Substance abuse: The scientific research

Below are a list of scientific research studies which have looked at the efficacy of CBD for treatment of addictive disorders. Click on the title to be redirected to the full research article.

 

1. Cannabidiol as an Intervention for Addictive Behaviors: A Systematic Review of the Evidence

 

Effects of CBD on tobacco-related addictive behaviors

Only one study looked at the impact of CBD on tobacco addiction. Morgan et al studied the impact of CBD on nicotine addiction by conducting a randomized, double-blind, placebo-controlled study on 24 smokers who wished to stop smoking.The results showed a significant reduction in the number of cigarettes smoked (≈40%) in the CBD inhaler group during the week of treatment, with a trend indicating a reduction after follow-up. Both groups also showed a reduction in cravings between day 1 and day 7, though not between day 1 and follow-up.

Effects of CBD on opioid-related addictive behaviors

Studies were found on all three phases of opioid addiction

Overall, CBD was found to have an impact on the intoxication and relapse phase of opioid addiction. Data on its effect during the withdrawal phase remain conflicting and vary based on co-administration of other cannabinoids such as THC.

Effects of CBD on psychostimulant-addictive behaviors

Few studies examined the effects of CBD on the intoxication and relapse phases of psychostimulant addiction.

Thus, CBD does not appear to have an impact on stimulants’ rewarding effect, but one study suggests that it may influence addictive behaviors during the relapse phase.

Effects of CBD on cannabis-related addictive behaviors

Few studies have examined the effects of CBD administration on various outcomes during the intoxication and relapse phase of cannabis addiction.

While CBD does not appear to be reinforcing on its own, its impact on cannabis-related addictive behaviors in animal models remains unclear.

Effects of CBD on cannabis-related addictive behaviors

Outcomes of CBD on all three phases of cannabis addiction were found. Crippa et al investigated the effects of CBD on cannabis addiction and its withdrawal syndrome.30 They conducted an experimental trial on a 19-year-old female with cannabis dependence, who experienced withdrawal syndrome when she tried to cease cannabis use.

CBD was administered for 11 days (300 mg on day 1, 600 mg on days 2–10, and 300 mg on day 11). Daily assessments using the Withdrawal Discomfort Score, Marijuana Withdrawal Symptom Checklist, Beck Anxiety Inventory, and Beck Depression Inventory showed a rapid decrease in withdrawal symptoms, leading to a score of zero in all tests by day 6. A 6-month follow-up showed a relapse in cannabis use, but at a lower frequency (one or twice a week vs. 7 days a week).

Effects of CBD on alcohol-addictive behaviors

Only the impact of CBD on the intoxication phase of alcohol addiction was extracted from the review of literature. Consroe et al assessed the effects of CBD on acute consumption of alcohol in 10 healthy volunteers in a randomized, double-blind, crossover study, by testing subjective responding after administration of alcohol (1 g/kg) and CBD (200 mg) alone or in combination.34 They found that there was no difference in feelings of being “drunk”, “drugged”, or “bad” in alcohol-alone and alcohol plus CBD groups.

2. Cannabidiol as a Novel Candidate Alcohol Use Disorder Pharmacotherapy: A Systematic Review

 

Protection of Cognition and Prevention of Neurodegeneration

Excessive alcohol use can give rise to neurodegeneration, which is a hypothesized cause of the observed cognitive and behavioral impairments noted in AUD (Crews and Boettiger, 2009). Previous studies have revealed that alcohol is particularly damaging to the frontal and temporal lobes (Crews and Nixon, 2008) and the hippocampus (Wilson et al., 2017), with induction of neuroinflammatory mediators and/or oxidative stress responsible for such consequences.

CBD has demonstrated neuroprotective effects, preventing oxidative damage in an in vitro model of excitotoxicity (e.g., Hampson et al., 1998), making it a highly credible pharmacotherapy for reducing adverse alcohol‐related cognitive consequences. Although the exact mechanism by which it elicits these actions remains unclear, 5HT1A or CB2 receptor mediation has been hypothesized (reviewed in Campos et al., 2016).

Preclinical Studies

Three studies were identified examining the extent to which CBD was able to prevent alcohol‐induced neurodegeneration in the rat entorhinal cortex (Hamelink et al., 2005; Liput et al., 2013) and hippocampus (Brenneman et al., 2018; Hamelink et al., 2005).

When 40 mg/kg/d of CBD was coadministered with alcohol, cell death was reduced by approximately 60% in both areas compared to controls. Neuronal rescue with both antioxidants and furosemide was comparable to the CBD group. Greater cell death was observed with dizocilpine, and there was no difference between the remaining NMDA receptor antagonists (Hamelink et al., 2005).

Most recently, Brenneman and colleagues (2018) examined the effect of CBD and a novel CBD‐derived compound (KLS‐13019) on rat hippocampal cultures to evaluate treatment of oxidative stress as it is relevant to hepatic encephalopathy. Hippocampal cultures were cotreated with toxic levels of alcohol (30 mM) and ammonium acetate (300 μ M), and the protective effects of CBD (concentrations ranging from 0.1 to 10 μ M) and KLS‐13019 (concentrations ranging from 1 nM to 10 μ M) were assessed.

 

Both compounds revealed a protective ability compared to control, although KLS‐13019 exhibited substantially higher potency. Specifically, 10 μ M CBD and 100 to 700 nM KLS‐13019 were required for full protection in hippocampal cultures (Brenneman et al., 2018).

Adverse functional cognitive performance is a potential sequela of neurodegeneration observed in AUD. Our search revealed 1 preclinical study that evaluated the impact of CBD in a neurocognitive domain, specifically impulsive choice, also referred to as delay discounting (i.e., preference for small immediate rewards compared to larger delayed rewards).

Impairments in impulse control are related to both alcohol use/AUD and risk of relapse (Amlung et al., 2017; MacKillop et al., 2011).

 Effects on impulsive choice were examined after termination of the intoxication protocol, and CBD was associated with significantly lower impulsive choice in the animals that received the alcohol dependence protocol. This finding provides evidence of CBD inhibiting the impaired impulse control typically seen in AUD.

Human Studies

In contrast to preclinical studies, no studies examining the effects of CBD on AUD‐related cognitive dysfunction were identified in humans. However, 3 studies were identified that examined the effects of concurrent alcohol and CBD intake on cognitive function in healthy humans. 

 

Bird and colleagues (1980) evaluated the effects of CBD (320 μ g/kg), THC (215 μ g/kg), and cannabinol (320 μ g/kg) alone or in all possible combinations with alcohol (0.54 g/kg). Overall, only THC produced significant synergistic declines on all performance measures, with no interaction effects by CBD or cannabinol pretreatment. Together, these findings provide evidence that CBD is not associated with the same detrimental cognitive effects as alcohol or THC, suggesting that it may be a well‐tolerated treatment from the perspective of cognition.

Alcohol Motivation and Relapse

Beyond excessive drug seeking, post treatment relapse is a primary driver of the chronicity of SUDs. Individuals with SUDs are at risk of relapse due to multiple factors including susceptibility to stress, craving induced by drug contexts, and heightened anxiety (MacKillop et al., 2010; Ramo and Brown, 2008; Sinha, 2012). Unlike existing AUD treatments, CBD is pointed to as a potential treatment as it targets multiple states associated with drug addiction and heightened relapse risk. Preclinical evidence has shown the potential of CBD in opioid and psychostimulant addiction, while human studies present preliminary evidence of a beneficial impact of CBD on cannabis and tobacco dependence (reviewed in Prud'homme et al., 2015).

Preclinical Studies

Four studies were identified examining the effects of CBD on alcohol consumption or self‐administration and processes associated with relapse and addiction (Gonzalez‐Cuevas et al., 2018; Viudez‐Martínez et al., 2018b,b; Filev et al., 2017).

 Some of the most compelling evidence for CBD's therapeutic capacity is derived from animal models of addiction and relapse. For example, Gonzalez‐Cuevas and colleagues (2018) systematically demonstrated the potential of CBD treatment on a number of risk factors of relapse. Using an established protocol, rats were trained to self‐administer oral alcohol in daily 30‐minute sessions.

CBD reduced both context‐ and yohimbine‐induced drug seeking when applied acutely (day 1) and with repeated treatment (day 7). The effect of CBD did not diminish with multiple administrations, implying no development of tolerance. Rather, both forms of reinstatement remained significantly reduced up to 138 days after CBD treatment was discontinued. In contrast, vehicle treatment was associated with increased drug‐seeking behaviors with yohimbine administration. CBD also reduced experimental anxiety.

Two studies investigated the effects of CBD on motivation for alcohol (Viudez‐Martínez et al., 2018b,b) using a 3‐stage operant oral alcohol self‐administration paradigm (Navarrete et al., 2014).

 

In this paradigm, animals underwent 5 daily sessions on a fixed ratio (FR)1 reinforcement schedule and then a FR3 schedule with a final session on a progressive ratio (PR) schedule. Once alcohol intake was normalized, mice underwent FR1 (5 days), FR3 (5 days), and PR (1 day) again. 

 

CBD reduced alcohol‐induced relapse behavior. In addition, less withdrawal (handling‐induced convulsion score) was observed in CBD (+ saline or alcohol)‐treated animals following a single dose of i.p. alcohol (4 g/kg) than the vehicle + alcohol group.

Hepatotoxicity

Chronic alcohol consumption is a leading cause of liver disease worldwide (Leggio and Lee, 2017). Alcohol‐related liver disease ranges in severity from mild and reversible fatty liver (steatohepatitis) to more severe forms including hepatitis, cirrhosis, or even hepatic failure (Leggio and Lee, 2017).

In terms of mechanisms, both oxidative stress and inflammation have been implicated in the induction of alcohol‐related liver injury, including steatohepatitis. In this context, CBD may be a credible pharmacotherapy based on existing evidence regarding its effects as an anti‐inflammatory and antioxidant molecule. Specifically, in non–alcohol‐related liver injury, CBD has improved brain and liver function in a fulminant hepatic failure‐induced model of hepatic encephalopathy (Avraham et al., 2011) and hepatotoxicity resulting from cadmium (Fouad et al., 2013) and cocaine (Vilela et al., 2015).

Preclinical

Of particular interest, Wang and colleagues (2017) evaluated CBD's role in modulating genes involved in metabolism and liver steatosis, neutrophil accumulation, and liver inflammation. Alcohol enhanced expression of several genes involved in fatty acid biosynthesis and decreased those involved in fatty acid oxidation. Further significant hepatic neutrophil accumulation was noted with alcohol; however, CBD treatment markedly attenuated such effects. CBD suppressed the alcohol‐induced increases in mRNA expression of chemokines (macrophage inflammatory protein‐1 alpha, chemokine ligand 2, and monocyte chemotactic protein‐1 and cytokines (tumor necrosis factor alpha, interleukin‐1 beta, and adhesion molecules [E‐selectin]). These findings suggest the protective effects of CBD were at least partially a result of anti‐inflammatory mechanisms (Wang et al., 2017).

Beyond inflammation, findings from both studies also supported antioxidant activity of CBD, with CBD inhibiting hepatic increase in reactive oxygen species induced by alcohol exposure. However, the proposed mechanisms of action differed. 

Wang and colleagues (2017) demonstrated that CBD's actions attenuated an inflammatory response involving E‐selectin and neutrophil recruitment, and it was this anti‐inflammatory effect that reduced oxidative stress.

In sum, this systematic review suggests that CBD may be a credible therapeutic for a wide variety of alcohol‐related harms based on the preclinical literature. Several candidate mechanisms by which CBD may produce therapeutic effects in AUD were identified, providing clear avenues for future research. Fundamentally, empirical studies are needed to determine whether these effects translate into favorable outcomes in human preclinical and clinical models and, ultimately, to inform the appropriateness of CBD as a potential pharmacotherapy for AUD.

3. Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial

Despite the staggering consequences of the opioid epidemic, limited nonopioid medication options have been developed to treat this medical and public health crisis. This study investigated the potential of cannabidiol (CBD), a nonintoxicating phytocannabinoid, to reduce cue-induced craving and anxiety, two critical features of addiction that often contribute to relapse and continued drug use, in drug-abstinent individuals with heroin use disorder.

This exploratory double-blind randomized placebo-controlled trial assessed the acute (1 hour, 2 hours, and 24 hours), short-term (3 consecutive days), and protracted (7 days after the last of three consecutive daily administrations) effects of CBD administration (400 or 800 mg, once daily for 3 consecutive days) on drug cue–induced craving and anxiety in drug-abstinent individuals with heroin use disorder. Secondary measures assessed participants’ positive and negative affect, cognition, and physiological status.

Acute CBD administration, in contrast to placebo, significantly reduced both craving and anxiety induced by the presentation of salient drug cues compared with neutral cues. CBD also showed significant protracted effects on these measures 7 days after the final short-term (3-day) CBD exposure. In addition, CBD reduced the drug cue–induced physiological measures of heart rate and salivary cortisol levels. There were no significant effects on cognition, and there were no serious adverse effects.