Cannabinoid compounds reduced physical morphine withdrawal signs in mice but not the emotional aversion to withdrawal | Research

The takeaway

THC and endocannabinoid-boosting drugs reduced physical withdrawal jumping in morphine-dependent mice but did not block the aversive emotional experience of withdrawal.

Read this if you're interested in whether cannabinoids could help with opioid withdrawal.

Physical withdrawal reduced; emotional aversion unchanged

What the researchers found

Researchers tested whether cannabinoid compounds could reduce different aspects of morphine withdrawal in mice. They examined both physical signs (jumping) and emotional aspects (conditioned place avoidance, where mice learn to avoid a location associated with withdrawal).

THC, the MAGL inhibitor JZL184, and the dual FAAH/MAGL inhibitor SA-57 all significantly reduced the percentage of mice that jumped during withdrawal. However, none of these compounds blocked the development of conditioned place avoidance, meaning mice still learned to avoid the withdrawal-associated environment.

The FAAH inhibitor PF-3845 (which boosts anandamide but not 2-AG) did not reduce either physical or emotional withdrawal. Importantly, none of the endocannabinoid-boosting drugs produced a place preference or aversion on their own, suggesting low abuse potential.

Why it matters

Separating physical and emotional aspects of withdrawal reveals that cannabinoids may help with some but not all dimensions of opioid withdrawal. This has implications for whether cannabinoid-based treatments could meaningfully improve the opioid withdrawal experience.

The numbers in context

THC, JZL184, and SA-57 reduced jumping but not place avoidance. PF-3845 reduced neither. None produced place preference in non-dependent mice. Morphine pretreatment prevented both physical and emotional withdrawal. Clonidine blocked only emotional withdrawal.

How the study worked

Controlled animal study using morphine-pelleted mice with naloxone-precipitated withdrawal. THC, JZL184 (MAGL inhibitor), PF-3845 (FAAH inhibitor), and SA-57 (dual inhibitor) were tested against conditioned place avoidance (emotional withdrawal) and jumping behavior (physical withdrawal). Non-dependent mice were tested for place preference/aversion.

What this study cannot tell us

Mouse model may not fully capture human withdrawal experience. Precipitated withdrawal (using naloxone) is more abrupt than natural withdrawal. Drug doses were specific and may not represent optimal therapeutic ranges. The conditioned place avoidance paradigm measures one specific aspect of emotional response.

How to read the evidence

Controlled animal study with multiple compounds and behavioral endpoints. Mechanistically informative but limited human translatability.

When this study was published

Published in 2015. Cannabinoid-opioid interaction research has continued.

The bigger picture

Opioid withdrawal has both physical and emotional components, and effective treatment needs to address both. This study shows that cannabinoid approaches may help with physical symptoms while leaving emotional distress intact, suggesting they would be insufficient as standalone withdrawal treatments.

Questions still open

Could higher doses or different cannabinoid compounds address emotional withdrawal? Would combining cannabinoids with clonidine (which blocked emotional but not physical aspects) provide comprehensive withdrawal relief? Do these findings translate to human opioid withdrawal?

Common questions

Can cannabinoids help with opioid withdrawal?

In mice, THC and drugs that boost endocannabinoid levels reduced physical withdrawal symptoms (jumping) but did not address the emotional distress of withdrawal. This suggests cannabinoids may help partially but are not a complete solution.

Do endocannabinoid-boosting drugs have abuse potential?

In this study, none of the endocannabinoid-boosting drugs produced a place preference in non-dependent mice, suggesting they may have lower abuse potential than direct cannabinoid receptor agonists like THC.

Read the original research

Differential effects of endocannabinoid catabolic inhibitors on morphine withdrawal in mice.

Drug and alcohol dependence, 146, 7-16

View on PubMed ↗Publisher’s paper ↗

Citation

Gamage, Thomas F; Ignatowska-Jankowska, Bogna M; Muldoon, Pretal P; Cravatt, Benjamin F; Damaj, M Imad; Lichtman, Aron H. (2015). Differential effects of endocannabinoid catabolic inhibitors on morphine withdrawal in mice.. Drug and alcohol dependence, 146, 7-16. https://doi.org/10.1016/j.drugalcdep.2014.11.015