Opioids/opiates have provided significant and sometimes life-saving relief to countless patients. They remain some of the strongest painkillers available and can be especially helpful in rendering comfort in otherwise extremely painful terminal illnesses. Opioids work by activating opioid receptors located in the brain, which are densely located in emotion-controlling areas that process pain. Unfortunately, prolonged or extreme use of opioids can lead to dependence, or the body adjusting by limiting natural opioid production and therefore resulting in the body physiologically needing increasing amounts of external opioids to function properly. However, aside from practical issues, high doses of opioids can lead to respiratory failure, death, and other serious health consequences, which means that for all but terminally ill users, opioid withdrawal will eventually occur. Withdrawal is not only unpleasant physically and psychologically (depression, lack of appetite, diarrhea), but potentially life-threatening. In fact, withdrawal is so severe that it can sometimes prevent patients from ending opiate use, causing a downward spiral. As a result, modern doctors are cautious to prescribe opioids and usually seek to wean patients off opioids through slowly decreasing prescriptions.

Perhaps more concerning though, aside from medical patients, roughly 4.3 million people in the US alone are currently non-medical users of narcotic pain relievers. Drugs like heroin, hydrocodone, oxycodone, etc. are all opiate-based drugs that are frequently abused for the recreational high. Meanwhile, even drugs intended to wean opiate use, such as buprenorphine, are commonly sold and traded. To date, only compounds that directly activate opioid receptors have been employed clinically to decrease opioid withdrawal. Ideally, new compounds that do not directly activate opioid receptors could be discovered. Such compounds would represent a step forward in opioid dependence treatment, not only because of the decreased chance of abuse, but also by giving doctors another option to mitigate withdrawal that does not involve guessing at the current level of opioid abuse.

As we’ve reviewed on the blog previously, cannabinoids have emerged as one such potential treatment. Although the cause is unknown, a multitude of experiments have confirmed the endocannabinoid system to be linked to opioid receptors and opioid dependence. One research group at the University of Guelph, Canada, reviewed the last two decades of medical literature to draw general conclusions about the future of cannabinoid research in regards to opioid dependence. We’ve summarized those conclusions below:

  • Withdrawal occurs both somatically (physical symptoms) and affectively (mostly neurological symptoms). As it turns out, THC or any cannabinoid that activates the CB1 receptor, can alleviate somatic withdrawal if given acutely before withdrawal occurs. To put in plain English, this means that if cannabis, for instance, is applied in a single, high dose before withdrawal, almost all of the physical symptoms accompanying withdrawal can be dampened. How can we observe this? In 1978, to facilitate the study of opiates, V. F. Gellert and S. G. Holtzman developed a weighted scale consisting of graded symptoms including percentage of weight loss, number of uncontrollable shakes and jumps, number of abdominal constrictions, abnormal posture, etc. This scale has been evaluated to give fairly consistent, accurate measurements of withdrawal and thus has been copied and modified over the years to serve as the basis for most experiments evaluating general physical/somatic withdrawal. As the authors of this review study have reported, over 25 studies, with cannabinoid receptor agonists including THC, synthetic lab-created cannabinoids, and the body’s own natural endocannabinoids (such as 2-AG and anandamide) have all been shown to reduce withdrawal effects. Despite the variety of cannabinoids and testing procedures, very few studies reported no effect or no significant effect, meaning that the scientific community has therefore consistently illustrated that cannabinoid application before withdrawal eases withdrawal. The data for cannabinoid application during affective withdrawal (the                 neurological/psychological component of opiate withdrawal) is not quite as strong as that for physical withdrawal. However, various tests, specifically a test which measures aversion to a physical place where withdrawal has occurred, illustrates that cannabinoid application can render similar positive effects. Cannabinoid application directly prior to withdrawal decreases the likelihood of avoidance of withdrawal environments, suggesting that the psychological impact of withdrawal is dampened by acute cannabinoid use. However, this specifically pertains to cannabinoids that activate CB1 receptors. Cannabidiol (CBD), which does not activate CB1 receptors to a significant degree, generally produces no effect.

 

  • With such clear evidence, readers may be tempted to conclude, “Got it, cannabinoids ease withdrawal,” assuming that the presence of cannabinoids is helpful, or at the very least benign to withdrawal in all cases. However, such a blanket statement is actually false. Contrary to acute cannabinoid application immediately before withdrawal, chronic cannabinoid use during opioid dependence prevents a dampening of withdrawal. As robust as the data is supporting cannabinoid use immediately prior, multiple experiments have established that prolonged cannabinoid receptor activation during opioid dependence may actually make withdrawal more difficult. In fact, somewhat surprisingly, cannabinoid receptor blockers, if applied during opioid dependence and halted immediately before withdrawal, have shown similar effects as cannabinoids applied directly before withdrawal without prior use! This seemingly opposite cause of a similar effect suggests that the relationship between the endocannabinoid system and opioid receptors may have something to do with the level of cannabinoid dependence. Shutting off the endocannabinoid system entirely during dependence and allowing it to function normally again during withdrawal is somewhat akin to a normally operating endocannabinoid system that has suddenly been supplied more cannabinoids; in either case, the cannabinoid system is activated to a greater degree than normal. However, if users’ cannabinoid systems are already firing on full cylinders, supplying cannabinoids during withdrawal may have no effect. This finding is particularly unfortunate, given that a large percentage of opioid addicts already use cannabis consistently and therefore may not benefit during withdrawal.

 

  • Cannabinoid enzyme inhibitors, chemicals that inhibit the enzymes that clear cannabinoids from receptors, have shown promise. In particular, MAGL inhibitors, which inhibit the enzyme that breaks down naturally-occurring 2-AG, have shown immediate success in reducing withdrawal symptoms without the side-effect of psychoactivity. Unfortunately, MAGL inhibitors can also become addictive with prolonged use, leading researchers to test various combinations of other enzyme inhibitors that would allow a lower dose of MAGL-inhibitor to be applied. These combinations have been illustrated in a preliminary round of studies to be equally effective without fostering dependence.

Regardless, how is this occurring? Clearly there is some link between the endocannabinoid system and opioid receptors, but what is that link? Scientists are currently unsure. Initial data suggests that the signal transfer methods of both systems in the brain are co-localized, meaning they are very close together. Perhaps signals become chemically “crossed”, allowing one system to affect the other. However, this has not been confirmed. Curiously enough, external cannabinoid application tends to increase opioid receptor density and vice-versa. In other words, some clear link exists, which means it’s a matter of time before researchers hone in on that link and are able to use it to develop new medicines. Those medicines, however, may be decades away from public release. In the meantime, opioid addicts should seek withdrawal treatment. Whether cannabinoid use should be a part of that depends on each individual patient’s history and plan of treatment. In a situation where cannabinoid use makes probability of relapse more likely, cannabinoids should be avoided. However, acute cannabinoid use can ease the uncomfortable withdrawal process and make relapse less likely. Ultimately that decision is best left to trained opioid addiction experts and evaluated on a case-by-case basis.

 

 

Works Cited

Wills KL and Parker LA (2016) Effect of Pharmacological Modulation of the Endocannabinoid System on Opiate Withdrawal: A Review of the Preclinical Animal Literature. Front. Pharmacol. 7:187. doi: 10.3389/fphar.2016.00187