Nancy A. Melville
February 06, 2017
The ever-increasing severity of the opioid addiction epidemic provides more justification than ever to pursue the largely overlooked potential of cannabis in the treatment of addiction, and the spread of medical marijuana laws around the country may help give those efforts a needed boost, experts say.
"It is important to move with a deep sense of urgency to leverage the opportunity presented by increased legalization of medical marijuana to expedite the development of cannabidiol for therapeutic interventions for opioid use disorder, thus curbing the opioid epidemic," writes Yasmin L. Hurd, PhD, of the Friedman Brain Institute, Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, Center for Addictive Disorders, Mount Sinai Behavioral Health System, New York City.
In a review article published this month in Trends in Neurosciences, Dr Hurd notes that although evidence involving humans is sorely lacking due to the continuing status of marijuana as a Schedule I drug, studies in preclinical animal models, particularly involving the phytocannabinoid cannabidiol, show promising improvements in opioid withdrawal symptoms and heroin-seeking behavior that need to be pursued in larger studies.
Research includes a study published in Addiction Biology in 2013 showing that cannabidiol inhibited the reward-facilitating effect of morphine, but not cocaine, in rats.
"Our results suggest that cannabidiol interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids, thus indicating that cannabidiol may be clinically useful in attenuating the rewarding effects of opioids," the authors wrote.
Another study, published in the Journal of Neuroscience and conducted by Dr Hurd and colleagues, showed an important effect of cannabidiol in normalizing heroin-induced impairment in the endocannabinoid system and glutamate receptors in the striatum, suggesting a possible effect of normalizing synaptic plasticity in the region.
Among the scant research in humans is a pilot study, also conducted by Dr Hurd and colleagues, showing similar results in reducing heroin-related cue-induced craving in heroin abusers.
The strongest effects in that study were seen in reducing anxiety related to heroin cues. Similar to effects seen in animals, the reduction in general craving lasted for up to 1 week after the last administration of cannabidiol.
"[The study] serves as an important foundation, along with accumulating evidence in animal models, to warrant expedited efforts for additional clinical studies to evaluate the potential therapeutic benefits of cannabidiol as a treatment for opioid use disorders," Dr Hurd writes.
Most evidence suggests that the mechanisms behind cannabidiol's effects relate to its modulation of the 5-HT1A (5-hydroxytryptamine 1A subtype) receptor, consistent with many antianxiety drugs, which have partial agonist properties at the 5HT1A receptors.
For the study involving humans, the researchers used a cannabidiol solution and an oral formulation of cannabidiol (Epidiolex, GW Pharmaceuticals, Plc), which has been shown to have a strong safety profile and is used in the treatment of children with epilepsy.
The formulation allows for cannabinoid treatment without the inclusion of tetrahydrocannabinol (THC), the psychoactive ingredient responsible for the "high" that results from cannabis use and is linked to an increased risk for opioid use.
Furthermore, in contrast to many existing opioid addiction medications, cannabidiol has a low risk for diversion to the black market and retains a safe profile when combined with a strong opioid agonist.
Marijuana a "Safer High"?
Dr Hurd noted that early data coming out of states where marijuana laws have been passed suggest that even as conventionally used, marijuana may be playing a role in offsetting the opioid addiction epidemic.
One report, for instance, suggests there is a trend toward reductions in prescriptions for opioid painkillers, as well as a reduction in opioid overdoses and lower opioid-positive screens associated with car fatalities, in states where medical marijuana laws have been passed.
Although emphasizing that any benefits would apply solely to people who are already addicted to opioids, Dr Hurd said that cannabis could feasibly represent a "safer high."
"It's important to note that the data are very clear that early marijuana use does associate with a risk of opioid use later in life," she stressed.
"However, the findings suggest that when opioids are already consumed, marijuana could be a safer replacement for opioids, since marijuana doesn't induce overdose," she said.
As more epidemiologic research becomes available on trends in states where marijuana laws have been passed, a clearer picture of those effects should emerge.
But the stronger evidence that can come from more rigorous studies and clinical trials regarding cannabis or individual phytocannabinoids remains elusive as long as federal restrictions are in place, and, paradoxically, only strong evidence can change those policies.
"We are in a ridiculous catch-22 situation right now," Dr Hurd said. "There has to be some way that research can be done that fits within a federal guideline to allow us to see which components of the marijuana plant could be beneficial and which ones aren't.
"Without that, we will still have these circular debates when we should be having evidence-based decisions and medicine."
She added that the growing tendency of states to loosen their marijuana laws, combined with the opioid use crisis, should help generate action to try to take research to the next level
"We could actually move very quickly if there was a federal mandate to put together a consortium that can quickly investigate this for opioid use disorder," Dr Hurd noted. "We could really answer all the questions that are there. It doesn't have to be 10 or 20 years from now."
Researchers in Montreal are currently evaluating the use of cannabidiol in the treatment of addiction in a clinical trial involving patients with cocaine addiction.
According to senior investigator Didier Jutras-Aswad, MD, psychiatrist and director of the Addiction Psychiatry Unit, the Centre hospitalier de l'Université de Montréal, in Quebec, Canada, the double-blind, placebo-controlled study has enrolled 110 persons who will be studied for 3 months.
"All subjects have cocaine use disorder, and half will be given cannabidiol and half given placebo," he told Medscape Medical News.
The primary outcome of the study is drug-induced craving and number of days to relapse. Secondary outcomes are stress-induced craving and assessment of cocaine use during the postdetoxification phase.
"The main hypothesis in the field is the mechanism of cannabidiol in the treatment of addiction is in its effect on anxiety, but we need more evidence of this in human trials," he said.
"We're trying to determine if the effect is through anxiety or purely through a reduction in craving."
Dr Jutras-Aswad echoed that the key benefits of cannabidiol over other addiction therapies are in its safety and its low potential for abuse.
"It's not reinforcing of drug-seeking behaviors, and it's not a source of abuse, which is often the case with a lot of antianxiety medications. So for a population already with addiction, it's a very attractive candidate."
Dr Jutras-Aswad's research is being supported by Insys Therapeutics, the manufacturer of the cannabinoid used in the study. He emphasized that the bottom line for the advancement of broader research is the need for more funding.
"Funding is not easy to get in the US, Canada, or elsewhere due to the somewhat controversial nature of this, but I strongly support Dr Hurd's call to action for more support and funding in these efforts," he said.
As reported by Medscape Medical News, the US Drug Enforcement Agency (DEA) denied two petitions to reschedule marijuana under the Controlled Substances Act from Schedule I to Schedule II last August.
But the agency did take the step of expanding the number of DEA-registered marijuana manufacturers to help give researchers "a more varied and robust supply of marijuana," the agency said.
The clinical trial that Dr Jutras-Aswad is conducting is receiving funding from Insys Therapeutics. Dr Hurd has disclosed no relevant financial relationships.
Trends Neurosci. Published February 2, 2017. Full text