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, Yasmin L. Hurd, Sharron Spriggs, et al., 2019

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

Yasmin L. Hurd, Ph.D., Sharron Spriggs, M.A., Julia Alishayev, R.P.A., Gary Winkel, Ph.D., Kristina Gurgov, R.P.A., Chris Kudrich, D.H.Sc., Anna M. Oprescu, M.P.H., Edwin Salsitz, M.D.

AJP in Advance, 2019

doi: 10.1176/appi.ajp.2019.18101191


Objective : 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 drugabstinent individuals with heroin use disorder.

Methods : This exploratory double-blind randomized placebocontrolled 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.

Results : 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.

Conclusions : CBD’s potential to reduce cue-induced craving and anxiety provides a strong basis for further investigation of this phytocannabinoid as a treatment option for opioid use disorder.

The wide availability and use of heroin and prescription opioid analgesics in the United States during the past decade have resulted in an unprecedented epidemic, with other countries at risk of following this trend as opioid use grows worldwide. The crisis has led to more than 300,000 opioidrelated deaths in the United States during the past decade (1), has contributed to more than 4 million years of life lost globally (2), and since 2007 has contributed to an increase in excess of 3,000% in medical services needed for patients with opioid use or misuse, which has led to a substantial economic burden (3). The opioid crisis has also increased awareness about the challenges that exist in treating opioid use disorder because current medications are predominantly mu opioid agonist substitution pharmacotherapies, such as methadone and buprenorphine (4, 5). Such pharmacotherapies are associated with marked stigma and tight governmental regulation because of their potential addictive liability and diversion to the black market, further burdening clinical care and access. Thus, these medications are underutilized in the treatment of millions of people diagnosed with opioid use disorder (6, 7). This treatment gap for the vast number of patients with opioid use disorder highlights the urgent need to develop novel therapeutic strategies that do not target the mu opioid receptor. To address this critical need, we initiated studies (8, 9) of cannabidiol (CBD), a nonintoxicating cannabinoid (10, 11), as a potential treatment of opioid use disorder. Our preclinical studies (10) demonstrated that CBD reduces reinstatement of heroin-seeking behavior specifically triggered by a prior drug-associated cue in animals with a history of heroin self-administration. The specific effects of CBD on cue-induced drug-seeking behavior are particularly important in the development of addiction therapeutics because environmental cues are one of the strongest triggers for craving, which is a core component of opioid use disorder as defined in DSM-5 (12) and which contributes to relapse (13, 14). Another aspect of our preclinical findings that is important for a potential medication for opioid use disorder is that the reduced heroin-seeking behavior is maintained for weeks following CBD administration (15). Other animal studies have reported consistent findings that CBD reduces contextual drug-related memories associated with drugseeking behavior for different substances of abuse (11, 16). To determine whether this preclinical evidence could be translated to humans, we conducted a series of clinical studies and demonstrated that CBD was safe in humans and did not result in adverse consequences when coexposed with a potent opioid agonist (8), in line with its safety and tolerability even at high doses (17). The aim of the present study was to use a double-blind, randomized, placebo-controlled design to explore the effects of acute and short-term CBD administration on craving and anxiety in heroin-addicted individuals. This was examined with the presentation of drug-associated environmental cues to induce craving and stress responsivity in these individuals because such stimuli are strong triggers for opioid use (13, 18, 19). In addition, CBD has been shown to reduce anxiety (20, 21), which we expected to be enhanced by the presentation of drug cues (22). The recent finding that CBD reduces the attentional bias to cigarette cues in tobacco smokers (23) also suggests that a potential strength of CBD for addiction treatment could be through the attenuation of the salience of drug cues. The secondary outcomes investigated in this study were general affect, cognition, and physiological factors, all of which are important in the development of medications for use in the treatment of substance use disorders. Weassessed the effects of CBD administered at doses of 400 mg and 800 mg. These doses were selected on the basis of our previoushumansafety study withCBD(8) and our cueinduced heroin-seeking animal model assessing CBD (15). Moreover, this dose range overlapped known effects of CBD on biological systems relevant to craving and stress responsivity (for example, cortisol levels) (24) and altered cerebral blood flow in limbic brain regions, such as the amygdala (25). We hypothesized that CBD would reduce cueinduced craving and anxiety in heroin abstinent individuals with heroin use disorder and have minimal adverse effects.