A CB1 Receptor Blocker Rapidly Reversed the Effects of Synthetic Cannabinoid Intoxication in Mice | Research

The takeaway

The CB1 receptor antagonist AM251 rapidly reversed the hypothermic and sedative effects of a synthetic cannabinoid in mice, suggesting CB1 blockers could serve as emergency antidotes for cannabinoid overdose.

Readers interested in harm reduction and emergency treatment for synthetic cannabinoid overdose.

CB1 antagonist rapidly reversed cannabinoid intoxication when given 20 minutes after exposure

What the researchers found

Researchers induced cannabinoid intoxication in mice using the synthetic CB1 agonist CB-13, which caused significant hypothermia and visible sedation. Twenty minutes after CB-13 administration, the CB1 receptor antagonist/inverse agonist AM251 was given.

AM251 rapidly reversed the hypothermic effects of CB-13, returning body temperature toward normal. There was also a subjective reversal of visible sedation. The key finding was that the antagonist worked therapeutically (after intoxication had already occurred), not just prophylactically (before exposure).

The authors argue that with the emergence of extremely potent synthetic cannabinoids ("Spice," "Black Mamba") causing life-threatening intoxications and deaths, a single-dose cannabinoid receptor antagonist could serve as a life-saving antidote, analogous to naloxone for opioid overdose.

Why it matters

Synthetic cannabinoid overdoses have caused numerous hospitalizations and deaths, and currently there is no specific antidote. This proof-of-concept study demonstrates that a CB1 receptor antagonist can reverse at least some cannabinoid effects after they have already begun, supporting the development of an emergency antidote for clinical use.

The numbers in context

AM251 administered 20 minutes after CB-13 intoxication. Hypothermic effect was rapidly reversed. CB1 receptor antagonists have been widely used in research with established safety profiles for single doses.

How the study worked

Biozzi ABH mice received the synthetic CB1 agonist CB-13. Body temperature was monitored as a measure of cannabinoid intoxication. AM251 was administered 20 minutes after CB-13 to test therapeutic (post-intoxication) reversal. Sedation was assessed observationally.

What this study cannot tell us

Mouse study using a single synthetic cannabinoid and a single antagonist. Many synthetic cannabinoids in recreational use may have off-target effects not mediated by CB1 receptors, which an antagonist would not reverse. AM251 is a research tool, not a clinical drug. The study measured hypothermia as a proxy for intoxication; more severe effects (seizures, psychosis, cardiovascular collapse) were not modeled.

How to read the evidence

Preliminary evidence from a single animal study demonstrating proof of concept.

When this study was published

Published in 2017. Synthetic cannabinoid overdose emergencies have continued to increase.

The bigger picture

The opioid crisis led to widespread naloxone availability as an overdose antidote. As synthetic cannabinoids become more potent and more dangerous, a similar approach for cannabinoid overdose becomes more relevant. This study provides preclinical evidence that such an antidote is pharmacologically feasible.

Questions still open

Would a CB1 antagonist reverse the most dangerous effects of synthetic cannabinoid intoxication (cardiovascular collapse, seizures)? Could a clinical-grade CB1 antagonist be developed and deployed like naloxone? What are the side effects of acutely blocking CB1 receptors in someone who is a chronic cannabis user?

Common questions

Is there an antidote for cannabis or synthetic cannabinoid overdose?

Not yet in clinical use. This study demonstrated in mice that a CB1 receptor antagonist can reverse some effects of synthetic cannabinoid intoxication. Development of a clinical antidote for human use would require significant further research and regulatory approval.

Would this work for natural cannabis intoxication too?

Theoretically, a CB1 antagonist could reverse THC's effects since THC acts primarily through CB1 receptors. However, natural cannabis intoxication is almost never life-threatening, so the clinical need is much greater for synthetic cannabinoid overdoses, which can be fatal.

Read the original research

Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB-13, in mice.

British journal of pharmacology, 174(21), 3790-3794

View on PubMed ↗Publisher’s paper ↗

Citation

Pryce, Gareth; Baker, David. (2017). Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB-13, in mice.. British journal of pharmacology, 174(21), 3790-3794. https://doi.org/10.1111/bph.13973