Metabolites of the deadly synthetic cannabinoid 5F-MDMB-PINACA retain potency and show unusual CB1 receptor behavior | Research

The takeaway

The synthetic cannabinoid 5F-MDMB-PINACA (linked to over 40 deaths) produces metabolites that remain active at CB1 receptors with unusual pharmacological properties, potentially explaining why this drug is so toxic.

Toxicologists, emergency physicians, pharmacologists, and public health professionals monitoring synthetic cannabinoid trends.

Linked to 40+ deaths; metabolites show atypical CB1 receptor behavior

What the researchers found

5F-MDMB-PINACA and its metabolite M2 showed nanomolar affinity and high efficacy at CB1 receptors. Metabolite M7 retained high efficacy but only micromolar affinity. The CB1 antagonist rimonabant blocked these compounds differently than it blocks THC. Chronic exposure caused CB1 receptor down-regulation, but only the parent compound produced desensitization. M2 produced dose-dependent hypothermia and analgesia in mice comparable to THC.

Why it matters

Understanding why synthetic cannabinoids like 5F-MDMB-PINACA are so much more dangerous than THC requires understanding their metabolites. The atypical pharmacology described here may explain the severe and sometimes fatal toxicity.

The numbers in context

Over 40 fatalities associated with 5F-MDMB-PINACA. Parent compound and M2 had nM affinity; M7 had only μM affinity. Rimonabant showed different antagonism profiles for synthetic cannabinoids vs. THC.

How the study worked

Competition binding and G-protein modulation studies at CB1 receptors. Rimonabant antagonism experiments compared to THC. Chronic administration studies measuring receptor down-regulation and desensitization. In vivo locomotor, hypothermia, and analgesia tests in mice for M2 and THC.

What this study cannot tell us

In vitro and mouse studies. The pharmacological differences observed may not fully explain human toxicity. M7 concentrations in vivo may not reach the μM levels needed for activity. Limited to CB1 receptor; other targets not examined.

How to read the evidence

Rigorous pharmacological characterization with in vitro and in vivo components, relevant to understanding synthetic cannabinoid toxicity.

When this study was published

Published in 2022.

The bigger picture

The finding that metabolites of synthetic cannabinoids retain activity and behave differently from THC metabolites at CB1 receptors helps explain why synthetic cannabinoids produce prolonged, severe, and unpredictable effects compared to plant cannabis.

Questions still open

Do the active metabolites accumulate to toxic levels in humans? Could the atypical antagonism profile explain why standard treatments fail in synthetic cannabinoid overdose? Are there better antidotes than rimonabant?

Common questions

Why are synthetic cannabinoids more dangerous than natural cannabis?

This study shows that 5F-MDMB-PINACA and its metabolites are high-efficacy agonists at CB1 receptors (vs. THC which is partial), produce atypical receptor interactions, and the metabolites remain active. This combination may lead to prolonged, severe, and sometimes fatal effects.

What is 5F-MDMB-PINACA?

Also known as 5F-ADB, it is a third-generation synthetic cannabinoid that has been associated with over 40 deaths worldwide. It is much more potent and pharmacologically distinct from THC.

Read the original research

Metabolites of Synthetic Cannabinoid 5F-MDMB-PINACA Retain Affinity, Act as High Efficacy Agonists and Exhibit Atypical Pharmacodynamic Properties at CB1 Receptors.

Toxicological sciences : an official journal of the Society of Toxicology, 187(1), 175-185

View on PubMed ↗Publisher’s paper ↗

Citation

Cabanlong, Christian V; Russell, Lauren N; Fantegrossi, William E; Prather, Paul L. (2022). Metabolites of Synthetic Cannabinoid 5F-MDMB-PINACA Retain Affinity, Act as High Efficacy Agonists and Exhibit Atypical Pharmacodynamic Properties at CB1 Receptors.. Toxicological sciences : an official journal of the Society of Toxicology, 187(1), 175-185. https://doi.org/10.1093/toxsci/kfac024