Safety of oral dronabinol during opioid withdrawal in humans

Abstract

Background Opioid dependence remains a significant public health problem worldwide with only three FDA-approved treatments, all targeting the mu-opioid receptor. Dronabinol, a cannabinoid (CB) 1 receptor agonist, is currently under investigation as a novel opioid withdrawal treatment. This study reports on safety outcomes of dronabinol among adults in opioid withdrawal. Methods Twelve adults physically dependent on short-acting opioids participated in this 5-week within-subject, randomized, double blind, placebo-controlled inpatient study. Volunteers were maintained on oral oxycodone 30mg qid. Double-blind placebo substitutions occurred for 21 hours before each of 7 experimental sessions in order to produce opioid withdrawal. A single oral test dose was administered each session (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Heart rate, blood pressure, respiratory outcomes and pupil diameter were assessed repeatedly. Results Dronabinol 40mg produced sustained sinus tachycardia accompanied by anxiety and panic necessitating dose reduction to 30mg. Sinus tachycardia and anxiety also occurred in one volunteer after dronabinol 20mg. Compared to placebo, dronabinol 20 and 30mg produced significant increases in heart rate beginning 1 hour after drug administration that lasted approximately two hours (p<0.05). Dronabinol 5 and 10mg produced placebo-like effects. Oxycodone produced prototypic mu-opioid agonist effects (e.g., miosis). Conclusion Dronabinol 20mg and higher increased heart rate among healthy adults at rest who were in a state of opioid withdrawal, raising concern about its safety. These results have important implications for future dosing strategies and may limit the utility of dronabinol as a treatment for opioid withdrawal.

Opioid withdrawal suppression efficacy of oral dronabinol in opioid dependent humans

“…However, these potentially therapeutic dronabinol doses also increased heart rate. Dronabinol 20 and 30mg doses increased average maximum heart rates to 107.6 and 112.6 bpm, respectively (Jicha et al, 2015). This was also detected and reported by subjects as “heart racing” suggesting that other dosing strategies, including drug combinations (e.g., with clonidine), may be needed in order to capitalize on the beneficial withdrawal effects while minimizing adverse effects on heart rate.…”

“…This dose was then reduced to 30mg thereafter, and the dose order was fully randomized except that dronabinol 20mg always preceded 30mg. The 40mg dose was excluded from all analyses, and those data are presented elsewhere (Jicha et al, 2015). …”

“…Physiologic measures (heart rate, blood pressure, oxygen saturation, respiratory rate, end-tidal CO 2 , pupil diameter) were repeatedly collected before and after drug administration; these outcomes are reported elsewhere (Jicha et al, 2015). …”

“…We previously reported on the physiologic and safety outcomes from this study whereby dronabinol 40mg was poorly tolerated, producing sinus tachycardia, anxiety and panic, which led to its replacement with a lower 30mg dose (Jicha et al, 2015). Herein, we report on the subjective- and observer-rated opiate withdrawal and agonist outcomes, subjective effects indicative of abuse liability, and cognitive outcomes.…”

Medications for substance use disorders (SUD): emerging approaches

“…CB1-r and its endogenous agonists (e.g., the endocannabinoids anandamide and 2-arachidonyl-glycerol) modulate major neurobiological pathways involved in SUD [145]. The potential pharmacotherapeutic use of cannabinoid formulations has been studied in specific SUD (including aspects of opioid use disorder), but their effectiveness is not broadly supported at this time [79,146,147]. CB1-r receptor systems can also be targeted by synthetic small molecules, and synthetic CB1-r full agonists are also abused [49,148].…”