The use of illicit substances is a major public health problem that affects hundreds of millions people worldwide.1 Exposure to crack-cocaine rapidly induces a pattern of compulsive use and dependence, which is associated with marked personal, social, and economic losses.2,3 In Brazil, the prevalence of crack-cocaine use suggests that the country is amongst the biggest consumer markets of these drugs worldwide.4

Recurrent, severe craving and a high frequency of relapses are remarkable clinical features of crack-cocaine dependence. It should be noted that craving is a critical factor for the onset of compulsive use and dependence, and adds to the failure in remaining abstinent.5,6 Craving measures have increasingly been used as a primary endpoint in clinical trials, as craving severity may predict relapse and treatment outcomes.5,7-9 Different studies have demonstrated that stimuli previously associated with drug use can consistently induce craving in individuals with crack-cocaine dependence,10 leading to the development of craving induction techniques (cue-induced craving) that can be used in the assessment of pharmacological interventions to treat dependence.11,12

Despite unquestionable advances in the understanding of neurobiological alterations associated with drug dependence in recent decades, there is no pharmacological treatment with proven efficacy in the treatment of crack-cocaine dependence.13-15 Different sources of evidence have suggested that the dopaminergic neurotransmission system is involved in the reinforcing effects of cocaine addiction, and may mediate its onset and maintenance.16-18 Furthermore, both preclinical and clinical studies have shown that cocaine withdrawal syndrome is associated with impaired dopamine function.19-22

Different studies have suggested that agonists of cannabinoid CB1 receptors increase the discharge of dopaminergic neurons in the ventral tegmental area, which project to the nucleus accumbens,23 leading to an increase in extracellular dopamine levels in this structure.24-27 This is probably an indirect effect that occurs via inhibition of GABA neurons, which results in tonic inhibition of dopaminergic neurons.28

The use of cannabinoids has been previously highlighted in uncontrolled observations as a strategy for reducing cocaine consumption and to reduce craving,5,29,30 suggesting that these compounds may have a crucial clinical therapeutic role for the treatment of crack-cocaine dependence. However, most of these studies were conducted with cannabis in natura or whole-plant extracts, which limits their reproducibility and raises ethical issues due to the harmful effects of the drug. Moreover, none of these studies tested pure, pharmaceutical-grade cannabidiol (CBD) for the treatment of crack-cocaine dependence.

CBD is a component of Cannabis sativa that is devoid of both psychotomimetic and typical effects of the plant.31-33 CBD inhibits the reuptake and enzymatic hydrolysis of anandamide34 and thus increases the availability of this endogenous CB1 receptor agonist. In animals, CBD reversed dopamine depletion induced by 6-hydroxydopamine in a model of Parkinson’s disease,35 and has been shown to regulate stress response and compulsive behaviors by activating the 5-HT1A serotonergic receptor.36 Moreover, CBD is an allosteric modulator at mu- and delta-receptors in the opioid system.37 Recent articles suggested that CBD may be useful to treat addiction to several substances17,38 including cannabis,39,40 tobacco,41,42 alcohol,43,44 heroin,45 and cocaine.46-49

Furthermore, CBD has demonstrated anxiolytic,38,50-54 antidepressant,55 and neuroprotective properties.56 Although the mechanisms underlying the neuroprotective properties of CBD are still poorly understood, findings from different sources have suggested the involvement of multiple pharmacological targets, including CB1 and 5-HT1A receptors,36,57 antioxidant properties,58 modulation of proinflammatory cytokines,59 and brain-derived neurotrophic factor (BDNF) expression.60 Altogether, findings from preclinical and clinical studies suggest that CBD is involved in different mechanisms related to acquisition of addiction and compulsive drug-seeking behaviors.

The main aim of the present study is to evaluate the efficacy and tolerability of CBD in treatment of crack-cocaine dependence. We hypothesized that CBD would show effectiveness in reducing craving symptoms while having good tolerability.

This was a randomized, double-blind, placebo-controlled trial. The trial was carried out at a therapeutic community unit specializing in the treatment of substance-related disorders affiliated with Instituto Bairral de Psiquiatria, a hospital that receives patients from the Brazilian public health system (Itapira, state of São Paulo, Brazil).

The results of this randomized, placebo-controlled trial suggest that, despite excellent safety and tolerability, CBD failed to demonstrate efficacy in the treatment of craving in subjects with crack-cocaine dependence. Despite these negative findings, to our knowledge, this is the first study examining the efficacy of CBD in the treatment of crack-cocaine dependence in humans.

Anxiety symptoms decreased significantly in both groups during the trial. Regarding depressive symptomatology, a significant reduction was found among participants in the control group, while the change in the experimental group only tended towards statistical significance. There were no differences between the experimental and control groups in terms of baseline and final assessments of anxiety and depression symptoms. This finding contrasts with studies reporting the efficacy of CBD in treating anxiety disorders.53,55 However, such evidence mainly comes from preclinical studies in which CBD was administered acutely; evidence from clinical studies investigating chronic CBD use in anxiety disorders is limited.82

The results of the CCQ-Brief and the MCCS showed the presence of moderate to high severity of craving in both groups at first assessment, which decreased significantly over the 10 days of the trial. Between-group comparisons, however, showed no differences, suggesting that CBD treatment did not contribute to the reduction in craving severity. This suggests that the observation that use of cannabis facilitates abstinence from crack cocaine83 cannot be attributed to CBD.

The decrease in craving intensity over the 10 days of the trial in the two groups does not seem to be related to the general treatment measures provided by the institution, since the experiment started, on average, 15 days after admission, and craving scores on the first day of the trial were high for both groups. In addition, decreases in anxiety and depressive symptomatology did not appear to be related to the resolution of withdrawal syndrome, since enrollment in the study occurred at 8 to 30 days of abstinence. Reductions in craving severity and significant decreases in anxiety and depression symptoms might be associated with a placebo effect related to the knowledge that subjects could be receiving a new medication, as well as to the individualized attention that patients received during the study period, with daily application of the assessment instruments. It may also have occurred due to the activities carried out at the facility, the general health care provided by the staff, the impossibility of using the drug during hospitalization, and of being away from the usual environment of drug use.

Different studies have shown that craving is an unstable condition affected by environmental, social, and emotional influences.5,9 Similarly, the duration of abstinence and deprivation of liberty, which makes use and contact with drug-use environments difficult or even impossible, do not favor craving induction.6 It should be noted that conditioned stimuli (such as seeing someone use crack, feeling the smell of the substance, handling paraphernalia, going to typical places of use) have consistently been described as triggers of craving among substance users.4-6

The use of a craving-inducing procedure in the present study increased craving intensity in the two groups, but with no significant differences between them. This finding is in line with a recent double-blind, placebo-controlled functional magnetic resonance imaging study in which CBD did not acutely affect the neural correlates of reward anticipation and feedback in healthy participants.84 However, this observation contrasts with previous animal literature that consistently shows that the administration of CBD reduces self-administration, cocaine-seeking behaviors, and cocaine-induced reward; attenuates the central adaptations induced by cocaine; and changes contextual and emotional memories associated with cocaine, thus decreasing the amount of drug use.47-49,85,86

The main limitation of the present study was related to the treatment setting, since craving and withdrawal symptoms tend to be less severe and to decrease linearly in hospitalized patients, unlike in an outpatient setting where these symptoms tend to be more frequent, intense, and persistent. Additionally, different aspects of the intervention, including the short treatment period and the long interval between cessation of use and the start of the trial, might have contributed to the negative findings. The dose of CBD (300 mg/day) was relatively low, with no uptitration; since the effects of CBD are biphasic,80 the use of a single dose also limits evaluation of the effectiveness of this cannabinoid. For instance, two recent double-blind placebo-controlled trials of CBD in subjects with heroin45 and cannabis40 use disorder, respectively, observed efficacy with the use of higher doses (400 and 800 mg).

Also, the tendency for the CBD group to have more previous hospitalizations, a fact that is usually associated with greater severity and increased substance use-related problems, might also have contributed to the absence of differences between the groups. Moreover, since the rates of psychiatric and infectious comorbidities are high among crack-cocaine users and may have influence treatment outcomes,87 such exclusions in our study would have produced a highly artefactual sample. Thus, the study sample may not represent the general socioclinical profile of crack-cocaine users in general, and in Brazil in particular. Finally, type-II statistical error cannot be ruled out in view of the relatively small overall sample size, and may mean that the study was underpowered for conclusive insights or for adequate testing of interactions with other crucial factors.

Although these preliminary findings failed to show evidence of the efficacy of CBD in reducing craving in subjects with crack-cocaine dependence, further investigations that overcome the limitations described above are necessary. This is particularly true if we consider the excellent tolerability and safety profiles of CBD and the encouraging animal evidence of this cannabinoid as an adjunct therapy for the treatment of crack-cocaine dependence.7,88,89 Therefore, future double-blind, placebo-controlled, randomized clinical trials with larger, less selective samples and using different doses of CBD in outpatients are of particular interest to elucidate the potential of CBD to reduce self-administration of crack cocaine.

JAC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) – National Health and Medical Research Council (NHMRC). JAC and JEH have received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm. JAC, JEH, and AWZ are coinventors of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023,” Def. US number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimarâes FS, Crippa JAS, Breuer A). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JAC, JEH, and AWZ are coinventors of the patent “Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same,” INPI on September 16, 2016 (BR 112018005423-2). RAB has received research grants from Janssen; and has participated in speaker bureaus for Janssen and Sanofi-Aventis. ALL has received grants and personal fees from Janssen Pharmaceutical; has received personal fees from Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharma, and Sanofi-Aventis; and has received grants from Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, and Forum Pharmaceuticals. The other authors report no conflicts of interest.