A review mapped out how 13 synthetic cannabinoids are metabolized and their potential for dangerous drug interactions | Research

The takeaway

A comprehensive review described the metabolic pathways of 13 prevalent synthetic cannabinoids, identifying which drug-metabolizing enzymes (CYPs, UGTs, carboxylesterases) process them and documenting their potential to inhibit these enzymes, creating risk for drug-drug interactions.

Toxicologists and emergency physicians treating synthetic cannabinoid poisoning; forensic scientists identifying metabolites; pharmacologists studying drug interactions.

Synthetic cannabinoids both use and block the same enzymes that metabolize other drugs

What the researchers found

Researchers reviewed the metabolism of 13 prevalent synthetic cannabinoids, mapping which cytochrome P450 (CYP) enzymes, UDP-glucuronosyltransferases (UGTs), and carboxylesterases are responsible for breaking them down.

Synthetic cannabinoids are substrates of multiple drug-metabolizing enzymes, meaning these enzymes process and eliminate them from the body.

Critically, synthetic cannabinoids also inhibit CYP and UGT enzymes. This means they can interfere with the metabolism of other drugs taken concurrently, potentially causing dangerous increases in blood levels of co-administered medications.

The review emphasized the urgency of understanding these interactions given the rise in synthetic cannabinoid poisonings and the likelihood that users are taking multiple substances simultaneously.

Why it matters

Synthetic cannabinoid users frequently use other drugs simultaneously, and emergency departments are seeing increasing poisoning cases. Understanding which enzymes process these substances and which other drugs might interact is essential for toxicology and emergency medicine.

The numbers in context

13 synthetic cannabinoids reviewed. Multiple CYP enzymes, UGTs, and carboxylesterases identified as metabolizing enzymes. Inhibitory effects on CYP and UGT activities documented for predicting drug-drug interactions.

How the study worked

Comprehensive review of published literature on metabolic pathways of 13 prevalent synthetic cannabinoids. Covered CYP enzyme characterization, UGT involvement, and inhibition studies.

What this study cannot tell us

Review of existing literature, which is incomplete for many newer synthetic cannabinoids. In vitro enzyme studies may not perfectly predict in vivo drug interactions. The rapid emergence of new compounds means the review is inherently incomplete.

How to read the evidence

Moderate. Comprehensive review of metabolic data with clinical relevance, though limited by gaps in primary research for newer compounds.

When this study was published

Published in 2018. New synthetic cannabinoids have continued to emerge, requiring ongoing metabolic characterization.

The bigger picture

As new synthetic cannabinoids are continuously developed to evade scheduling, understanding their metabolic profiles helps forensic labs identify them in biological samples and helps clinicians anticipate drug interactions in overdose situations.

Questions still open

Which clinically significant drug-drug interactions are most likely with synthetic cannabinoids? Can metabolic profiling help predict toxicity of novel synthetic cannabinoids before they appear in clinical settings?

Common questions

Why are drug interactions with synthetic cannabinoids dangerous?

When synthetic cannabinoids block the enzymes that break down other drugs, blood levels of those other drugs can rise to toxic levels. This is especially dangerous because synthetic cannabinoid users often take multiple substances, and emergency physicians may not know what drugs are involved.

How are synthetic cannabinoids different from natural cannabis?

Synthetic cannabinoids are lab-made chemicals sprayed onto plant material. They bind cannabinoid receptors much more potently than THC, often as full agonists rather than partial agonists. Their metabolism and drug interaction profiles can be very different from natural cannabis compounds.

Read the original research

Synthetic cannabinoids are substrates and inhibitors of multiple drug-metabolizing enzymes.

Archives of pharmacal research, 41(7), 691-710

View on PubMed ↗Publisher’s paper ↗

Citation

Kong, Tae Yeon; Kim, Ju-Hyun; Kim, Dong Kyun; Lee, Hye Suk. (2018). Synthetic cannabinoids are substrates and inhibitors of multiple drug-metabolizing enzymes.. Archives of pharmacal research, 41(7), 691-710. https://doi.org/10.1007/s12272-018-1055-x