Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9-THC: Mechanism underlying greater toxicity?

Abstract

K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a “safe” and “legal” alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ9-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ9-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both 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 CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed “advantages” have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products 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 CB2Rs, highlights the inherent danger that may accompany use of these substances.

User Experiences of Development of Dependence on the Synthetic Cannabinoids, 5f-AKB48 and 5F-PB-22, and Subsequent Withdrawal Syndromes

“…Known as 'K2, Spice and Kronic' (Bright et al 2013;Baumann et al 2014;Fantegrossi et al 2014), an ever diverse range of SCBs are manufactured and designed for circumvention of contemporary legislative controls (Vandrey et al 2012). The occurrence of SCBs was recognised in Europe as early as 2004 when sold as 'legal highs' or 'herbal highs' (Bryner 2010;Deluca et al 2009;Griffiths et al 2010;Schifano et al 2009;Seely et al 2011).…”

Synthetic Cannabinoids (SCs) in Metaphors: a Metaphorical Analysis of User Experiences of Synthetic Cannabinoids in Two Countries

“…One such NPS are the synthetic cannabinoids (SCs) known as Spice, K2, Kronic (Bright et al 2013;Baumann et al 2014;Fantegrossi et al 2014;Zawilska and Wojcieszak 2014), intended to replace natural cannabis and generally sold as herbal smoking mixtures. SCs emerged in Europe as early as 2004 (Griffiths et al 2010;Schifano et al 2009).…”

“…In comparison to natural cannabis, available literature indicates that more unpredictable and adverse symptomatology is reported by users (Bonar et al 2014;Castaneto et al 2014;Fantegrossi et al 2014;Van Hout and Hearne 2017;Kassai et al 2017a). Users describe intense and rapid trajectories of SC use from positive toward the negative and with dependent resulting in severe psychopathological and withdrawal symptoms (Zimmermann et al 2009;Van Der Veer and Friday 2011;Nacca et al 2013;Macfarlane and Christie 2015;Bilgrei 2016) and solitary daily use (Van Hout and Hearne 2017; Kassai et al 2017a).…”

Synthetic cannabinoids severely elevate amino transferase levels. Natural cannabidiol does not.

“…Reported side effects of synthetic cannabinoid use include extreme anxiety, confusion, hallucinations and paranoia, violent behavior, suicidal thoughts, tachycardia, nausea, and vomiting. Unlike CBD, synthetic cannabinoids are extremely potent, full agonists of the cannabinoid receptors (Weinstein, Rosca, Fattore, & London, 2017;Spaderna, Addy, D'Souza, 2013;Fantegrossi, Moran, Radominska-Pandya, & Prather, 2014).…”