A CB1 receptor enhancer reduced opioid withdrawal symptoms in mice without cannabis-like side effects | Research

The takeaway

The CB1 receptor positive allosteric modulator ZCZ011 fully blocked opioid withdrawal-induced diarrhea and weight loss in mice without producing the side effects associated with THC.

Researchers and clinicians interested in novel opioid withdrawal treatments.

Fully blocked withdrawal diarrhea and weight loss via CB1 mechanism

What the researchers found

ZCZ011 completely eliminated naloxone-precipitated diarrhea and weight loss in oxycodone-dependent mice and reduced paw flutters by about half. These effects were mediated specifically through CB1 receptors, confirmed by antagonist reversal and CB1 knockout mice. Unlike THC, ZCZ011 did not produce overt cannabimimetic behavioral effects.

Why it matters

Current opioid withdrawal treatments have abuse liability or limited effectiveness. A CB1 enhancer that reduces withdrawal without cannabis-like intoxication could offer a new treatment approach.

The numbers in context

ZCZ011 fully blocked withdrawal-induced diarrhea and weight loss, reduced paw flutters by ~50%, had unreliable effects on head shakes, and did not affect jumping.

How the study worked

Mice were made opioid-dependent using escalating oxycodone doses, then given naloxone to precipitate withdrawal. ZCZ011 was tested against withdrawal signs including diarrhea, weight loss, jumping, paw flutters, and head shakes. CB1 and CB2 antagonists and CB1 knockout mice were used to confirm the mechanism.

What this study cannot tell us

Mouse model only. Did not block all withdrawal signs (jumping was unaffected). Doses used may not translate to humans. Long-term safety of CB1 PAMs is unknown.

How to read the evidence

Well-designed preclinical study with mechanism confirmation, but limited to mice and did not address all withdrawal symptoms.

When this study was published

Published in 2022.

The bigger picture

Positive allosteric modulators work by enhancing the body's own endocannabinoid signaling rather than directly activating receptors, which may explain the reduced side effect profile compared to THC.

Questions still open

Would ZCZ011 or similar CB1 PAMs be effective in human opioid withdrawal? Could combining a CB1 PAM with existing treatments improve outcomes across all withdrawal symptoms?

Common questions

How is this different from using THC for opioid withdrawal?

Unlike THC, which directly activates CB1 receptors and causes intoxication, ZCZ011 enhances the receptor's response to the body's own endocannabinoids. This produced withdrawal relief without the psychoactive side effects, tolerance, or dependence seen with THC.

Did it eliminate all withdrawal symptoms?

No. It fully blocked diarrhea and weight loss, reduced paw flutters by half, but did not affect jumping behavior. Its effects on head shakes were inconsistent.

Read the original research

The Cannabinoid Receptor Type 1 Positive Allosteric Modulator ZCZ011 Attenuates Naloxone-Precipitated Diarrhea and Weight Loss in Oxycodone-Dependent Mice.

The Journal of pharmacology and experimental therapeutics, 380(1), 1-14

View on PubMed ↗Publisher’s paper ↗

Citation

Dodu, Julien C; Moncayo, Rebecca K; Damaj, M Imad; Schlosburg, Joel E; Akbarali, Hamid I; O'Brien, Lesley D; Kendall, Debra A; Wu, Zhixing; Lu, Dai; Lichtman, Aron H. (2022). The Cannabinoid Receptor Type 1 Positive Allosteric Modulator ZCZ011 Attenuates Naloxone-Precipitated Diarrhea and Weight Loss in Oxycodone-Dependent Mice.. The Journal of pharmacology and experimental therapeutics, 380(1), 1-14. https://doi.org/10.1124/jpet.121.000723