A clinical trial on 42 participants has found that CBD efficiently reduces cue-induced cravings and anxiety in abstinents with heroin use disorder. The effects are seen even after the very first dose and last longer than the presence of CBD in the body. These findings can present a turning point in the fight against the global opioid crisis.
Growing opioid problem
Opioids, which include opiates (heroin and opium) and pharmaceutical and other synthetic opioids, are a major concern in many countries because of the severe health consequences associated with their use. According to the UN 2020 World Drug Report, in 2017, the use of opioids accounted for nearly 80 percent of the 42 million years of “healthy” life lost as a result of disability and premature death.
In 2018, 57.8 million people globally were estimated to have used opioids in the past year. The prevalence of opioid use is 1.2 percent of the global population aged 15–64. The use of opioids is higher than the global average in North America (3.6 percent), Australia and New Zealand (3.3 percent), the Near and the Middle East and South-West Asia (2.6 percent), and South Asia (2.0 percent).
Although global estimates are not available, the nonmedical use of pharmaceutical opioids is reported in many countries, in particular in countries in West and North Africa and the Near and Middle East (tramadol), and in North America (hydrocodone, oxycodone, codeine, tramadol, and fentanyl).
In Canada, opioid overdose deaths increased by 50 percent in two years, from 3,023 deaths in 2016 to 4,398 deaths in 2018, the majority of them (80 percent) involving fentanyl.
According to the EMCDDA European Drug Report 2020, heroin and other opioids are found in 82% of fatal overdoses, and there are around 1.3 million high-risk users, with 660.000 who received substitution treatment in 2018.
The opioid crisis has increased awareness about the challenges in treating opioid use disorder. Current medications are associated with stigma and tight governmental regulation because of their potential addictive liability and diversion to the black market, further burdening clinical care and access. That highlights the urgent need to develop novel therapeutic strategies that don’t target the mu opioid receptor and don’t cause addiction, such as CBD.
CBD prevents relapse
The environmental cues are one of the strongest triggers for craving, causing relapse in drug users. This led the scientist to examine the specific effects of CBD on cue-induced drug-seeking behavior as particularly important in the development of addiction therapeutics. Also, preclinical trials reported that reduced heroin-seeking behavior is maintained for weeks following CBD administration. A study on rats found that CBD had prolonged effects on drug-seeking and anxiety-like behavior that lasted for five months after its short-term administration. On top of that, other animal studies have reported consistent findings that CBD reduces contextual drug-related memories associated with drug-seeking behavior for different substances of abuse.
A clinical study published in the American Journal of Psychiatry in 2019 investigated the potential of CBD to reduce craving and anxiety, two critical features of addiction that contribute to relapse in drug abstinent humans with heroin use disorder.
This double-blind placebo-controlled randomized clinical trial was conducted at the Mount Sinai Beth Israel Hospital in New York. Abstinent men and women with heroin use disorder between 21 and 65 years of age were recruited through advertisements posted in local newspapers, social service organizations, halfway houses, and college campuses in New York City. Some were also directly recruited from clinical addiction treatment sites.
Participants were excluded if they tested positive for any psychoactive drug other than nicotine; met criteria for any diagnosis other than heroin or nicotine dependence within the previous three months; were being maintained on methadone, buprenorphine, or an opioid antagonist; had a significant medical history or condition; had hypersensitivity to cannabinoids, or showed signs of acute heroin withdrawal.
Out of 50 participants included in the study, eight were excluded because of voluntary withdrawal, positive toxicology results, and health issues. Most participants (78.6%) indicated a preference for intranasal heroin use, and 83.3% reported using more than 10 bags of heroin (one bag=1 g) daily. On average, participants had been using heroin for approximately 13.2 years. The majority of participants (64.3%) had been abstinent from heroin use for less than a month, 14.3% for 1–2 months, and 21.4% for 2–3 months.
Epidiolex used as CBD oral solution
Patients were randomly assigned to receive 400 mg of CBD, 800mg of CBD, or placebo. The 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. The CBD oral solution (100 mg/mL; Epidiolex) and the matched placebo solution were obtained from GW Pharmaceuticals. Other ingredients were ethanol (79.0 mg/mL), sucralose (0.5 mg/mL), strawberry flavor (0.2mg/mL), and refined sesame oil (to a volume of 1mL). The placebo oral solution was identical in appearance, taste, and composition, except for the active ingredient of pure CBD. Oral solutions of 400 mg and 800 mg of CBD were approximately 5 mg/kg and 10 mg/kg of participant weight.
Participants were exposed to neutral and drug-related cues at different points during test sessions. They watched a 3-minute video showing relaxing scenarios, such as scenes in nature, or a 3-minute video that showed intravenous or intranasal drug use, depending on the reported preferred route of drug use. At one point, the participants were also exposed to neutral objects or heroin-related tools (e.g., syringe, rubber tie, and packets of powder resembling heroin) for two minutes.
Either CBD or placebo was administered 60 minutes before the first cue test. The second session assessed the protracted effects 24 hours after the first CBD or placebo administration, and the second dose of CBD or placebo was administered at the end of the session after the cue tests had been finished. The thirds session assessed the effects of the prior short-term accumulated CBD exposure on cognition, and the final dose of CBD or placebo was administered just before starting the cognitive tasks. The fourth session was conducted one week after the final CBD dose.
Significantly greater craving in the placebo group
There was no significant difference between the groups in their baseline craving scores, but there was a significant contribution of sex, with women reporting nearly twofold greater cravings than men. After experiencing the drug cues, craving scores for all participants were significantly higher than when they were exposed to the neutral cues. Across all sessions, individuals receiving placebo reported significantly greater craving after the drug cues compared with participants in either of the CBD groups. There was no significant difference in craving scores between the groups of participants administered with the two CBD doses, indicating that both doses equally reduced craving.
Furthermore, the effects of CBD on craving were most prominent during session 1, which was conducted from 1 to 2 hours after CBD administration. There was a significant interaction between the cue condition and the drug group. The highest level of craving was evident for participants receiving placebo under the drug cue condition, followed by those who received 400 mg of CBD and then those who received 800 mg of CBD.
In session 4, which occurred one week after the last CBD administration, participants who had received a placebo in the previous week reported significantly greater cravings compared with those who had received 800 mg of CBD.
Significantly greater anxiety in the placebo group
Sex was not significantly associated with anxiety in any session, but female participants tended to report greater anxiety than males. The drug cues were significantly associated with greater baseline-adjusted anxiety than those experienced with the neutral cues. Again, participants in the placebo group reported significantly greater baseline-adjusted anxiety after the cues compared with those in both the 400 mg and 800 mg CBD groups. The greater anxiety was recorded across all sessions. However, there was no significant difference in anxiety between the two CBD groups. For all groups, the level of anxiety was greater when participants were exposed to the drug cues than when they were exposed to the neutral cues. However, this difference was most pronounced for those receiving placebo, followed by those who received 400 mg of CBD and then those who received 800 mg of CBD.
The results of this trial indicated that administration of 400 mg or 800 mg of CBD reduced cue-induced craving and anxiety in heroin-abstinent individuals, suggesting a potential role for CBD to alleviate clinical signs and symptoms critical to the continued cycle of addiction. CBD effects on drug cue-induced craving and anxiety were evident soon after acute exposure to the drug (session 1). In addition, there was a protracted effect on these measures one week after short-term repeated administration of CBD (session 4). CBD also tended to reduce physiological measures of stress reactivity, such as increased heart rate and cortisol levels induced by salient drug cues. Most importantly, CBD administration (at 400 mg or 800 mg) was associated with only mild adverse events.
The capacity of CBD to reduce craving and anxiety one week after the final administration mirrors the results of the original preclinical animal study, suggesting that the effects of CBD are long-lasting, even when the cannabinoid would not be expected to be present in the body.
The potential of CBD to reduce cue-induced craving and anxiety, along with its safe pharmacological profile, low mortality risk, and lack of hedonic properties, indicates that CBD holds significant promise for treating individuals with heroin use disorder. A successful nonopioid medication would add significantly to the existing addiction medication toolbox to help reduce the growing death toll, enormous health care costs, and treatment limitations imposed by stringent government regulations amid this persistent opioid epidemic.