Tripping with Synthetic Cannabinoids (“Spice”): Anecdotal and Experimental Observations in Animals and Man Torbjorn€ U.C. Ja¨rbe and Jimit Girish Raghav Abstract The phenomenon of consuming synthetic cannabinoids (“Spice”) for recreational purposes is a fairly recent trend. However, consumption of cannabis dates back millennia, with numerous accounts written on the experience of its consumption, and thousands of scientific reports published on the effects of its constituents in laboratory animals and humans. Here, we focus on consolidating the scientific literature on the effects of “Spice” compounds in various behavioral assays, including assessing abuse liability, tolerance, dependence, withdrawal, and potential toxicity. In most cases, the behavioral effects of “Spice” compounds are compared with those of Δ9-tetrahydrocannabinol. Methodological aspects, such as modes of administration and other logistical issues, are also discussed. As the original “Spice” molecules never were intended for human consumption, scientif- ically based information about potential toxicity and short- and long-term behav- ioral effects are very limited. Consequently, preclinical behavioral studies with “Spice” compounds are still in a nascent stage. Research is needed to address the addiction potential and other effects, including propensity for producing tissue/ organ toxicity, of these synthetic cannabimimetic “Spice” compounds. Keywords Cannabinoid • Cannabinoid receptor 1 • Marijuana • ‘Spice’ • Synthetic marijuana • THC Contents 1 The Cannabis Plant ......................................................................... 264 2 Personal Testimonies ....................................................................... 265 3 Synthetic Cannabinoids ..................................................................... 265 T.U.C. Ja¨rbe (*) and J.G. Raghav Department of Pharmaceutical Sciences, Center for Drug Discovery (CDD), Northeastern University, 116 Mugar Hall, 360 Huntington Ave, Boston, MA 02115, USA e-mail: [email protected] 264 T.U.C. Ja¨rbe and J.G. Raghav 4 Common Cannabinoid Screens: Tetrad and Drug Discrimination .. ...................... 267 4.1 Tetrad .................................................................................. 267 4.2 Drug Discrimination .................................................................. 268 4.3 Drug Discrimination and “Spice” .................................................... 269 5 Logistical Issues ............................................................................. 269 5.1 “Spice” Toxicity ...................................................................... 269 5.2 Metabolism ............................................................................ 270 5.3 Mode of Administration .............................................................. 270 5.4 Methodological/Procedural Considerations .......................................... 271 6 Drug Reinforcement ........................................................................ 272 6.1 SA and Cannabinergics ................................................ ............... 272 6.2 CPP and Cannabinergics .............................................................. 273 6.3 ICSS and Cannabinergics ............................................................. 274 7 Tolerance, Dependence, and Withdrawal .................................................. 274 8 “Spice”: Neurological and Sensomotor Aspects ........................................... 275 References ....................................................................................... 276 Abbreviations 11-OH-THC 11-Hydroxy-Δ9-tetrahydrocannabinol 2-AG 2-Arachidonoyl glycerol AM Alexandros Makriyannis CB1R Cannabinoid receptor type-1 CB2R Cannabinoid receptor type-2 CBD Cannabidiol CP Compound Pfizer CPP Conditioned place preference ECS Endocannabinoid system ER Emergency room HU Hebrew University i.p. Intraperitoneal i.v. Intravenous ICSS Intra-cranial self-stimulation JWH John W. Huffman MFB medial forebrain bundle SA Self-administration THC Δ9-Tetrahydrocannabinol 1 The Cannabis Plant The relationship between cannabis and man has a long and varied history spanning millennia. The plant has been used for hemp production, a food source, as a medicine, and as a recreational drug. Although its exact geographical origin is unknown, many taxonomists have suggested its origins to be central Asia. The original plant composition likely no longer exists, as humans have greatly Tripping with Synthetic Cannabinoids (“Spice”): Anecdotal and... 265 influenced the genome through selective breeding. One can grossly divide the plant into two main sub-strains, one emphasizing its use for fiber (cordage) production (high cannabidiol, CBD, and content) and the other strain emphasizing its use as an intoxicant, the latter primarily due to the phytocannabinoid chemical Δ9-tetrahy- drocannabinol (THC). The amount and ratios of cannabinoids, terpenes, and other chemicals also show regional variations [1]. 2 Personal Testimonies Many personal accounts surrounding the mind altering effects of cannabis are dispersed throughout history, including those of members of the hashish eaters club in Paris around the early to mid-seventeenth century. One likely member of the club was the French psychiatrist J. J. Moreau de Tours (1804–1884) who, in his youth, had traveled abroad extensively including visiting the Middle East where he had encountered hashish (cannabis resin). Moreau was fascinated with the topic of the mind and psychosis/mental illness. He believed that valuable insights into the “psychotic state of mind” could be achieved by inducing a temporary “insanity” episode through the means of taking mind altering drugs. He and his students ingested various amounts of hashish resin and systematically recorded their obser- vations. Such observations/recordings formed the foundation for the publication “Du Hachisch et de l’Alienation Mentale; Etudes Psychologiques” (Hashish and Mental Illness; Psychological studies). The 400-page book by Moreau was origi- nally published in 1845 and an English translation was reissued in 1973 by Raven Press. Given Moreau’s belief in the usefulness for psychiatry of the revelations of the workings of the brain by mind altering drugs (model psychosis), many scholars view him as the founding father of the discipline we today refer to as Psychophar- macology [2–4]. Description(s) of the mental and physiological effects of high-dose ingestion of hashish (“A young physician, terrified, pressed his head with both hands as if to keep it from bursting, crying: I am lost; I have lost my head; I am going crazy!”; p. 83, English version) are akin to descriptions related to the more recent phenomenon of using synthetic cannabinoids for recreational purposes, here collectively referred to as “Spice” (“My heart starts pounding so fast and hard and doesn’t feel real. As of that moment, I no longer know who I am, where I am and what is real”; The Day AM-2201 Ruined My Life, Anonymous testimony, Erowid. org. Aug 11, 2015). 3 Synthetic Cannabinoids AM-2201 is a synthetic chemical capable of activating brain cannabinoid receptors (CB1R and CB2R) with high receptor binding affinity and potency. While its effects mimic those induced by THC in rat drug discrimination studies, AM-2201 266 T.U.C. Ja¨rbe and J.G. Raghav Fig. 1 Substitution test 100 ED50: 0.06 mg/kg ED50: 0.76 mg/kg data for AM-2201 and Δ9-THC in rats trained to 80 discriminate between THC (3 mg/kg) and vehicle 20 min i.p. post- 60 administration. Graph modified from Ja¨rbe 40 et al. [5] AM2201 20 THC THC (3 mg/kg) responding (%) responding THC mg/kg) (3 0 0.01 0.1 1 10 Dose (mg/kg) is 5–12 times (see Fig. 1) more potent than THC and its duration of action appears shorter [5, 6]. (Note: Potency estimates will depend on the particular endpoint being examined.) Originally, AM-2201 and similar indole-based ligands (see Fig. 2 for examples) were developed to gain insight into the workings of the endocannabinoid system (ECS), a modulatory signaling system present in brain as well as peripheral body tissues. Endogenous ligands include anandamide and 2-arachidonoyl glycerol (2-AG), but other fatty acid related constituents also have been identified in brain [1]; for chemical structures of the phytocannabinoids THC and CBD, as well as the endogenous ligands anandamide and 2-AG, see Fig. 3. Endocannabinoids bind to and activate both CB1R and CB2R, but the cannabis/THC produced “high” is primarily mediated through activation of CB1R; the contribution by CB2R, if any, remains elusive. Thus, clandestine manufacturing has targeted compounds that activate CB1R. Offerings through the internet, “head-shops,” convenience stores, and other venues aim to provide alternatives to cannabis that are not detected by analytical screening assays. As forensic chemists have developed assays to detect synthetic cannabinoids, the clandestine manufacturers have made tweaks in the chemical structures to continue drug trafficking and to evade legal restrictions after previous chemicals have been banned. In addition, the package wrapping usually contains a disclaimer which states that the herbal incense “is not for human consumption.” Although the initial wave of recreational synthetic cannabi- noids borrowed design and synthetic routes that were already available in the scientific literature, many more recent chemicals are novel and have not been described before; for references, see [7, 8]. Information on the biological effects of many clandestine synthetic