex, a key prefrontal regulatory region, as well as in subcortical regions associated with reward processing, specifically the ventral striatum. Importantly, this finding was replicated in a second study in which 69 patients were studied in relation to their length of abstinence prior to treatment and treatment outcomes. The results demonstrated that individuals with the shortest abstinence times had greater alterations in neural responses to stress and alcohol cues. The authors also found that an individual’s length of abstinence prior to treatment, independent of the number of days of abstinence, was a predictor of relapse and that the magnitude of an individual’s neural alterations predicted the amount of heavy drinking occurring early in treatment. Although relapse is an all too common outcome in patients with substance use disorders, this study highlights an approach that has the potential to refine and develop new treatments that are based on addiction- and abstinence-related brain changes. In her thoughtful editorial, Dr. Edith Sullivan from Stanford University comments on the details of the study, the value of studying patients during early abstinence, and the implications of these findings for new treatment development ( 6 ).

Relatively Low Amounts of Alcohol Intake During Pregnancy Are Associated With Subtle Neurodevelopmental Effects in Preadolescent Offspring

Excessive substance use not only affects the user and their immediate family but also has transgenerational effects that can be mediated in utero. Lees et al. ( 7 ) present data suggesting that even the consumption of relatively low amounts of alcohol by expectant mothers can affect brain development, cognition, and emotion in their offspring. The researchers used data from the Adolescent Brain Cognitive Development Study, a large national community-based study, which allowed them to assess brain structure and function as well as behavioral, cognitive, and psychological outcomes in 9,719 preadolescents. The mothers of 2,518 of the subjects in this study reported some alcohol use during pregnancy, albeit at relatively low levels (0 to 80 drinks throughout pregnancy). Interestingly, and opposite of that expected in relation to data from individuals with fetal alcohol spectrum disorders, increases in brain volume and surface area were found in offspring of mothers who consumed the relatively low amounts of alcohol. Notably, any prenatal alcohol exposure was associated with small but significant increases in psychological problems that included increases in separation anxiety disorder and oppositional defiant disorder. Additionally, a dose-response effect was found for internalizing psychopathology, somatic complaints, and attentional deficits. While subtle, these findings point to neurodevelopmental alterations that may be mediated by even small amounts of prenatal alcohol consumption. Drs. Clare McCormack and Catherine Monk from Columbia University contribute an editorial that provides an in-depth assessment of these findings in relation to other studies, including those assessing severe deficits in individuals with fetal alcohol syndrome ( 8 ). McCormack and Monk emphasize that the behavioral and psychological effects reported in the Lees et al. article would not be clinically meaningful. However, it is feasible that the influences of these low amounts of alcohol could interact with other predisposing factors that might lead to more substantial negative outcomes.

Increased Comorbidity Between Substance Use and Psychiatric Disorders in Sexual Identity Minorities

There is no question that victims of societal marginalization experience disproportionate adversity and stress. Evans-Polce et al. ( 9 ) focus on this concern in relation to individuals who identify as sexual minorities by comparing their incidence of comorbid substance use and psychiatric disorders with that of individuals who identify as heterosexual. By using 2012−2013 data from 36,309 participants in the National Epidemiologic Study on Alcohol and Related Conditions–III, the authors examine the incidence of comorbid alcohol and tobacco use disorders with anxiety, mood disorders, and posttraumatic stress disorder (PTSD). The findings demonstrate increased incidences of substance use and psychiatric disorders in individuals who identified as bisexual or as gay or lesbian compared with those who identified as heterosexual. For example, a fourfold increase in the prevalence of PTSD was found in bisexual individuals compared with heterosexual individuals. In addition, the authors found an increased prevalence of substance use and psychiatric comorbidities in individuals who identified as bisexual and as gay or lesbian compared with individuals who identified as heterosexual. This was most prominent in women who identified as bisexual. For example, of the bisexual women who had an alcohol use disorder, 60.5% also had a psychiatric comorbidity, compared with 44.6% of heterosexual women. Additionally, the amount of reported sexual orientation discrimination and number of lifetime stressful events were associated with a greater likelihood of having comorbid substance use and psychiatric disorders. These findings are important but not surprising, as sexual minority individuals have a history of increased early-life trauma and throughout their lives may experience the painful and unwarranted consequences of bias and denigration. Nonetheless, these findings underscore the strong negative societal impacts experienced by minority groups and should sensitize providers to the additional needs of these individuals.

Trends in Nicotine Use and Dependence From 2001–2002 to 2012–2013

Although considerable efforts over earlier years have curbed the use of tobacco and nicotine, the use of these substances continues to be a significant public health problem. As noted above, individuals with psychiatric disorders are particularly vulnerable. Grant et al. ( 10 ) use data from the National Epidemiologic Survey on Alcohol and Related Conditions collected from a very large cohort to characterize trends in nicotine use and dependence over time. Results from their analysis support the so-called hardening hypothesis, which posits that although intervention-related reductions in nicotine use may have occurred over time, the impact of these interventions is less potent in individuals with more severe addictive behavior (i.e., nicotine dependence). When adjusted for sociodemographic factors, the results demonstrated a small but significant increase in nicotine use from 2001–2002 to 2012–2013. However, a much greater increase in nicotine dependence (46.1% to 52%) was observed over this time frame in individuals who had used nicotine during the preceding 12 months. The increases in nicotine use and dependence were associated with factors related to socioeconomic status, such as lower income and lower educational attainment. The authors interpret these findings as evidence for the hardening hypothesis, suggesting that despite the impression that nicotine use has plateaued, there is a growing number of highly dependent nicotine users who would benefit from nicotine dependence intervention programs. Dr. Kathleen Brady, from the Medical University of South Carolina, provides an editorial ( 11 ) that reviews the consequences of tobacco use and the history of the public measures that were initially taken to combat its use. Importantly, her editorial emphasizes the need to address health care inequity issues that affect individuals of lower socioeconomic status by devoting resources to develop and deploy effective smoking cessation interventions for at-risk and underresourced populations.

Conclusions

Maladaptive substance use and substance use disorders are highly prevalent and are among the most significant public health problems. Substance use is commonly comorbid with psychiatric disorders, and treatment efforts need to concurrently address both. The papers in this issue highlight new findings that are directly relevant to understanding, treating, and developing policies to better serve those afflicted with addictions. While treatments exist, the need for more effective treatments is clear, especially those focused on decreasing relapse rates. The negative affective state, hyperkatifeia, that accompanies longer-term abstinence is an important treatment target that should be emphasized in current practice as well as in new treatment development. In addition to developing a better understanding of the neurobiology of addictions and abstinence, it is necessary to ensure that there is equitable access to currently available treatments and treatment programs. Additional resources must be allocated to this cause. This depends on the recognition that health care inequities and societal barriers are major contributors to the continued high prevalence of substance use disorders, the individual suffering they inflict, and the huge toll that they incur at a societal level.

Disclosures of Editors’ financial relationships appear in the April 2020 issue of the Journal .

1 US Department of Health and Human Services: Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality: National Survey on Drug Use and Health 2018. Rockville, Md, SAMHSA, 2019 ( https://www.samhsa.gov/data/nsduh/reports-detailed-tables-2018-NSDUH ) Google Scholar

2 Koob GF, Powell P, White A : Addiction as a coping response: hyperkatifeia, deaths of despair, and COVID-19 . Am J Psychiatry 2020 ; 177:1031–1037 Link ,  Google Scholar

3 Cassidy CM, Carpenter KM, Konova AB, et al. : Evidence for dopamine abnormalities in the substantia nigra in cocaine addiction revealed by neuromelanin-sensitive MRI . Am J Psychiatry 2020 ; 177:1038–1047 Link ,  Google Scholar

4 Bradberry CW : Neuromelanin MRI: dark substance shines a light on dopamine dysfunction and cocaine use (editorial). Am J Psychiatry 2020 ; 177:1019–1021 Abstract ,  Google Scholar

5 Blaine SK, Wemm S, Fogelman N, et al. : Association of prefrontal-striatal functional pathology with alcohol abstinence days at treatment initiation and heavy drinking after treatment initiation . Am J Psychiatry 2020 ; 177:1048–1059 Abstract ,  Google Scholar

6 Sullivan EV : Why timing matters in alcohol use disorder recovery (editorial). Am J Psychiatry 2020 ; 177:1022–1024 Abstract ,  Google Scholar

7 Lees B, Mewton L, Jacobus J, et al. : Association of prenatal alcohol exposure with psychological, behavioral, and neurodevelopmental outcomes in children from the Adolescent Brain Cognitive Development Study . Am J Psychiatry 2020 ; 177:1060–1072 Link ,  Google Scholar

8 McCormack C, Monk C : Considering prenatal alcohol exposure in a developmental origins of health and disease framework (editorial). Am J Psychiatry 2020 ; 177:1025–1028 Abstract ,  Google Scholar

9 Evans-Polce RJ, Kcomt L, Veliz PT, et al. : Alcohol, tobacco, and comorbid psychiatric disorders and associations with sexual identity and stress-related correlates . Am J Psychiatry 2020 ; 177:1073–1081 Abstract ,  Google Scholar

10 Grant BF, Shmulewitz D, Compton WM : Nicotine use and DSM-IV nicotine dependence in the United States, 2001–2002 and 2012–2013 . Am J Psychiatry 2020 ; 177:1082–1090 Link ,  Google Scholar

11 Brady KT : Social determinants of health and smoking cessation: a challenge (editorial). Am J Psychiatry 2020 ; 177:1029–1030 Abstract ,  Google Scholar

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• Published: 12 August 2021

Drug addiction: from bench to bedside

• Julian Cheron 1 &
• Alban de Kerchove d’Exaerde   ORCID: orcid.org/0000-0002-0682-5877 1  

Translational Psychiatry volume  11 , Article number:  424 ( 2021 ) Cite this article

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• Molecular neuroscience

Drug addiction is responsible for millions of deaths per year around the world. Still, its management as a chronic disease is shadowed by misconceptions from the general public. Indeed, drug consumers are often labelled as “weak”, “immoral” or “depraved”. Consequently, drug addiction is often perceived as an individual problem and not societal. In technical terms, drug addiction is defined as a chronic, relapsing disease resulting from sustained effects of drugs on the brain. Through a better characterisation of the cerebral circuits involved, and the long-term modifications of the brain induced by addictive drugs administrations, first, we might be able to change the way the general public see the patient who is suffering from drug addiction, and second, we might be able to find new treatments to normalise the altered brain homeostasis. In this review, we synthetise the contribution of fundamental research to the understanding drug addiction and its contribution to potential novel therapeutics. Mostly based on drug-induced modifications of synaptic plasticity and epigenetic mechanisms (and their behavioural correlates) and after demonstration of their reversibility, we tried to highlight promising therapeutics. We also underline the specific temporal dynamics and psychosocial aspects of this complex psychiatric disease adding parameters to be considered in clinical trials and paving the way to test new therapeutic venues.

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Introduction

Drug addiction including smoking, alcohol and illicit drug use is indirectly or directly responsible for 11.8 million deaths each year in the world [ 1 ]. According to the Global Burden of Disease study, this number is higher than deaths from cancer and accounts for a fifth of all deaths around the world [ 1 ].

Drug addiction is defined as a chronic, relapsing disease that results from the prolonged effects of drugs on the brain. Similarly to other neuropsychiatric diseases, drug addiction is intermingled with behavioural and social aspects that are equally important parts of the disease, complicating the overall therapeutic approach. Actually, it is only recently, in the beginning of the 21st century, that we started to see “the drug-addict” as someone suffering from a disease and whose brain has been altered fundamentally by drugs [ 2 ]. Therefore, the most effective treatment approaches include biological, behavioural and social-context components. Based on the latest scientific advances, treatment and management of drug addiction patients point towards a personalised strategy [ 3 ]. However, there are very few objective and effective strategies for treating drug addiction. Without the mandatory mechanistic basic knowledge on drug addiction, the development of new therapeutic strategies is postponed.

The neurobiological circuits and mechanisms that support compulsive seeking and consumption of drugs with addictive potential are partially known. They comprise a progressive shift in the involvement of ventral to dorsal and medial to lateral striatal circuitry [ 4 , 5 ], along with molecular and cellular adaptations to drugs of abuse exposure. They include neuronal and synaptic plasticity and modifications in gene expression, in part through epigenetic mechanisms [ 6 ]. Notably, drug-induced neuronal modifications can also occur in non-pathological processes, underlying the fact that drugs of abuse hijack normal adaptive changes in the brain [ 7 ]. Indeed, laboratory and clinical observations suggest that addiction is driven by the usurpation of neuronal processes that normally serve reward-related learning and memory. Most of the modifications that have been shown to be involved in a state of addiction (modified gene transcription, epigenetics, neuronal plasticity and neurotrophic mechanisms) are also associated with physiological forms of behavioural memory in murine model such as spatial memory, fear conditioning and operant conditioning [ 7 , 8 ].

We know that only a proportion of individuals (depending of the drug type) will develop drug addiction after several exposures [ 9 ]. This individual vulnerability is probably linked to both genetic and environmental factors [ 10 ]. Drug addiction is highly polygenic, as hundreds of genetic variations combined result in variable vulnerability [ 11 , 12 ]. Several types of environmental factors have been characterised and interact with an individual genetic background [ 12 , 13 ]. Psychosocial stress is one of the factors, but the most important one, is by far, the exposure to drugs of abuse. Usually, drug abuse starts with a ‘gateway’ drug (mostly socially driven) catapulting the individual vulnerability to other drugs of abuse [ 14 ].

During the last three decades, combine effort has been dedicated to identify brain regions and molecular pathways involved in the development of addiction to drugs of abuse. Here, we will focus on experimental approaches that helped to provide a clearer picture on the physiopathology of drug addiction guiding therapeutic opportunities.

Converging actions on brain reward pathway elicit its remodelling

The circuit at the centre of the disease is the mesolimbic pathway, also referred as the reward pathway (Fig. 1 ). The mesolimbic pathway includes dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain and their targets in the limbic forebrain, especially the nucleus accumbens (NAc), a major component of the ventral striatum. The GABA medium-sized spiny neurons (MSNs, ~95% of striatal neurons), which are targets of glutamatergic and dopaminergic inputs, form two pathways [ 15 ]. The dopamine D1 receptor–positive (D1R) striatonigral MSNs project to the medial globus pallidus and substantia nigra pars reticulata (direct pathway) and coexpress dopamine D1 receptors and substance P, whereas D2R striatopallidal MSNs project to the lateral globus pallidus (indirect pathway) and coexpress dopamine D2 receptor, adenosine A2A receptor and enkephalin [ 16 , 17 ]. Through different initial mechanisms, drugs of abuse increase the release of dopamine in the NAc from the VTA [ 18 , 19 , 20 ]. This VTA-NAc pathway could be seen as primum movens for the acute rewarding effects of all drugs of abuse. Regardless that drugs of abuse have distinct protein targets and mechanisms of action, in the end, the main addiction-related modifications are common to nearly all drugs of abuse and converge on the VTA and NAc with common acute functional effects [ 21 ]. It is schematically conjectured, that when stimulated by dopamine, cells in the NAc produce feelings of reward and satisfaction [ 22 ]. The physiological function of this response is to facilitate the motivation for basic biological goal-directed behaviours as survival, social interaction and reproduction. By artificially causing a build-up of dopamine in the NAc, drugs of abuse generate an artificial reward effect [ 22 ]. As all drugs of abuse increase dopaminergic transmission to the NAc after acute administration, they also produce shared modifications in the mesolimbic system after chronic exposure. They include (i) hypofunction of the dopamine pathway that is seen as a major contributor to the negative emotional symptoms associated to drug withdrawal, leading to drug craving and relapse, and (ii) drug-induced adaptations in glutamatergic afferents to the NAc [ 23 , 24 ]. Clearly, these modifications in the mesolimbic system after the exposure to drugs of abuse is oversimplified. The hypofunction of dopaminergic system hypothesis is self-fulfilling in that research work has principally focused on dopamine to the exclusion of other neurotransmitters. Actually, some drug of abuse reinforcement appears to be independent of the mesocorticolimbic dopamine system (e.g. opioids [ 25 ], nicotine [ 26 ]), but support self-administration by imitating the effect of dopamine in the nucleus accumbens [ 21 , 27 , 28 ].

Addictive drugs of different types have a common effect of increasing levels of dopamine released by neurons projecting from the ventral tegmental area (VTA). This effect is central for initial drug reinforcement. Notably, drug taking with initial reinforcement involves a potentiation of the projection from prefrontal cortex (PFC) to nucleus accumbens (NAc), while other glutamatergic projections are mostly involved in craving, like basolateral amygdala (BLA)-NAc projection, or in withdrawal/negative symptoms, like paraventricular thalamus (PVT)-NAc projection. With increasing administration of drugs of abuse and progressive shift toward compulsive abuse, the dorsal (dorso-lateral) striatum seems more and more implicated, with dopaminergic cells involved shifting progressively from the VTA to the substantia nigra pars compacta (SNc) [ 4 ]. Recently, data acquired through optogenetic dopamine neuron self-stimulation suggested prominent synaptic strengthening of the orbitofrontal cortex (OFC) to dorsal (dorso-medial) striatum projection in compulsive mice [ 31 ].

Drug addiction is conceptually defined as a three-stages cycle: (1) consumption/binge/intoxication, (2) withdrawal with its negative affect and (3) craving stage (Fig. 2 ) [ 27 ]. Animal models and human imaging studies have exposed the different brain areas involved in each of these stages. Briefly, the VTA-NAc (for reinforcement) and dorsal striatum (for stimulus-response habits) are important for the consumption/binge/intoxication stage, the extended amygdala with the hypothalamus and the brainstem in the withdrawal stage and cortical areas, the dorsal striatum, the hippocampus and the basolateral amygdala in the craving stage (Fig. 2 ).

Progression to addiction is defined as a transition between three consecutive phases [ 252 ]: (1) Recreational, sporadic drug taking, in which drug of abuse administration is occasional and one activity among many other distractions of the individual. (2) Intensified and sustained drug use, in which drug administration strengthens and becomes the principal recreational activity of the individual; at this phase drug taking becomes a habit. (3) Loss of control of drug use and addiction, in which drug seeking and taking are now the principal activity of the patient. The first phase can occur to every person as drugs of abuse hijack the same brain circuit as natural rewards. The second phase occurs only in vulnerable users. The phase of addiction seems to be due to a second vulnerable trait with loss of control and compulsivity. Three stages of addiction are described [ 27 ]: (1) Binge/intoxication stage: reinforcing effects of drugs may initially use mainly dopamine and opioid peptides in the nucleus accumbens (NAc) and involves the ventral tegmental area (VTA). Subsequently, cue–response habits develop and includes the substantia nigra pars compacta (SNc) and the dorsal striatum. (2) Withdrawal/negative affect stage: the negative emotional state of withdrawal may involve the extended amygdala with corticotropin-releasing factor (CRF), norepinephrine and dynorphin as key neurotransmitters. Main projections of the extended amygdala consist of the hypothalamus and brainstem. (3) Craving stage: this stage includes conditioned reinforcement in the basolateral amygdala (BLA) and contextual processes in the hippocampus. This is controlled by cortical areas (prefrontal cortex (PFC) and orbitofrontal cortex (OFC)). A key neurotransmitter involved in the craving stage is glutamate.

The progression of drug addiction begins with the first exposure, mostly when the drug is taken voluntarily for its recreational and hedonic effect, and progressively consolidates during repeated but still controlled drug use. While administration intensifies along with loss of control over drug intake, drug use becomes habitual and compulsive in vulnerable individuals [ 4 , 29 , 30 ] (Fig. 2 ). This progression from voluntary drug intake to habitual and compulsive use represents a progression from ventromedial to more dorsolateral regions of the striatum and from prefrontal cortex (PFC) to orbitofrontal (OFC) and more global cortical region [ 4 , 31 ] (Fig. 1 ).

Synaptic plasticity

Brain plasticity is a fascinating capacity allowing appropriate modification of the neural activity in response to new experiences and environmental stimuli [ 32 ]. Modifying the synaptic strength between neurons is widely assumed to be the mechanism by which memory is encoded and stored in the brain [ 7 ]. Hence, it is appealing to hypothesise that drugs of abuse cause long-term alterations on behaviour by changing synaptic plasticity in key brain circuits [ 4 , 7 , 32 ].

Drugs of abuse such as cocaine induce specific synaptic plasticity in the mesolimbic circuitry. One single injection of an addictive drug can already modify the excitatory synaptic strengths in the VTA. Indeed, it has been extensively shown that the AMPA/NMDA ratio is increased in VTA dopamine neurons after one dose of cocaine and that some glutamate AMPA receptor 2 (GluA2)-containing AMPA receptors (AMPARs) are exchanged for GluA2-lacking ones [ 33 , 34 ]. At the same time, NMDA receptor (NMDAR) function decreases. All these elements cause an impairment in eliciting long-term potentiation (LTP). Different types of synaptic plasticity in VTA dopamine neurons induced by rewarding and aversive experiences are comprehensively reviewed by Pignatelli and Bonci [ 35 ]. Midbrain dopamine neurons are central in the mesolimbic circuitry for both natural rewards and drugs of abuse [ 18 , 36 ]. The VTA is known to be a central hub integrating numerous inhibitory inputs as GABAergic synapses represents 50–80% of all synapses onto VTA dopamine neurons [ 37 , 38 , 39 ]. GABAergic inhibition of dopamine neurons is mediated by both fast ionotropic GABA A receptors and slow metabotropic GABA B receptors [ 40 ].

In 2017, Edwards et al. [ 41 ] showed that the principal monosynaptic projection to VTA dopamine neurons arising from the NAc [ 42 ] inhibits the firing of dopamine neurons via activation of GABA B receptors, whereas local VTA inhibitory interneurons inhibits dopamine neurons through GABA A receptors. Today, it is well established that pharmacological activation of GABA B receptors (e.g. by baclofen) reduces cue-associated cocaine craving as well as reduce cocaine use in humans [ 43 , 44 , 45 ] and it reduces rewarding and reinforcing effects of cocaine on animal models [ 46 , 47 , 48 , 49 ]. Edwards et al. report [ 41 ] indicates that the therapeutic effects of baclofen might pass through VTA dopamine neurons’ GABA B receptors. Intrathecal Baclofen is an effective and safe long-term treatment used worldwide to treat severe spasticity [ 50 , 51 ]. Oral baclofen is less effective and has significant rates of side effects, like sedation, somnolence, vertigo and headache especially when prescribed off-label for drug addiction (because higher doses are commonly used) [ 51 , 52 ] . . Indeed, contrasting results on the effect of baclofen in reducing alcohol craving [ 53 , 54 , 55 ] and cocaine dependence [ 43 , 56 ] were probably due to different severity of alcohol dependence of the enroled patients. This is way higher dose are tested and often prescribed off-label for drug addiction [ 55 ]. Thus, self-poisoning that could lead to severe toxicity and death represents one the major concern of baclofen use in drug addiction. Therefore, baclofen should be prescribed with caution and close monitoring [ 52 , 57 ].

Together with drug of abuse-induced LTP at excitatory synapses, plasticity of GABAergic inhibitory synapse in the VTA also have an impact on the firing rate of VTA neurons, at least following opioid [ 58 ] and cocaine administration [ 59 ]. Normally, NMDA activation, during excitatory LTP (induced by high-frequency stimulation), leads to the release of NO that will activate guanylate cyclase in adjacent GABAergic terminals, which in turn, leads to increase in GABA release. This presynaptic NMDA receptor-dependent GABAergic LTP heterosynaptic plasticity, is named LTP GABA . Nugent el al. [ 58 ] showed that opioids blocks LTP GABA through a disruption of the coupling between nitric oxide (NO) and guanylate cyclase. The incapability of GABAergic synapses to potentiate after morphine or cocaine administration may promote LTP of glutamatergic synapses [ 58 , 59 ]. The early loss of inhibitory control combined with potentiation of glutamatergic synapses on dopaminergic neurons might represent adaptations that increase vulnerability to addiction [ 58 , 59 ]. Furthermore, GABA A receptor modulators modify the addictive drugs effects [ 60 , 61 ], and targeting these receptors might be seen as an effective therapeutic strategy but precluded by many side effects among which dependence itself [ 62 , 63 , 64 ].

In addition to the discovery of LTP GABA , Nugent’s group showed that morphine is also able to modulate a form of postsynaptic LTD (LTD GABA ) at GABAergic synapses onto VTA dopamine neurons. Remarkably, after a single administration of morphine, LTD GABA was absent in slices from morphine-treated rats while unaffected in slices from saline-treated rats, indicating a bidirectional control of morphine on GABAergic synaptic plasticity in the VTA [ 65 ]. This absence of LTD GABA is suggested to result from an occlusion effect due to prior morphine-induced decrease in GABAergic synaptic strength through potentiation of glutamatergic transmission and mediated by endocannabinoid signalling [ 66 ]. It is also possible that morphine alters the ability of synapses to exhibit evoked LTP or LTD in the VTA. Previous experiences such as exposure to drugs of abuse, stress, visual or sensory deprivation can change the ability of synapses to undergo subsequent plasticity in response to LTP and LTD induction protocols. This concept of modification of plasticity capability is referred as metaplasticity [ 67 ].

In the NAc, chronic exposure to addictive drugs induces specific synaptic changes that are different from those of the VTA, including a decrease of the AMPA/NMDA ratio as some AMPARs are endocytosed. This leads to a depressed synapse (sometimes referred as long-term depression (LTD) like state), where NMDAR-dependent LTD is reduced or, in some experiments, abolished [ 68 , 69 ]. Highlighting the importance of temporal aspects, studies of withdrawal period after chronic administration of cocaine, showed that synaptic AMPAR levels increase during the first week of withdrawal and persist elevated for weeks [ 70 , 71 , 72 ]. It is established that cocaine challenge transiently decreases AMPAR surface expression, while AMPARs recover back to upregulated levels within a week, with a continuous increase during what is known to be the incubation of craving stage [ 73 ].

The abstinence period after withdrawal is of particular interest considering the classical progression of the disease, the chance of relapse and the opportunity for new therapeutic targets. A seemingly counterintuitive concept named ‘incubation of cocaine craving’ was introduced by Grimm et al. [ 74 ] who modelled cocaine-craving behaviour by using rats trained to press a lever to receive an injection of cocaine and were then forced in a withdrawal period where cocaine reward was no longer given. This concept of ‘incubation’ did not originate in drug addiction research but came from a four-stage model of the creative process proposed by Graham Wallas in 1926 [ 75 ]. Consistent with clinical observations in humans [ 76 , 77 , 78 ], they showed that relapse was progressively stronger over 2 months of cocaine withdrawal and suggest that a craving syndrome progresses or ‘incubates’ during the first 2 months of cocaine abstinence, and probably lasts for longer [ 74 ]. Subsequently, it was shown that this increase was due to the addition of new AMPARs lacking GluA2 and that these new receptors mediate the ‘incubation of cocaine craving’ [ 72 ]. Conrad et al. [ 72 ] showed that after extended withdrawal from cocaine, addition of synaptic AMPARs together with the increased conductance of GluA2-lacking AMPARs triggers higher sensitivity of NAc neurons to cocaine-related cues, leading to a strengthening of drug craving syndrome and relapse. In line with these results, it was suggested that as soon as abstinence is reached, the risk of relapse might be reduced if GluA2-lacking AMPARs were inactivated or removed from NAc synapses. It was thus proposed that GluA2-lacking AMPARs could be a new target for drug development for the treatment of cocaine addiction. While these calcium permeable AMPARs are also critical for the pathogenesis of numerous other neurological disorders (including epilepsy [ 79 ], fragile X syndrome [ 80 ], amyotrophic lateral sclerosis [ 81 ], Parkinson’s [ 82 ] and Alzheimer’s [ 83 ] diseases), developing drugs that specifically target them and not calcium-impermeable AMPARs, which are critical for normal CNS function, is challenging [ 84 ] (Fig. 3 ).

DNA is packaged inside nuclei with the help of histones. These are positively charged proteins that strongly adhere to negatively charged DNA and form complexes called nucleosomes. Each nucleosome is composed of DNA wound around histone octomers (H2A, H2B, H3 and H4). Nucleosomes fold up to form chromatin fibre, which forms loops compressed and folded to produce fibres, which are coiled into the chromatid of a chromosome. Only by loosening compacted chromatin, the DNA of a specific gene can be made accessible to transcription. Some of these drug-induced modifications at the chromatin level are extremely stable and sustain the drug of abuse-induced long-term behaviours. Among them, histone post-translational modifications (PTMs) are known to be causally involved in drug-induced behaviours [ 194 ]. PTMs include acetylation (Ac), methylation (Me), phosphorylation (P), ADP ribosylation (PolyADP-R) and dopaminylation (DA), among a growing list of newly discovered modifications [ 162 , 172 ]. For example, while ubiquitylation (Ub) of H2A is known to be a key interactor of H3 methylation [ 253 ], its supposed role in drug addiction is still unknown. At this epigenetic level, some drugs were demonstrated to have an influence on drug-induces behaviours such as histone deacetylase (HDAC), bromodomain and DNA methyltransferase inhibitors. Locus-specific epigenome editing is now encouraging as a new field of investigation as it might help to the discovery of new specific and causal drug of abuse targets. Overview of the tetrapartite glutamatergic synapse composed of a medium spiny neuron (MSN), a glutamatergic projection, a glial cell and the extracellular matrix (ECM). Here, we focused on synaptic potentiation after drug of abuse administration with the addition at the post-synaptic membrane of glutamate AMPA receptor 2 (GluA2) lacking AMPA receptors (AMPARs). This mechanism might be reduced by metabotropic glutamate receptor 1 (mGluR1) positive allosteric modulator or more directly by GluA2-lacking AMPARs antagonists. In the same way, it was also shown that presynaptic mGluR2 agonists can potentially abolish drug seeking and impair craving incubation. Optogenetically-inspired 12 Hz deep brain stimulation (DBS) in the nucleus accumbens can also be a promising novel therapeutic for addiction. Finally, ceftriaxone, N-acetylcysteine, and inhibitor of matrix metalloproteases 9 (MMP-9), mainly through their action on glial cell and the ECM, are very interesting molecules that may be added in the addiction therapeutic arsenal.

Inspired by previous work performed in the VTA showing that metabotropic glutamate receptor 1 (mGluR1) LTD induces removal of GluA2-lacking AMPARs from synapses [ 33 , 34 ], Loweth et al. [ 85 ] demonstrated that synaptic GluA2-lacking AMPAR decrease could be accomplished by in vivo evoked mGluR1 LTD in the NAc. More importantly, their group showed that after prolonged cocaine or methamphetamine withdrawal, systemic injection of a mGluR1 positive allosteric modulator attenuated the expression of incubated craving by reducing GluA2-lacking AMPARs in the NAc [ 85 , 86 ]. These results suggest a strategy in which abstinent methamphetamine or cocaine users could use a systemically active compound to protect themselves against cue-induced relapse.

These latter studies were conducted without differentiating between D1 receptor D1R MSNs and D2R MSNs. In 2014, Pascoli et al. [ 87 ] demonstrated that this increase in the strength of excitatory afferents was exclusively related to D1R MSNs. Interestingly, the type of drug-evoked plasticity involved is also dependent on the input. It has been shown that even in the same D1R MSN a synapse connecting the PFC to the NAc increases its strength by inserting GluA2-lacking AMPARs whereas a synapse connecting the ventral hippocampus to the NAc increases the AMPA/NMDA ratio by inserting GluA2-containing AMPARs [ 87 ].

Besides operant self-administration, all these long-term synaptic modifications also underlie behavioural changes associated with drugs of abuse, such as locomotor sensitisation [ 88 , 89 ]. Locomotor sensitisation is a behavioural protocol used to model drug-induced behaviour [ 90 , 91 ]. In rodents, repeated cocaine injection induces gradually increased locomotor activity; after 5 days of consecutive injections, the locomotor response reaches a ceiling level. This state lasts for months after cocaine withdrawal [ 91 ]. As an experimental model, locomotor sensitisation is linked with increased tendency to self-administer psychostimulants [ 92 , 93 ] and with reinstatement of previously extinguished self-administration [ 94 , 95 ]. Whereas the existence of psychomotor sensitisation in humans is discussed [ 96 , 97 ], it is a key aspect of vulnerability to drug addiction and relapse, specifically drug craving or compulsive drug-seeking behaviour [ 91 , 98 , 99 ]. Still, locomotor sensitisation can be dissociated from the rewarding effect of a drug of abuse and conditioned place preference or self-administration are more appropriate experimental paradigms to test this aspect [ 100 , 101 , 102 ]. Even if drug-induced locomotor sensitisation is unclearly present in humans, as an animal model it offers a clear readout to understand the mechanisms by which drugs of abuse induce long-term brain modifications [ 91 ].

Furthermore, it has been elegantly demonstrated that optogenetic stimulation of the excitatory projections to the NAc is able to reverse cocaine and alcohol-evoked plasticity [ 87 , 88 , 89 ]. Briefly, applying a NMDAR or mGluR1-dependent LTD on cortico-accumbal glutamatergic synapses, before a drug of abuse administration, diminishes its effect. In another study, Luscher’s team took advantage of the knowledge, obtained from optogenetic in vivo experiment in rodents, to implement a novel deep brain stimulation (DBS) protocol that abolishes behavioural sensitization to cocaine (and thus that would be efficient during the relapse phase) [ 103 ]. Basically, the idea is to manipulate synaptic plasticity in the NAc to reverse pathological synaptic transmission and its associated behaviours following exposure to drugs of abuse. In this study, as a therapeutic use of optogenetic tools in humans is for now inapplicable [ 104 ], the authors reversed cocaine-evoked plasticity and thus drug-induced behaviours by using DBS instead of optogenetic. Indeed, DBS is routinely used in clinic and a new DBS protocol can easily be translationally implemented to the human therapeutics [ 105 , 106 ]. They refined the classical high-frequency DBS protocol (that has no sustained effect on cocaine sensitization, probably because it does not affect synaptic plasticity) by applying a low frequency stimulation (12 Hz to equal the one used in the optogenetic endocannabinoid- dependent LTD protocol) in the NAc together with the administration of a D1R antagonist necessary to unmask the mGluR-dependent LTD in D1R MSNs as demonstrated previously [ 107 ] (Fig. 3 , see section on clinical treatment for broader discussion on DBS).

Kalivas’ group showed in 2009 [ 108 ] that after extended withdrawal from chronic cocaine self-administration, cocaine-induced metaplasticity at the excitatory synapses in the NAc that impairs the ability of PFC stimulation to produce LTP or LTD in NAc MSNs. They also showed that N-acetylcysteine reverses cocaine-induced metaplasticity, allowing the induction of both LTP and LTD and that N-acetylcysteine decreases cocaine-relapse in a rodent model. We are currently awaiting the results of a randomised and control study that is testing newly detoxified (and therefore abstinent) hospitalised patients who received a 3–4 week course of treatment, in order determine if N-acetylcysteine can be a useful medication candidate to avoid relapse in patients with cocaine dependence (NCT03423667).

GABAergic D1R and D2R MSNs, equally compose and are mosaically intermingled throughout the striatum [ 109 ]. As explained above, D1R and D2R MSNs send axonal projections outside the striatum, forming the two main output pathways, respectively the direct and indirect pathways [ 16 , 17 ]. In a certainly oversimplified model, the activation of the D1R MSNs result in facilitation of locomotion, reward, and reinforcement while the activation of D2R MSNs result in opposing effects [ 110 , 111 , 112 , 113 ]. In addition to the long-range projections, these neurons form short-range synaptic connections with one another within the striatum, and because they consist of inhibitory collaterals, a mechanism known as lateral inhibition [ 114 , 115 , 116 , 117 ]. Interestingly, these connections are not symmetrical, with D2R MSNs forming more synaptic connections on D1R MSNs [ 115 , 117 ]. Through this previously understudied collateral transmission, Dobbs et al. [ 115 ] presented a novel mechanism by which cocaine exerts its stimulant effect: cocaine, by blocking DAT receptors enhance levels of dopamine and subsequently activating D2Rs, causes a suppression of lateral inhibition and thus disinhibition of D1R MSNs in the NAc which in turn promotes locomotion [ 115 ]. Furthermore, Alvarez’ group suggested that constitutive low D2R levels, through imbalanced lateral inhibition, might pre-sensitised D1R MSNs, facilitate behavioural plasticity to repeated cocaine and promotes an addiction vulnerable phenotype [ 116 ].

The characterisation of the role of glia and the extracellular matrix (ECM) in drug-induced synaptic plasticity is an exciting emerging field of drug addiction research as it comes with promising new therapeutic possibilitiess [ 118 , 119 , 120 ]. Mulholland et al. [ 118 ] summarised and emphasised the role of the ECM and of astroglial cells in the regulation of synaptic plasticity. Of great interest, restoring downregulated glutamate transporter 1 (EAAT2) with ceftriaxone reduces drug seeking in animal models [ 121 , 122 ]. Matrix metalloproteases (MMP) are important regulators of the ECM and contribute to synaptic plasticity [ 123 ]. Inhibiting their activity result in suppression of the reinstatement of cocaine conditioned place preference [ 124 ] and selectively inhibiting MMP-9 prevents cue- and cocaine-induced reinstatement of cocaine self-administration [ 119 ]; these results open additional therapeutic possibilities with the use of inhibitors of MMP-9 as an innovative targeted approach [ 119 , 124 , 125 ] (Fig. 3 ). Still, at our knowledge, there are no randomised controlled study currently investigating these ECM-related drugs.

Drugs of abuse-induced modifications in glutamatergic nuclei targeting the NAc, or the VTA and essential part of the reward circuit, are less studied than cortico-striatal synapses despite the fact that they play a crucial role in the development of drug addiction. Indeed, in the OFC and PFC, chronic alcohol exposure significantly increases LTP in pyramidal neurons [ 126 , 127 ]. Kazanetz et al. [ 128 ] showed that repeated cocaine injections impair endocannabinoid-LTD and mGluR2/3-LTD in the PFC. They postulated that this might mechanistically participate in the induction of a postsynaptic, observed LTP-like phenomenon with an enhanced AMPA/NMDA ratio. It was also demonstrated that neurons of the infralimbic cortex present a decrease in mGluR2 [ 129 ]. In addition, alcohol-dependent rats exhibit an escalation of ethanol seeking, which was abolished by restoring mGluR2 expression in the infralimbic cortex via viral-mediated gene transfer [ 129 ]. Notably, mGluR2 agonist was shown to impair the incubation of cocaine craving [ 130 ] and to attenuate reinstatement of cocaine-seeking [ 131 , 132 ](Fig. 3 ). Recently, Caprioli et al. [ 133 ] extensively reviewed preclinical studies on allosteric modulators of mGluRs on animal models of drug addiction and their potential translational implications. The results reviewed [ 133 ] indicate an remarkable effect of allosteric modulators of presynaptic mGluR2 and possibly mGluR7, supporting the idea that these compounds should be tested as potential medications for addiction treatments.

Besides the PFC, other brain regions appear to be key areas in drug addiction as the paraventricular thalamus (PVT) - a central hub for cortical, sensory and limbic information [ 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. In 2016, Zhu et al. [ 141 ] showed that chronic morphine administration potentiates excitatory synapses between the PVT and D2R MSNs via insertion of GluA2-lacking AMPARs. Remarkably, in vivo optogenetic depotentiation at these synapses abolishes morphine withdrawal symptoms. In a recent paper, projections from the PVT to the NAc were shown to be critical for augmentation of heroin seeking in food-restricted rats [ 142 ] (Fig. 1 ). Actually, Otis et al. [ 143 ] demonstrated that the PVT is an integrative hub for reward seeking behaviour and that PVT-NAc neurons integrate different inputs from the PFC and the lateral hypothalamus to precisely guide reward seeking behaviour. In a recent review, De Groote et al. [ 140 ] focused on the new advances in the understanding of the roles of the PVT-NAc connections in motivated behaviours, highlighting their implications in drug addiction.

Drug addiction-related genes and transcriptomic regulation

Modifications in gene expression contribute to the long-lasting effect sustaining drug addiction; thanks to gene-expression arrays, RNA-sequencing and candidate gene approaches, the specific genes and their regulatory transcriptomic mechanisms involved in drug addiction development and maintenance are now better understood.

Drug addiction-related genes

For example, the use of conditional gene knockout in mice emphasises the importance of monoamine membrane transporters (dopamine transporter, and serotonin transporter) [ 144 , 145 ] and of mGluRs [ 146 , 147 ]. As new animal models of drug addiction, these approaches are also useful to better characterise fine-tuning of important pathways involved in addiction. For example, a scaffold protein known as Maged1 has been shown to be involved in cocaine reward and reinforcement [ 148 ]. We demonstrated that Maged1 inactivation impairs drug-evoked dopamine release and glutamatergic synaptic plasticity in the NAc. Inactivation of Maged1 in mice was able to abolish behavioural sensitization to cocaine as well as cocaine conditioned place preference and operant self-administration behaviours [ 148 ]. This sole genetic alteration, causally linked to a strong alteration of drug-induced behaviours, impairs (at least) two core neuronal mechanisms leading to addictive behaviours: (1) cocaine-evoked release of dopamine in the NAc and (2) NAc plasticity, with a reduced AMPA/NMDA ratio and a resistance to LTD. Actually, it seems that, after Maged1 inactivation, the excitatory synapses in the NAc shift to a depressed state. Our hypothesis is that, in line with the previously discussed in vivo optogenetic induced LTD, this impairment could be a key factor for the significant decrease in sensitization to psychostimulants [ 87 , 103 , 148 ]. Actually, it seems that placing neurons in a state of ‘presensitization’ is able to prevent drug-induced sensitization itself [ 148 , 149 ]. Our group is now trying to understand what are the cellular and molecular pathways directly altered by Maged1 inactivation and responsible for this strong anti-addictive drug phenotype. Remarkably, the promoter of Maged1 was found in a list of 213 promoters that co-precipitate with acetylated histones and with the activated form of cAMP response element binding protein (CREB) after chronic drug taking [ 150 ]. In line with this result, preliminary and unpublished results from our laboratory point out a specific epigenetic mechanism, in parallel with an alteration of synaptic plasticity in excitatory projection to the NAc, that would link Maged1 to its major effect on drug-induced behaviours. This selected gene approach is of great interest in refining our knowledge of pathways hijacked by addictive drugs. Using cell sorting of D1R MSNs and D2R MSNs as described previously [ 151 ], our group also identified the G-protein-regulated inducer of neurite outgrowth 3 (GPRIN3) in both MSN populations but strikingly more expressed in D2R MSNs [ 149 ]. The GPRIN family (GPRIN1, GPRIN2 and GPRIN3) are Gαi/o-regulated proteins suggested to intermediate the communication between GPCRs and the sequential intracellular target [ 152 ]. Indeed, GPRIN1 and GPRIN2 have been described as alternative (to adenylyl cyclase) mediators of GPCRs signalling but GPRIN3 had a much less defined role [ 152 , 153 ]. To understand the role of GPRIN3 in the pathophysiology of the D2R-indirect pathway, we induced a D2R-MSNs-specific knockdown (KD) of GPRIN3 using small hairpin RNA and lentiviruses [ 151 , 154 ]. We first observed a significant increase in distal branching, the points of convergence between glutamate and dopamine synapses in MSNs [ 155 ] and also key targets of cocaine, which itself promotes increase in distal branching in the NAc of mice [ 156 , 157 , 158 , 159 ]. Thus, we tested the cocaine acute effect and locomotor sensitization and observed a decrease in cocaine-induced hyperlocomotion after inactivation of GPRIN3 using a CRISP/Cas9 approach. The significant increase in distal branching in GPRIN3 D2R-MSNs KD corroborates our hypothesis that the lack of GPRIN3 induces a ‘presensitization process’, able to change the targets of cocaine and therefore altering its effects [ 149 ]. Finally, we provide the first evidence that GPRIN3 partners with D2R in the striatum and modulates cocaine-induced behaviours [ 149 ].

Transcriptomic and epigenetic regulations

Epigenetics is a broad field and has multiple definitions that comprise several biochemical mechanisms (including DNA methylation and histone modifications) sustaining modifications in gene expression throughout the lifecycle of an organism without mutations of the DNA itself [ 160 , 161 , 162 ]. Epigenetics can be considered as the process through which environment (and normal development) interacts with an individual’s genome to determine all phenotypic traits, in health and disease. Stable modifications in gene expression are also said to be ‘epigenetic’, because they are heritable in the short term (through mitosis) [ 160 ] and in some cases trans-generationally, thus, providing a potential mechanism for environmental influences to be passed from parents to offspring [ 163 , 164 , 165 ]. Handel and Romagopalan [ 163 ] mentioned that “epigenetics allows the peaceful co-existence of Darwinian and Lamarckian evolution”. Such trans-generational epigenetic inheritance of drug addiction vulnerability remains debatable [ 161 ], but has been increasingly studied for the last 20 years [ 166 , 167 ]. Some epigenetic changes are very stable, an thus mediate both drug addiction susceptibility and drug-induced brain alterations that underlie the development of drug addiction [ 161 ].

As the NAc is seen as the central hub of drug addiction, with the notion that chronic drug use induces long-lasting structural, electrophysiological and transcriptional changes in the NAc, researchers are mostly targeting epigenetic modifications in NAc cells. Still, considering initial reports of cocaine-induced epigenetic modifications [ 168 , 169 ], it might be relevant to study further epigenetic changes in other regions such as glutamatergic inputs to the NAc, and further in the VTA, as they are implicated in the physiopathology of drug addiction [ 170 , 171 ] as mentioned above.

To date, the three main epigenetic mechanisms consist of (1) DNA methylation, (2) action of the non-coding RNAs and (3) histone post-translational modifications (PTMs). As an illustrative example, we will focus here only on histone PTMs. PTMs of histone residues on their N-terminal tails, that protrude from the nucleosome core, control chromatin condensation and the switch between euchromatin and heterochromatin and thus DNA-accessibility and gene expressions. PTMs include acetylation, methylation, phosphorylation, ADP ribosylation, ubiquitylation and sumoylation, among a growing list of newly discovered modifications [ 162 , 172 ].

Among these PTMs, the most studied is the acetylation of H3 and H4, that is increased in the NAc after chronic exposure to drugs of abuse [ 150 , 173 , 174 ]. This increase in global acetylation levels is the result of drug-induced alterations in the balance of histone acetyltransferase and histone deacetylase (HDAC) function and is associated with gene activation. CREB-binding protein, a histone acetyltransferase critical to memory processes [ 175 ], is required for cocaine-induced increases in histone acetylation in the NAc [ 176 ].

Fifteen years ago, Tsankova et al. [ 177 ] showed that imipramine, a monoamine reuptake inhibitor used for decades to treat depression, was effective through histone remodelling in depression and highlight the therapeutic potential for chromatin regulation with histone methylation and deacetylation inhibitors in depression. Nevertheless, like with synaptic plasticity (see above), discovering a drug that would interfere with epigenetic mechanisms and thus decrease drugs of abuse effect faces temporal aspects issues [ 173 , 176 , 178 , 179 , 180 , 181 , 182 ]. Indeed, timing has a strong impact considering conflicting results obtained after experimental manipulations of histone acetylation. An acute administration of HDAC inhibitors systemically or directly into the NAc, promotes behavioural responses to the drugs. However, prolonged administration decreases cocaine behavioural effects. In 2013, adding a new layer of complexity, Kennedy et al. provided comprehension to this time-dependent regulation [ 183 ]. Remarkably, they showed that prolonged intraNAc administration (but not acute administration) of a HDAC inhibitor attenuated cocaine behavioural effects by inducing a form of repressive histone methylation. This study showed, for the first time, cross-talk among different types of histone modifications [ 183 ]. Besides cross-talk between different epigenetic modifications, multiple modifications work in parallel and there is often a decoupling between an observed modification at a specific locus and its final transcription [ 161 ]. Decoding these chromatin marks will be a future challenging field. Like with HDAC inhibitors, there are promising findings based on the use of DNA methyltransferases inhibitor [ 184 , 185 ] (Fig. 3 ). Though, the main issue with these new potential treatments for drug addiction is their lack of specificity. One of the key challenge for the pharmaceutical industry will be to generate small molecules with more specific targets [ 6 ].

While histone acetylation and methylation are increasingly studied, an important field of future investigation will be to understand the other drug-induced histone PTMs. It already seems that chronic cocaine alters levels of histone phosphorylation [ 174 , 186 , 187 ], and poly-ADP ribosylation [ 188 ]. Recently, an unexpected role for the intracellular dopamine in VTA has been revealed, showing that DA interacts with chromatin to initiate a new form of epigenetic regulation called dopaminylation [ 189 ] (see Table 1 for a summary of cocaine-related epigenetic modifications).

Further studies showed that histone PTMs that occur in the NAc after chronic drug administration are locus specific [ 150 , 190 , 191 ]. Even though, drugs of abuse alter global levels of multiple histone PTMs, such as increased histone acetylation or decreased methylation in the NAc, genome-wide studies have confirmed that a greater number of genomic sites show increased acetylation [ 150 ] or decreased methylation [ 190 , 191 ]. Conversely, hundreds of genes show opposite or no changes in these same PTMs after drug exposure. What defines whether, and in which direction, a specific gene is modified in the context of a global histone PTM is an intriguing and unsolved question [ 161 ]. These genome-wide studies (ChIp on chip or ChIpSeq) are nowadays fundamental to understand where PTMs and other epigenetic modifications are deposited. This will be fundamental to guide new therapeutics.

Actually, with new tools such as zinc finger proteins (ZFPs) DNA-binding domains and, more recently, RNA-guided CRISPR/dCas9 (drastically easier to design) [ 192 , 193 ], it is now possible to control epigenetic modifications at a single gene in a specific type of cell in a specific brain region [ 162 ]. Heller et al. demonstrated that gene-targeted epigenetic editing (targeted to the Fosb [ 194 ] and Cdk5 [ 195 ] locus with ZFP technology) can alter drug-related behaviours [ 194 , 195 ]. This represents crucial evidence that gene-specific changes to the epigenome are not simply correlated, but rather causal, in regulating transcriptional responses to drugs of abuse administrations. These new results of “causal epigenomics” are very encouraging as they open the way to precise translational therapeutic approaches for drug addiction and other CNS diseases.

Linking epigenetics and synaptic plasticity

Today, most studies investigate synaptic plasticity and epigenetic as two distinct fields and it is not clear how these research topics are connected to each other. Understanding how epigenetics is connected to synaptic plasticity is an emerging research issue [ 6 ].

Of course, bridging epigenetic mechanisms with synaptic plasticity is not limited to drug addiction field. For example, in 2011, Monsey et al. [ 196 ] elegantly demonstrated that DNA methylation and histone H3 acetylation regulate auditory fear conditioning and its related synaptic plasticity in the amygdala. In 2014, Massart et al. [ 197 ] suggested that sleep deprivation induces epigenetic modification (alteration in DNA methylation and hydroxymethylation) that triggers synaptic plasticity modifications by changing expression of plasticity related genes.

Regarding drug addiction, some epigenetic marks seem fundamental and upstream as illustrated by HDAC inhibitors effect on drug-induced synaptic and behavioural modifications [ 178 , 198 , 199 , 200 ]. Additionally, Maze et al. [ 201 ] demonstrated morphological plasticity induced by cocaine through the histone methyltransferase G9a. Again advocating for causal epigenetic, Authement et al. [ 66 ] demonstrated that HDAC inhibition locally in the VTA is sufficient to reverse epigenetic modifications and synaptic plasticity changes after morphine administration.

Two transcription factors implicated in addiction exemplify this bridging attempt: CREB and ∆FosB (a truncated form of the FosB gene) are both activated by several drugs of abuse [ 202 ]. CREB activation occurs in both subtypes of NAc MSNs (D1R and D2R), while ∆FosB activation is limited to D1R MSNs in response to all drugs of abuse except for opioids, which remarkably induce the protein in both MSNs [ 203 ]. Expression of active CREB in NAc MSNs increases their excitability [ 204 ] and underlies drug-induced long-term synaptic plasticity and associated changes in dendritic spine plasticity [ 205 ]. ∆FosB is also linked to synaptic plasticity but evokes contrasting effects on the two MSN subtypes, with increased AMPA receptor function induced in D1R MSNs and decreased AMPA receptor function induced in D2R MSNs [ 206 ]. Renthal et al. [ 150 ] unravelled CREB and ∆FosB target genes and observed that these genes are mainly involved in neuronal excitability and synaptic function. Moreover, as already briefly discussed above, CREB and ∆FosB action have also been related to multiple epigenetic regulations, including histone acetylation and methylation [ 150 ]. Besides, a novel mechanism for bridging the gap between epigenetic control of transcription and synapse plasticity might be seen in microRNAs [ 207 ]. The most studied miRNA in the context of synaptic plasticity is miR-132 and is known to be CREB-dependent [ 208 ]. In the striatum, miR-212 targets the epigenetic regulator methyl CpG binding protein 2 (MeCP2). MeCP2 acts as a transcriptional repressor through recruitment of histone deacetylases to methylated DNA segments [ 209 , 210 ].

Clinical treatments for drug addiction

Besides psychosocial interventions [ 211 ] such as cognitive behavioural therapy, the most widely used treatment for drug addiction involves agonist-like medication, a solution inadequately called replacement or substitution therapy [ 212 ]. This type of treatment has been successfully implemented in the daily practice for opioid use disorder (e.g.: methadone, buprenorphine) [ 213 ] and tobacco use disorder (e.g.: nicotine patch or gum, varenicline) [ 214 ]. Currently, this agonist-like treatment is also promising for psychostimulant use disorder [ 215 ]. Still, considering the addictive drug-like effect, the risk of abuse, misuse and diversion, replacement therapy should be prescribed with caution [ 215 , 216 ].

Recently, a randomised and control study on a cocaine vaccine failed to show an effectiveness but instead raised an important issue: immunised subjects may have increased their cocaine use to overcome the competitive anti-cocaine antibody inhibition [ 217 ]. Even though significant improvements have been developed for immunopharmacotherapies for psychostimulant addiction over the last decade, very few candidates have been evaluated so far in clinical trials [ 218 ]. These considerations are some of the reasons why other treatments for drug addiction should emerge with the help of neurobiological research [ 219 ].

Following successful subthalamic nucleus DBS for Parkinson’s disease [ 220 , 221 , 222 ], DBS was investigated for diverse psychiatric diseases including depression [ 223 ], obsessive-compulsive disorder [ 224 ] and Tourette syndrome [ 225 ]. Today, indications for DBS are enlarging, with several positive case reports and small cases series that studied NAc DBS for drug addiction. The first studies showing potential positive effects on drug addiction were reports on application of NAc DBS primarily intended for other medication-refractory neuropsychiatric disorder where a comorbid drug addiction was unexpectedly resolved [ 226 , 227 ]. For DBS treatment in drug addiction, it seems that clinical empirical results led to further bench investigations and refinement [ 88 , 103 , 228 , 229 , 230 , 231 ], or at least, clinical and animal studies evolved in parallel with poor connectivity between the two.

Afterwards, many case reports and small cases series studied NAc DBS being used primarily for drug addiction, all showing encouraging decreases in drug use [ 232 , 233 , 234 , 235 , 236 , 237 ]. However, these studies are limited by their descriptive nature, inconstant follow-up, multiple publication bias, small patient numbers and lack of blinded stimulation and standardised outcome measures. At this stage, additional preclinical and clinical research are needed to clarify the role of DBS in the treatment of drug addiction [ 237 ]. Currently, randomised and control clinical studies are conducted (NCT01245075).

In a recent review, Sanna et al. [ 238 ] highlighted how repetitive transcranial magnetic stimulation (rTMS) confirms the hypodopaminergic hypothesis of drug addiction. While enhancing dopaminergic function through direct or indirect pharmacological approaches does not significantly alleviate symptoms, in numerous studies, and has not yielded a single FDA-approved medication [ 239 ], rTMS might indirectly modulate the dopaminergic system. Many rTMS studies stimulate the dorsolateral PFC [ 240 , 241 ] that projects to the VTA and thus induces an increase in dopamine release in the synaptic cleft in the NAc [ 55 , 242 , 243 ]. Nevertheless, considering the heterogeneity of methods used in rTMS studies during the last 10 years [ 238 ], protocols and guidelines, were recently suggested by an international network of experts in neuromodulation and addiction to improve homogeneity of studies [ 244 ]. From this report, it is clear that multiple technical details for optimal stimulation need further investigations that might be achieved through preclinical studies. For example, low frequency (but not high-frequency) rTMS before methamphetamine exposure in rats blocked drug-induced conditioned place preference [ 245 ]. Being non-invasive, with insignificant side effects, rTMS could be seen as a great opportunity for drug addiction treatment. We are currently waiting for the results of a randomised and control study that aims at determine if, in heavy alcohol users, a single session of TMS can lower a patient’s craving and brain response to alcohol cues (NCT02939313).

Interesting views of clinical treatments for drug addiction are discussed in some other reviews [ 212 , 215 , 216 , 219 ]. The clinical impact of new treatments also depends on their translation into clinical practice which is mainly promoted by the pharmaceutical industry [ 219 ]. Indeed, even when an effective treatment is identified through basic research, it is commonly challenging to translate it to clinical practice, as illustrated by naltrexone as a treatment of alcoholism [ 219 ]. Another example of problematic translation to clinic is illustrated by modafinil, a treatment that has been reported to attenuate cocaine euphoria but for which larger clinical randomised and controlled studies showed controversial results [ 246 , 247 ].

Future directions

Drug addiction is a brain disease strongly influenced by environment and psychosocial aspects. The psychosocial conditions in which it has developed are extremely important. Exposure to conditioned cues can be a central issue in causing drug cravings and relapses, even after successful treatment, and thus they have to be minimised [ 2 , 74 , 77 ]. The pathophysiological aspects are particularly unsteady. For instance, as discussed in this review and in other ones [ 73 , 248 ], synaptic plasticity is dynamically altered after psychostimulant administration, so that a treatment could have opposite effects depending on timing aspects of the administration protocol. In addition, a prolonged treatment may involve compensatory mechanisms, giving unexpected results (e.g.: when HDAC inhibitors and psychostimulants are both administered acutely, they have synergistic effects through hyperacetylation and thus transcriptional activation of psychostimulant-regulated target genes. Conversely, when a drug of abuse is given in the context of chronic HDAC inhibitor, compensatory mechanisms may promote acetylated histone to the promoters of genes responsible for inducing histone methylation and thus chromatin condensation and gene repression, all of which, in turn, gave opposite effect [ 183 ]). Thus, the evolution through the different stages of the disease has to be taken into account [ 249 ] and treatment must follow them. These two aspects have to be incorporated in a holistic treatment strategy. Besides, studying combination of different cutting-edge approaches, with animal models of addiction, such as targeted rTMS or DBS with more systemic epigenetic modulation might show a better restoration of altered synaptic transmission and decrease the probability of relapse in drug addiction. Basically, drug addiction is a disease that seems to be difficult to treat preventively but it is more conceivable to help patients that would be in an abstinence stage not to experience relapse of their disease. As addiction is chronic and relapsing, a good treatment outcome is a significant reduction of drug administration and long periods of withdrawal, with only sporadic relapses [ 2 ].

It is clear that the main issues for optimal therapeutic management of this specific psychiatric disease belong to its dynamic complexity, diverse temporal evolution and undeniably psychosocial aspects. In this review, we focused mostly on the effects of drugs of abuse on synaptic plasticity and epigenetic modifications. Nowadays, these two subfields are mostly studied separately and the understanding of how these two main addictive drug-induced brain modifications interact might be fundamental for addiction research [ 6 ]. Indeed, argument for clinical trials for new treatments emerge from fundamental behavioural studies that should be implemented in a global approach to the addicted patient.

Conclusions

Here, we highlight, from a vast fundamental literature (mainly based on rodent models), promising therapeutics that would potentially treat drug addiction. Based on effect, on synaptic plasticity and epigenetic mechanisms, treatments such as GluA2-lacking AMPAR antagonists [ 72 , 84 ], mGluR1 positive allosteric modulator [ 85 ], NAc 12Hz-DBS [ 103 ] (in line with other promising neuromodulation therapeutics such as rTMS or transcranial direct current stimulation [ 250 ]), N-acetylcysteine [ 108 ], HDAC inhibitors [ 183 ] or even (in very early stages of investigation) CRISPR/dCas9 epigenetic editing [ 194 , 195 ] could be potential candidates for human randomised clinical trials (Fig. 3 ).

Finally, it is fundamental to consider the specific clinical aspects of the disease that would help to develop a personalised-treatment strategy. Indeed, after going from the bench to the bedside it will also be essential to assess the reversed route.

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Acknowledgements

We thank Michele Zoli, Romain Icick and Daniel Rial for helpful comments and corrections on the manuscript. Julian Cheron is supported by a fellowship of the FRS-FNRS (Belgium). Alban de Kerchove d´Exaerde is a Research Director of the FRS-FNRS. FRS-FNRS (Belgium). Fondation Simone et Pierre Clerdent, Fondation ULB, supported this study.

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Cheron, J., Kerchove d’Exaerde, A.d. Drug addiction: from bench to bedside. Transl Psychiatry 11 , 424 (2021). https://doi.org/10.1038/s41398-021-01542-0

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RANKING EVIDENCE IN SUBSTANCE USE AND ADDICTION

Hudson reddon.

1. British Columbia Centre on Substance Use, 1045 Howe Street, Vancouver, BC V6Z 2A9, Canada

2. CIHR Canadian HIV Trials Network, 588-1081 Burrard Street, Vancouver, BC V6B 3E6, Canada

Thomas Kerr

3. Department of Medicine, University of British Columbia, St. Paul’s Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada

Hudson Reddon: Writing-Original draft, Writing-Review and Editing Thomas Kerr: Writing-Review and Editing M-J Milloy: Writing-Review and Editing

Evidence-based medicine has consistently prized the epistemological value of randomized-controlled trials (RCTs) owing to their methodological advantages over alternative designs such as observational studies. However, there are limitations to RCTs that hinder their ability to study chronic and dynamic conditions such as substance use and addiction. For these conditions, observational studies may provide superior evidence based on methodological and practical strengths. Assuming epistemic superiority of RCTs has led to an inappropriate devaluation of other study designs and the findings they support, including support for harm reduction services, especially needle exchange programs and supervised injection facilities. The value offered by observational studies should be reflected in evidence-based medicine by allowing more flexibility in evidence hierarchies that presume methodological superiority of RCTs. Despite the popularity of evidence ranking systems and hierarchies, nothing should replace critical appraisal of study methodology and examining the suitability of applying a given study design to a specific research question.

Long-regarded the gold standard of medical evidence, randomized-controlled trials (RCTs) have been given the paramount role in evaluating the safety and efficacy of new interventions to improve human health and wellbeing. Several ranking systems, including evidence hierarchies and the GRADE framework, consistently bestow superiority to the RCT and place limitations on the value that can be assigned to observational studies ( Guyatt, Oxman, Vist, et al., 2008 ; Rawlins, 2008 ; Schunemann, Fretheim, & Oxman, 2006 ). However, the limitations of RCTs are seldom acknowledged, nor is the fact that observational designs are often better suited to characterize certain health conditions, in particular, chronic diseases. Assuming epistemic superiority of RCTs has led to an inappropriate devaluation of other study designs and the findings they support. This trend is particularly important for fields that are less ethically or scientifically well-suited to RCTs, such as substance use and addiction.

Critique of current evidence ranking

The methodological strength from which RCTs draw their scientific credibility is the random allocation of the intervention among trial participants. Other primary strengths include, but are not limited to, blinding, the use of a control group and applying an intervention. Randomization is presumed to remove any between-group differences in prognostic factors associated with the development of the study outcome ( Sackett, 1996 ; Sackett, Strauss, Richardson, Rosenberg, & Haynes, 2000 ). Observational studies are able to control for known confounders, yet RCTs are the only design to address the distribution of unknown confounders through randomization. However, randomization is not a guarantee that known or unknown confounders will be balanced between groups at the outset of a given study. The distribution of covariates between the intervention and control group after randomization is typically assessed by the trialists, and if uneven distributions are observed the randomization is deemed to have failed and is repeated until balanced groups are produced. Most importantly, it is also possible that imbalances in unknown confounders exist post-randomization, which cannot be detected or corrected by study investigators. Therefore, the extent to which RCTs can remove baseline imbalances between study arms is limited, to some degree, by the existing knowledge of the disease under study (i.e., the number of known confounders that can be assessed by the study investigators post-randomization). Imbalances in confounders are also an issue for observational studies. While randomization is a more effective strategy to balance these factors than approaches used in observational studies (e.g., propensity scores), randomization does not guarantee that prognostic balance is achieved ( Austin, 2011 ; Han, Enas, & McEntegart, 2009 ; Worrall, 2010 ).

The ability to establish external validity and extrapolate a trial’s findings beyond the study protocol is a second issue—one particularly germane to RCTs in substance use and addiction. With the objective of restricting any change in study outcome to the treatment intervention, RCTs typically seek to recruit a select and specific group of participants undergoing a highly structured intervention for a brief period with limited follow-up ( Rawlins, 2008 ; Worrall, 2010 ). Patients living with comorbidities or receiving multiple medications tend to be excluded in order to minimize the heterogeneity among study participants and minimize the risk of randomizing an intervention to vulnerable patients. Among people who use illicit drugs and are living with substance use disorders, minimizing heterogeneity in the study sample is challenging due to the high prevalence of comorbid health conditions and engagement with diverse health and social services. For example, current estimates among people who inject drugs report that upwards of 50% have a lifetime diagnosis of depression, 50% are living with hepatitis C virus infection, 13% are living with HIV and the medications/treatments prescribed to these patients are highly personalized ( Conner, Pinquart, & Duberstein, 2008 ; Kessler et al., 1994 ; Lengauer, Pfeifer, & Kaiser, 2014 ; United Nations Office on Drugs and Crime, 2017 ). Notwithstanding the ethical challenges of placing restrictions on inclusion and exclusion criteria, identifying a homogeneous group of participants based on these complex comorbidities and co-interventions is often practically untenable. Administering a structured intervention to this population is further complicated by high rates of marginalization (e.g., homelessness, social instability, stigmatization) and criminalization ( Marshall et al., 2016 ; Stone et al., 2018 ). In consequence, the average treatment effect calculated from an RCT is only as valuable as the sample from which it was estimated ( Dahabreh, 2018 ; Deaton & Cartwright, 2018b ; Ioannidis, 2018 ). The superior internal validity of an RCT does not translate to invariance in the treatment effect across contexts if the sample is not representative of all the patients to which the study could be applied ( Deaton & Cartwright, 2018a , 2018b ). Nevertheless, the results of RCTs are often extrapolated generously despite the limitations imposed by selection criteria and artificial environments that do not reflect real-world applications of the target intervention ( Deaton & Cartwright, 2018a , 2018b ). As an alternative, some authors advocate for strategies such as propensity scores, instrumental variables and matching to strengthen the methodology of observational studies ( Concato & Horwitz, 2018 ; Deaton & Cartwright, 2018b ). Empirical comparisons between RCTs and well-designed observational studies have found similar summary measures of effect size with neither design producing a consistently greater effect ( Anglemyer, Horvath, & Bero, 2014 ; Benson & Hartz, 2000 ; Concato, Shah, & Horwitz, 2000 ; Sterne et al., 2002 ). Moreover, many treatments that continue to be used in clinical and non-clinical settings have been evaluated through observational methods have been found to be both safe and effective ( Concato & Horwitz, 2018 ; Deaton & Cartwright, 2018b ; Tsimberidou, Braiteh, Stewart, & Kurzrock, 2009 ). In these cases, conducting an RCT on the basis that the existing evidence is observational is unnecessary based on the long-term record of safety and effectiveness and RCTs may expose patients to unnecessary risk if patients are denied treatment shown to be beneficial ( Deaton & Cartwright, 2018b ; Vandenbroucke, 2008 ).

Some authors have also questioned the value of RCTs and evidence hierarchies for identifying unintended or adverse effects of new treatment interventions ( Osimani, 2013 ; Vandenbroucke, 2008 ). As the unintended or possibly adverse effects of novel treatments are typically unknown, the treatment allocation is masked with respect to the unintended effects even if the investigator is aware of who is receiving the treatment ( Vandenbroucke, 2004 ). These authors argue that this achieves the same separation between intervention allocation and prognosis that is accomplished through blinding ( Osimani, 2013 ). As a result, observational studies examining adverse events will not be as vulnerable to confounding and selection bias as observational studies evaluating intervention efficacy ( Vandenbroucke, 2004 , 2006 , 2008 ; Vandenbroucke & Psaty, 2008 ). This view is supported by empirical evidence that shows no systematic difference in risk estimation for adverse events between RCTs and observational studies ( Benson & Hartz, 2000 ; Concato et al., 2000 ; Papanikolaou, Christidi, & Ioannidis, 2006 ). A second critique is that the strict inclusion criteria of RCTs may exclude vulnerable participants with complex comorbidities at an increased risk of experiencing adverse events, which applies to many people who use drugs ( Conner et al., 2008 ; Rawlins, 2008 ). In these circumstances case reports or case series may be the most sensitive or only tool available to identify side effects ( Glasziou, Chalmers, Rawlins, & McCulloch, 2007 ; Stricker & Psaty, 2004 ). Based on these arguments, it has been suggested that the evidence hierarchy should be inverted when the objective is to identify unknown adverse events ( Vandenbroucke, 2008 ).

Although RCTs excel at investigating the safety and efficacy of novel pharmacological formulations, issues arise in testing harm reduction-based interventions to benefit people who inject drugs. The risk environments in which needle exchange programs (NEP) and supervised injection facilities (SIF) are implemented are highly variable between settings. For example, the criminalization of illicit drug use in North America has adjusted as policies legalizing and regulating non-medical cannabis continue to expand in the context of an opioid overdose crisis sparked by the contamination of the illicit drug supply. In these circumstances, long-term observational studies in real world or natural settings may be better suited to evaluate the evolving impacts of changes in substance use policy and criminalization than RCTs. While RCTs are not feasible or ethical in this situation, observational studies are advantageous in that they can often include more follow-up time than RCTs, which is needed to better evaluate the long-term effects of structural factors such as policy change and criminalization on the chronic and dynamic nature of substance use and addiction ( Kelly, Greene, & Bergman, 2018 ; Worrall, 2010 ). The utility of real world data has sparked calls for the integration of alternative data sources such as electronic health records and patient registries to study patient groups who may have been excluded from RCTs (e.g., elderly people living with comorbidities) ( Nabhan, Klink, & Prasad, 2019 ). Other alternatives that have been applied to evaluating substance use include pragmatic trials that blend the traits of observational studies with traditional RCTs ( Coulton et al., 2017 ; Henderson et al., 2017 ). Alternative trial designs including stepped wedge and crossover trials have been effectively applied to study diseases requiring extended follow-up evaluation ( Chotard et al., 1992 ; Hemming, Haines, Chilton, Girling, & Lilford, 2015 ). These designs have been used in diverse areas, including HIV and social policy, although they are challenging when the intervention is believed to be effective and receipt should not be denied or delayed, or there are complex contextual and patient factors that moderate the impact of the intervention on the study outcome ( Bonell et al., 2011 ; Brown & Lilford, 2006 ). Unfortunately, these challenges are common among interventions for people who use drugs. Blinding and providing a placebo are often not possible for these interventions and extrapolating the effects of the intervention beyond the study protocol must be done with caution given that substance use and addiction are chronic and relapsing conditions ( Kelly et al., 2018 ; Kelly, Greene, Bergman, White, & Hoeppner, 2019 ).

Perhaps the most significant unacknowledged weakness of RCTs is their typically limited periods for the intervention and follow-up. Due to their substantial expense, funding for post-study follow-up is typically limited to six to 24 months, which is often insufficient for chronic diseases ( Bluhm, 2010 ; Vlieland, 2002 ) such as substance use disorders, characterized as chronically relapsing conditions with recurring transitions between substance use, abstinence, treatment engagement and incarceration ( Dennis & Scott, 2007 ; Kelly et al., 2019 ). For example, the median time from first to final instance of substance use was estimated at 27 years among people admitted to publicly-funded treatment who were able to abstain for at least one year, and the average time between the first episode of substance use treatment and last instance of substance use was nine years ( Dennis, Scott, Funk, & Foss, 2005 ). A recent analyses from a national study of adults in recovery in the United States (N=39,809) found that an average of two to five attempts were required to resolve an alcohol or drug problem and the number of attempts varied by demographic characteristics, type of treatment and clinical history ( Kelly et al., 2019 ). African American ethnicity, previous use of treatment and mutual-help groups and psychiatric comorbidity were associated with a greater number of recovery attempts ( Kelly et al., 2019 ). Moreover, many patient-important outcomes including quality of life, happiness and self-esteem do not increase monotonically during recovery. These measures were found to decrease significantly in the first year following resolution of an alcohol or drug problem and then increase over subsequent years ( Kelly et al., 2018 ). As a result, the methodological strengths of RCTs are, to some extent, mitigated by the limitations of administering brief structured interventions to a heterogeneous population living with chronic and dynamic disorders. For conditions such as substance use and addiction, RCTs are often limited to providing a snapshot of the effectiveness of interventions in the short term and may fail to identify long-term effects among heterogeneous groups of participants living with chronic and dynamic disorders. In these circumstances, observational studies are often better suited to study interventions designed for a more representative sample of individuals who are often excluded from studies requiring randomization, and who require long-term follow to evaluate enduring changes in study outcomes ( Bluhm, 2010 ; Worrall, 2010 ). Rather than viewing observational designs as a next best option in situations where RCTs are perceived as practically or ethically unfeasible, it should be recognized that the methodological strengths of observational studies may provide the best available evidence to evaluate the course of chronic conditions and the effect of interventions to address them ( Bluhm, 2010 ; Worrall, 2010 ).

In contrast to the approach of evidence-based medicine that strives to identify the most accurate estimate of an average treatment effect, other researchers have proposed a framework that conceptualizes health interventions as “evidence-making” ( Rhodes & Lancaster, 2019 ). Rather than assuming a singular and universal effect of an intervention, the evidence-making framework posits that the variability of practice and patients produces multiple realities of the effects of an intervention and treats evidence, interventions and their effects as emergent, contingent and multiple ( Rhodes & Lancaster, 2019 ). By recognizing that the diversity of practices creates multiple realities of an intervention, evidence-making frameworks foster dialogue across diverse forms of knowledge and knowledge actors to recognize how the politics of intervention knowledge and the realities they create influence their effects across settings ( Rhodes & Lancaster, 2019 ). While it is beyond the scope of this paper to provide a detailed analysis of this framework, similar approaches have been raised by authors who advocate for a process of cumulative scientific understanding that is often challenged by the assumptions of evidence-based medicine and evidence hierarchies ( Deaton & Cartwright, 2018b ). The production of new scientific evidence should build upon and be integrated with existing knowledge to enhance collective scientific knowledge. Unfortunately, it is not uncommon for the findings from observational studies to be dismissed if more recent evidence from a randomized study contradicts the original results ( Deaton & Cartwright, 2018a , 2018b ). Some experts argue that new findings must be able to explain or be integrated with previous results as knowledge advances, even if previous results are believed to be invalid ( Deaton & Cartwright, 2018b ). Failure to integrate results from randomized and non-randomized studies undermines the responsibility of science to advance the cumulative understanding of health interventions and acknowledge the legitimate variability of intervention effects created by the diversity of practice and patients ( Concato et al., 2000 ; Rhodes & Lancaster, 2019 ).

The inappropriate devaluation of observational studies has slowed the implementation and scale-up of several harm reduction interventions for PWUD. The observational evidence supporting SIF and NEP includes many large-scale prospective cohort studies with several years of follow-up from multiple countries ( Aspinall et al., 2014 ; Potier, Laprevote, Dubois-Arber, Cottencin, & Rolland, 2014 ; Wood, Tyndall, Montaner, & Kerr, 2006 ). The advantages of being able to prospectively evaluate the health impacts of these interventions among heterogeneous samples of people who use drugs in real-world settings are unique methodological strengths that provide evidence into the long-term trajectories of this population. Existing evaluations of NEP and SIF have provided strong evidence for reducing HIV risk behaviours, overdose mortality and increasing engagement with addiction treatment services without adverse effects on broader public health and safety ( Aspinall et al., 2014 ; Marshall, Milloy, Wood, Montaner, & Kerr, 2011 ; Potier et al., 2014 ). In spite of this evidence, these services remain limited in many countries contending with the challenges of substance use harms ( Degenhardt et al., 2014 ).

Although ideological opposition to harm reduction-based interventions like NEP and SIF remains the primary barrier limiting their availability in many settings worldwide ( Nadelmann & LaSalle, 2017 ), their establishment and expansion has also been hindered by an ironic epistemic predicament regarding their scientific evaluation. As these services provide self-evident health and safety benefits to profoundly marginalized and vulnerable individuals, regulators and trialists have determined it would be unethical to evaluate them through RCTs as randomization would restrict the control group from accessing potentially life-saving interventions ( Bastos & Strathdee, 2000 ; Bluthenthal & Kral, 2010 ; Lurie, 1998 ). Yet, when observational evidence accumulates demonstrating the benefit of these interventions, the lack of RCTs is critiqued as a methodological weakness ( Bluthenthal & Kral, 2010 ). In effect, the anticipated benefit of these services limits the credibility of subsequent empirical evidence supporting these services ( Bluthenthal & Kral, 2010 ). Throughout the implementation of NEP and SIF, the use of observational methodologies to evaluate these services has often been referenced as a precaution against their expansion or a methodological limitation ( Palmateer et al., 2010 ; Wood et al., 2006 ).

In addition, the effectiveness of SIFs has been challenged based on uncertainty regarding the effect size of these services, despite the large evidence base that is nearly unanimous in support of SIF, with no SIF overdose deaths reported to date and no reported adverse effects ( Caulkins, Pardo, & Kilmer, 2019 ; May, Holloway, & Bennett, 2019 ). Criticism about effect heterogeneity relates to the EBM objective of estimating a singular treatment effect, whereas it is entirely possible, and we would argue likely, that the effect size of these interventions may vary across patient populations and contexts ( Deaton & Cartwright, 2018b ; Rhodes & Lancaster, 2019 ). Rather than this heterogeneity being perceived as a weakness of study methodology, we would argue that this variability is consistent with the evidence-making intervention framework whereby the diversity of practice and patients creates multiple realities of an intervention’s effects ( Rhodes & Lancaster, 2019 ). In fact, this variability should be expected based on the specific crisis situations in which these services are often implemented ( Caulkins et al., 2019 ). SIFs have been established in diverse countries experiencing different types of illicit substance use, patient populations, service models, local contexts, adjunct services and drug policy ( Caulkins et al., 2019 ). These situations are not well-suited to the evidence-based medicine perspective that attempts to minimize patient and intervention heterogeneity to estimate a precise and singular treatment effect ( Deaton & Cartwright, 2018b ; Rhodes & Lancaster, 2019 ). Instead, the existence of multiple contingent effects of an intervention that are adaptive is in keeping with the ontology of the evidence-making intervention framework ( Rhodes & Lancaster, 2019 ). While we acknowledge that randomizing participants to SIF participation (e.g., through community-randomized trials or wait-list studies) would be theoretically valuable, we contend that this is has become unethical and unnecessary given the evidence of benefit and absence of harm associated with these services ( Caulkins et al., 2019 ; Kennedy, Hayashi, Milloy, Wood, & Kerr, 2019 ). As previously mentioned, RCTs do not have the same benefits for assessing adverse outcomes and the risks associated with denying or delaying SIF use among vulnerable populations of PWUD through RCTs is difficult to justify ( May et al., 2019 ; Osimani, 2013 ; Vandenbroucke, 2006 ). Although RCTs are held as the gold-standard for identifying causal associations, observational and qualitative studies are able to provide valuable evidence about the causal mechanisms underlying these associations and contribute to advancing the cumulative understanding of an intervention without the need for experimental closure ( Deaton & Cartwright, 2018b ; Rhodes & Lancaster, 2019 ). The study design that provides the best evidence may therefore vary depending on the theory or research question being evaluated; this should be reflected in evidence ranking systems such as the GRADE framework and the Maryland Scientific Methods Scale that place limits on the value that can be assigned to non-randomized studies ( Alonso-Coello et al., 2016 ; Worrall, 2010 ).

There are examples where observational studies have been sufficient to demonstrate effectiveness and continue to be used clinically without the need for verification through RCTs. An analysis of oncology drugs approved by the United States Food and Drug Administration found that 31 of 68 drugs were approved without an RCT and 30 of these drugs remain fully approved ( Concato & Horwitz, 2018 ; Tsimberidou et al., 2009 ). Studies using objective endpoints were the most common among those approved and these drugs demonstrated a long-term record of efficacy and safety based on observational evidence ( Tsimberidou et al., 2009 ). There are also cases where the belief that RCTs are needed to confirm observational evidence has caused harm. The controversy surrounding the RCTs of extracorporeal membrane oxygenation (ECMO) therapy in newborns has been well described ( Bluhm, 2010 ; Truog, 1992 ). Both ECMO and the standard treatment were evolving rapidly and observational studies had already supported the benefit of ECMO ( Bartlett, 1984 ; Wung, James, Kilchevsky, & James, 1985 ). Yet, variability in the success rate of ECMO across centres prompted many researchers to call for RCTs before ECMO became an accepted therapy ( Bluhm, 2010 ). In the first trial, the one infant who received conventional therapy did not survive while all 11 who received ECMO survived ( Bartlett et al., 1985 ). In phase one of the second trial, four of the ten newborns receiving conventional therapy did not survive while all nine who received ECMO survived ( O’Rourke et al., 1989 ). In phase two, 20 patients received ECMO and 19 survived ( O’Rourke et al., 1989 ). These examples have led some experts to suggest that RCTs should not be used in cases where interventions are rapidly evolving and are potentially life saving ( Truog, 1992 ). In these cases, the interventions or their implementation may be out-dated by the time the RCT has concluded and observational studies of clinical practice (e.g., outcomes research) may provide better evidence of intervention effectiveness while avoiding some of the ethical challenges of withholding or delaying novel treatments in RCTs ( Truog, 1992 ; Worrall, 2010 ). This is particularly relevant to the situation of SIFs, which are often implemented in situations of crisis that are rapidly evolving as new challenges arise, such as the multiple waves of the opioid overdose crisis. Under these circumstances, variability in the effect should not detract from the fact the evidence is, even in the opinion of critics, “almost unanimous in its support” and is potentially life saving ( Caulkins et al., 2019 ; Kennedy et al., 2019 ; May et al., 2019 ). Performing RCTs of SIFs to ascertain a singular measure of effect should be viewed as unnecessary and unethical given the existing evidence and that observational studies may provide better information to evaluate these interventions based on the evolving context of their implementation and the potential for them to be life saving.

Future directions for addiction science and evidence ranking

An alternative observational design that has gained considerable attention, particularly for studying chronic diseases, is Mendelian randomization ( Lawlor, Harbord, Sterne, Timpson, & Davey Smith, 2008 ; Smith, 2006 ). These studies integrate genetic variants into observational epidemiology to enhance the causal inferences that can be drawn about modifiable risk factors and health outcomes ( Smith & Ebrahim, 2003 ; Youngman, Keavney, & Palmer, 2000 ). Rather than randomize participants to receive the exposure being studied, Mendelian randomization studies take advantage of the random assignment of an individual’s genotype from their parents to conduct a ‘natural’ RCT ( Davey Smith & Ebrahim, 2005 ; Hingorani & Humphries, 2005 ). If germline genetic variants for an environmental exposure (e.g., substance use) have been identified, these variants can be used as a proxy measure of the exposure in observational studies and be treated as randomly distributed ( Lawlor et al., 2008 ; Pasman et al., 2018 ). Mendelian randomization studies can also be performed in representative population samples without the need for exclusion criteria or randomizing participants as is necessary in traditional RCTs ( Lawlor et al., 2008 ; Smith & Ebrahim, 2003 ). In addition, the associations between these gene variants and health outcomes are not susceptible to reverse causality as germline genotypes are not affected by disease progression, and, if the gene variant is not pleiotropic, the risk of confounding is mitigated ( Smith & Ebrahim, 2004 ). Finally, genetic variants that predict an environmental exposure typically do so throughout the life span, a fact which minimizes regression dilution bias ( Smith & Ebrahim, 2004 ). As the cost of genome sequencing continues to decrease and more large-scale consortia are forming, integrating genetic data into observational designs is becoming increasingly feasible for studies of substance use and addiction ( Pasman et al., 2018 ; Phillips, Deverka, Hooker, & Douglas, 2018 ; Vaucher et al., 2018 ). For example, Mendelian randomization studies have been applied to investigate the longstanding debate surrounding the association between schizophrenia and cannabis use ( Gage et al., 2017 ; Pasman et al., 2018 ; Vaucher et al., 2018 ). The limitations of Mendelian randomization studies include population stratification, identifying a reliable genetic variant for the exposure of interest that does not have pleiotropic effects on the outcome and is not in linkage disequilibrium with other gene variants associated with the outcome ( Cardon & Palmer, 2003 ; Lawlor et al., 2008 ; Smith & Ebrahim, 2004 ). Additional challenges include developmental compensation, contextual influences on the exposures predicted by gene variants and non-linear associations ( Gibson & Wagner, 2000 ). Despite these limitations, Mendelian randomization studies retain the ability of traditional observational studies to study the development of chronic conditions over time with the advantage of studying gene variants for exposures that are randomly distributed ( Lawlor et al., 2008 ; Smith & Ebrahim, 2003 ). The ability to combine the strengths of observational studies while adding a component of randomization should challenge the assumed superiority of RCTs among policymakers and healthcare professionals. The evidence from these studies may also prevent the need to conduct RCTs to address certain research questions. For example, a Mendelian randomization study evaluating the effects of selenium supplementation on prostate cancer risk provided evidence of no effect, which was consistent with the largest ever prostate cancer prevention trial ( Yarmolinsky et al., 2018 ). This trial was stopped before completion based on a lack of efficacy and adverse events, at a cost of $114 million ( Yarmolinsky et al., 2018 ). As the efficacy and adverse events were predicted by this Mendelian randomization study, these designs may be an efficient and affordable means to study interventions traditionally assessed RCTs as big data resources for genetic information continue to expand ( Yarmolinsky et al., 2018 ).

A second area for improvement in substance use and addiction research is the further integration of patient-important outcomes. The underrepresentation of patient-reported outcomes has been highlighted in several study designs yet is more pronounced in RCTs ( Pardo-Hernandez & Alonso-Coello, 2017 ; Saldanha et al., 2017 ). Previous field-specific systematic reviews of RCTs have found that less than 25% include a patient-important outcome as a primary outcome ( Gaudry et al., 2017 ; Rahimi, Malhotra, Banning, & Jenkinson, 2010 ). The lack of patient-important outcomes is highly germane to substance use research and a systematic review is currently ongoing to identify patient-important outcomes to assess the effectiveness of opioid use disorder in the context of the overdose epidemic ( Dennis et al., 2015 ; Sanger et al., 2018 ). Increased recognition of the value of patient-important data is reflected in the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, which recommends their inclusion at two different stages (the outset of study design and when ranking the importance of study outcomes) ( Guyatt, Oxman, Kunz, et al., 2008 ). Other frameworks designed to help stakeholders translate scientific evidence to healthcare decisions prioritize the inclusion of patient-important outcomes and considers the degree to which patients value each outcome ( Alonso-Coello et al., 2016 ). The Core Outcome Measures in Effectiveness Trials (COMET) initiative extends this view by promoting the selection of a standardized set of outcomes for each health condition to compare effectiveness across studies (“ The COMET Initiative,” 2010 ; Gorst et al., 2016 ; Williamson et al., 2012 ). The lack of patient-important outcomes in addiction literature, and the fact that these measures vary significantly in different stages of addiction, calls for further integration of these outcomes in future research ( Kelly et al., 2018 ; Sanger et al., 2018 ). Given the value of patient-important outcomes—and that they are prioritized in stakeholder frameworks including GRADE and COMET—further evaluation of these outcomes will be important to promote the uptake of observational evidence on substance use and addiction among policymakers and healthcare officials ( Gorst et al., 2016 ; Guyatt, Oxman, Kunz, et al., 2008 ; Pardo-Hernandez & Alonso-Coello, 2017 ; Williamson et al., 2012 ).

There are, without question, important limitations to studies with non-randomized designs. However, the value offered by observational studies should be reflected in evidence-based medicine by allowing more flexibility in evidence hierarchies that presume methodological superiority of RCTs. Observational designs may provide the best evidence to evaluate interventions to address chronic conditions such as substance use and addiction. Unfortunately, assuming epistemic superiority of RCTs has unnecessarily slowed the uptake of substance use research and harm reduction services for people who use drugs. Despite the popularity of evidence ranking systems and hierarchies, nothing should replace critical appraisal of study methodology and examining the suitability of applying a given study design to a specific clinical question.

Acknowledgments:

This work was supported by the CIHR Canadian HIV Trials Network (CTN 222). Dr. Hudson Reddon is supported by a Sponsor/CTN Postdoctoral Fellowship Award and a Michael Smith Research Trainee Award. Dr. M-J Milloy is supported in part by the United States National Institutes of Health (U01-DA021525), a New Investigator Award from CIHR and a Scholar Award from MSFHR. His institution has received an unstructured gift to support him from NG Biomed, Ltd., a private firm applying for a government license to produce cannabis. The Canopy Growth professorship in cannabis science was established through unstructured gifts to the University of British Columbia from Canopy Growth, a licensed producer of cannabis, and the Ministry of Mental Health and Addictions of the Government of British Columbia.

Competing Interests: None to declare.

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• Signs of Addiction

Addiction Research

Discover the latest in addiction research, from the neuroscience of substance use disorders to evidence-based treatment practices. reports, updates, case studies and white papers are available to you at hazelden betty ford’s butler center for research..

Why do people become addicted to alcohol and other drugs? How effective is addiction treatment? What makes certain substances so addictive? The Butler Center for Research at the Hazelden Betty Ford Foundation investigates these and other questions and publishes its scientific findings in a variety of alcohol and drug addiction research papers and reports. Research topics include:

• Evidence-based treatment practices
• Addiction treatment outcomes
• Addiction, psychiatry and the brain
• Addictive substances such as prescription opioids and heroin
• Substance abuse in youth/teens, older adults and other demographic groups such as health care or legal professionals

These research queries and findings are presented in the form of updates, white papers and case studies. In addition, the Butler Center for Research collaborates with the Recovery Advocacy team to study special-focus addiction research topics, summarized in monthly  Emerging Drug Trends  reports. Altogether, these studies provide the latest in addiction research for anyone interested in learning more about the neuroscience of addiction and how addiction affects individuals, families and society in general. The research also helps clinicians and health care professionals further understand, diagnose and treat drug and alcohol addiction. Learn more about each of the Butler Center's addiction research studies below.

Research Updates

Written by Butler Center for Research staff, our one-page, topic-specific summaries discuss current research on topics of interest within the drug abuse and addiction treatment field.

View our most recent updates, or view the archive at the bottom of the page.

Patient Outcomes Study Results at Hazelden Betty Ford

Trends and Patterns in Cannabis Use across Different Age Groups

Alcohol and Tobacco Harm Reduction Interventions

Harm Reduction: History and Context

Racial and Ethnic Health Disparities and Addiction

Psychedelics as Therapeutic Treatment

Sexual and Gender Minority Youth and SUDs

Health Care Professionals and Mental Health

Grief and Addiction

Helping Families Cope with Addiction

Emerging Drug Trends Report and National Surveys

Shedding New Light on America’s No. 1 Health Problem

In collaboration with the University of Maryland School of Public Health and with support from the Butler Center for Research, the Recovery Advocacy team routinely issues research reports on emerging drug trends in America. Recovery Advocacy also commissions national surveys on attitudes, behaviors and perspectives related to substance use. From binge drinking and excessive alcohol use on college campuses, to marijuana potency concerns in an age of legalized marijuana, deeper analysis and understanding of emerging drug trends allows for greater opportunities to educate, inform and prevent misuse and deaths.

Each drug trends report explores the topic at hand, documenting the prevalence of the problem, relevant demographics, prevention and treatment options available, as well as providing insight and perspectives from thought leaders throughout the Hazelden Betty Ford Foundation.

View the latest  Emerging Drug Trends  Report:

Pediatricians First Responders for Preventing Substance Use

• Clearing Away the Confusion: Marijuana Is Not a Public Health Solution to the Opioid Crisis
• Does Socioeconomic Advantage Lessen the Risk of Adolescent Substance Use?
• The Collegiate Recovery Movement Is Gaining Strength
• Considerations for Policymakers Regarding Involuntary Commitment for Substance Use Disorders
• Widening the Lens on the Opioid Crisis
• Concerns Rising Over High-Potency Marijuana Use
• Beyond Binging: “High-Intensity Drinking”

View the latest  National Surveys :

• College Administrators See Problems As More Students View Marijuana As Safe

College Parents See Serious Problems From Campus Alcohol Use

• Youth Opioid Study: Attitudes and Usage

About Recovery Advocacy

Our mission is to provide a trusted national voice on all issues related to addiction prevention, treatment and recovery, and to facilitate conversation among those in recovery, those still suffering and society at large. We are committed to smashing stigma, shaping public policy and educating people everywhere about the problems of addiction and the promise of recovery. Learn more about recovery advocacy and how you can make a difference.

Evidence-Based Treatment Series

To help get consumers and clinicians on the same page, the Butler Center for Research has created a series of informational summaries describing:

• Evidence-based addiction treatment modalities
• Distinctive levels of substance use disorder treatment
• Specialized drug and alcohol treatment programs

Each evidence-based treatment series summary includes:

• A definition of the therapeutic approach, level of care or specialized program
• A discussion of applicability, usage and practice
• A description of outcomes and efficacy
• Research citations and related resources for more information

View the latest in this series:

Motivational Interviewing

Cognitive Behavioral Therapy

Case Studies and White Papers

Written by Hazelden Betty Ford Foundation researchers and clinicians, case studies and white papers presented by the Butler Center for Research provide invaluable insight into clinical processes and complex issues related to addiction prevention, treatment and recovery. These in-depth reports examine and chronicle clinical activities, initiatives and developments as a means of informing practitioners and continually improving the quality and delivery of substance use disorder services and related resources and initiatives.

• What does it really mean to be providing medication-assisted treatment for opioid addiction?

Adolescent Motivational Interviewing

Peer Recovery Support: Walking the Path Together

Addiction and Violence During COVID-19

The Brain Disease Model of Addiction

Healthcare Professionals and Compassion Fatigue

Moving to Trauma-Responsive Care

Virtual Intensive Outpatient Outcomes: Preliminary Findings

Driving Under the Influence of Cannabis

Vaping and E-Cigarettes

Using Telehealth for Addiction Treatment

Grandparents Raising Grandchildren

Substance Use Disorders Among Military Populations

Co-Occurring Mental Health and Substance Use Disorders

Women and Alcohol

Prescription Rates of Opioid Analgesics in Medical Treatment Settings

Applications of Positive Psychology to Substance Use Disorder

Substance Use Disorders Among Legal Professionals

Factors Impacting Early Alcohol and Drug Use Among Youths

Animal-Assisted Therapy for Substance Use Disorders

Prevalence of Adolescent Substance Misuse

Problem Drinking Behaviors Among College Students

The Importance of Recovery Management

Substance Use Factors Among LGBTQ individuals

Prescription Opioids and Dependence

Alcohol Abuse Among Law Enforcement Officers

Helping Families Cope with Substance Dependence

The Social Norms Approach to Student Substance Abuse Prevention

Drug Abuse, Dopamine and the Brain's Reward System

Women and Substance Abuse

Substance Use in the Workplace

Health Care Professionals: Addiction and Treatment

Cognitive Improvement and Alcohol Recovery

Drug Use, Misuse and Dependence Among Older Adults

Emerging Drug Trends

Does Socioeconomic Advantage Lessen the Risk of Adolescent Substance Use

The Collegiate Recovery Movement is Gaining Strength

Involuntary Commitment for Substance Use Disorders

Widening the Lens of the Opioid Crisis

Beyond Binge Drinking: High Intensity Drinking

High Potency Marijuana

National Surveys

College Administrators See Problems as More Students View Marijuana as Safe

Risky Opioid Use Among College-Age Youth

Case Studies/ White Papers

What does it really mean to be providing medication-assisted treatment for opioid addiction

Are you or a loved one struggling with alcohol or other drugs? Call today to speak confidentially with a recovery expert. Most insurance accepted.

Harnessing science, love and the wisdom of lived experience, we are a force of healing and hope ​​​​​​​for individuals, families and communities affected by substance use and mental health conditions..