Synthetic Cannabinoids: Pharmacology, Behavioral Effects, and Abuse Potential

Abstract

Cannabis has been used throughout the world for centuries. The psychoactive effects of cannabis are largely attributable to Δ9-tetrahydrocannabinol (Δ9-THC), the prototypical cannabinoid that occurs naturally in the plant. More recently, chemically- and pharmacologically-distinct synthetic cannabinoids (SCBs) have emerged as drugs of abuse. As compared to Δ9-THC, the distinct structures of these compounds allow them to avoid legal restrictions (at least initially) and detection in standard drug screens. This has contributed to the popularity of SCBs among drug users who seek to avoid positive drug screens. Importantly, the distinct structures of the SCBs also typically result in increased affinity for and efficacy at cannabinoid CB1 receptors, which are thought to be responsible for the psychoactive effects of Δ9-THC and its analogues. Accordingly, it seems likely that these more powerful cannabimimetic effects could result in increased adverse reactions and toxicities not elicited by Δ9-THC in cannabis. Animal models useful for the study of emerging SCBs include the cannabinoid tetrad, drug discrimination, and assays of tolerance, dependence, and withdrawal. However, these in vivo procedures have not been particularly informative with regards to drug efficacy, where the majority of SCB effects are comparable to those of Δ9-THC. In contrast, essentially all in vitro measures of drug efficacy confirm Δ9-THC as a relatively weak CB1 partial agonist, while the majority of the SCBs detected in commercial preparations are full agonists at the CB1 receptor. As use of these emerging SCBs continues to rise, there is an urgent need to better understand the pharmacology and toxicology of these novel compounds.

Mechanisms Underlying Sex Differences in Cannabis Use

“…Briefly, the cannabinoid-1 receptor (CB1-R) is the primary mediator of cannabinoid signaling in the central nervous system [16, 17], and is accompanied in lower levels by cannabinoid-2 receptors (CB2-R) [18, 19]. Cannabinoid receptors (CB-Rs) are activated by the endogenous ligands N-arachidonoylethanolamine (AEA) [20] and 2-arachidonoylglycerol (2-AG) [21–23], as well as exogenous ligands including THC and synthetic cannabinoids [24]. CB1-Rs are widely distributed in brain regions including frontal cortex, hippocampus, cerebellum, hypothalamus, basal ganglia, and reward circuit areas such as ventral tegmental area and nucleus accumbens [14].…”

The effects of adolescent cannabinoid exposure on seizure susceptibility and lethality in adult male rats

“…Non-human studies can generate different findings, depending upon whether researchers administer natural or synthetic cannabinoids during the treatment window. Nevertheless, there is great value in studying the developmental effects of synthetic cannabinoids, specifically, especially given the recent surge in their recreational use among adolescents (Tai and Fantegrossi, 2014).…”

“…This information is valuable for researchers and medical practitioners interested in the potential benefits of cannabinoid receptor agonists for chronic medical conditions, including seizure disorders. Recent years have also seen a significant rise in the recreational use of synthetic cannabinoids among adolescents in the United States (Tai and Fantegrossi, 2014). It is therefore imperative that we continue exploring the potential long-term consequences of early exposure to cannabinoids.…”

Pneumomediastinum: A Complication of Synthetic Cannabinoid K2 Use

“…Activation of CB receptors causes elation, irritability and anxiety. CB receptors are located in the immune system and podocytes in glomeruli [3][4][5][6][7][8]. They are Manuscript accepted for publication September 16, 2016 Pneumomediastinum due to Cannabinoid K2 Use J Med Cases.…”