3 Citations (SciVal)


Synthetic cannabinoid receptor agonists (SCRAs) are one of the fastest growing classes of recreational drugs. Despite their growth in use, their vast chemical diversity and rapidly changing landscape of structures make understanding their effects challenging. In particular, the side effects for SCRA use are extremely diverse, but notably include severe outcomes such as cardiac arrest. These side effects appear at odds with the main putative mode of action, as full agonists of cannabinoid receptors. We have hypothesized that SCRAs may act as MAO inhibitors, owing to their structural similarity to known monoamine oxidase inhibitors (MAOI's) as well as matching clinical outcomes (hypertensive crisis) of ‘monoaminergic toxicity’ for users of MAOIs and some SCRA use. We have studied the potential for SCRA-mediated inhibition of MAO-A and MAO-B via a range of SCRAs used commonly in the UK, as well as structural analogues to prove the atomistic determinants of inhibition. By combining in silico and experimental kinetic studies we demonstrate that SCRAs are MAO-A-specific inhibitors and their affinity can vary significantly between SCRAs, most notably affected by the nature of the SCRA ‘head’ group. Our data allow us to posit a putative mechanism of inhibition. Crucially our data demonstrate that SCRA activity is not limited to just cannabinoid receptor agonism and that alternative interactions might account for some of the diversity of the observed side effects and that these effects can be SCRA-specific.

Original languageEnglish
Pages (from-to)3243-3257
Number of pages15
JournalFEBS Journal
Issue number12
Early online date28 Jan 2023
Publication statusPublished - 21 Feb 2023

Bibliographical note

Funding Information:
SH and RA acknowledge studentship funding from the BBSRC and EPSRC, respectively. MWvdK acknowledges the BBSRC for funding (BB/M026280/1). JLRA thanks BrisSynBio, a BBSRC/EPSRC Synthetic Biology Research Centre (Grant Number: BB/L01386X/1). CRP acknowledges the EPSRC for funding (EP/V026917/1 and EP/L016354/1).

Publisher Copyright:
© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.


  • MAO-A
  • MAO-B
  • SCRAs
  • enzyme inhibition
  • flexible docking analysis
  • monoamine oxidase
  • synthetic cannabinoid receptor agonists

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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