Pharmacological and Toxicological Effects of Synthetic Cannabinoids and Their Metabolites

Abstract

Commercial preparations containing synthetic cannabinoids (SCBs) are rapidly emerging as drugs of abuse. Although often assumed to be “safe” and “legal” alternatives to cannabis, reports indicate that SCBs induce toxicity not often associated with the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). This chapter will summarize the evidence that use of SCBs poses greater health risks relative to marijuana and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ9-THC may contribute to this increased toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ9-THC typically observed in vitro, SCBs act as full CB1 and CB2 receptor agonists both in cellular assays and animal studies. Furthermore, unlike Δ9-THC metabolism, several SCB metabolites retain high affinity for and exhibit a range of intrinsic activities at CB1 and CB2 receptors. Finally, the potential for SCBs to cause adverse drug–drug interactions with other drugs of abuse, as well as with common therapeutic agents, will be discussed. Collectively, the evidence provided in this chapter indicates that SCBs should not be considered safe and legal alternatives to marijuana. Instead, the enhanced toxicity of SCBs relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2 receptors, highlights the inherent danger that may accompany use of these substances.

Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB1/CB2 versus GPR55 receptors

“…microinjections of Δ 9 ‐THC produced dose‐dependent tetrad effects in WT mice, but not in CB 1 ‐KO mice, while systemic administration of low doses (<10 mg·kg −1 ) or the same micro‐amount of Δ 9 ‐THC (200 μg) failed to produce any tetrad effects in WT mice (data not shown), suggesting that brain CB 1 receptors mediate these effects. Our behavioural findings with these three cannabinoids are consistent with their high binding affinities to CB 1 receptors (Paronis, Nikas, Shukla, & Makriyannis, ; Pertwee, ; Tai & Fantegrossi, ).…”

“…For WT, n = 7; for CB 1 -KO, n = 8; for CB 2 -KO, n = 6; for GPR55-KO, n = 8 THC (200 μg) failed to produce any tetrad effects in WT mice (data not shown), suggesting that brain CB 1 receptors mediate these effects. Our behavioural findings with these three cannabinoids are consistent with their high binding affinities to CB 1 receptors (Paronis, Nikas, Shukla, & Makriyannis, 2012;Pertwee, 2010;Tai & Fantegrossi, 2017).…”

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

“…Data suggest that seizure activity of the abused synthetic cannabinoids JWH-018 (Malyshevskaya et al, 2017), and AM2201 (Funada and Takebayashi-Ohsawa, 2018) is CB 1 -dependent; thus, metabolites with activity at these receptors may contribute to the observed pharmacology and toxicity associated with synthetic cannabinoids. Synthetic cannabinoids are metabolized via cytochrome P450 enzymes, resulting in phase I hydroxylated metabolites (Tai and Fantegrossi, 2017). An alkyl side chain, when present, appears as if it would undergo hydroxylation at several positions.…”

Synthetic Cannabinoid Use in a Psychiatric Patient Population: A Pilot Study

“…Additionally, they have strong cannabimimetic effects, can induce euphoria and relaxation, and enable patients to feel calm and safe [10,11,16,17]. However, accumulating evidence indicates that SCs can induce serious side effects, including psychosis [9,18,19,20].…”

“…Common street names of these drugs include Spice (the most common), Aroma, K2, Fake Weed, Mojo, and Dr. Feel Good [4,5,6,7]. Increasing evidence indicates that SCs have potentially dangerous side effects [4,8,9,10,11]. However, to circumvent drug legislation, manufacturers of these substances continue to develop new compounds with slightly modified chemical structures.…”