CHAPTER e10 Cannabis and the Use of Amphetamine-Like Substances A. Porcu , M.P. Castelli Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, Cittadella Universitaria, Monserrato, CA, Italy SUMMARY POINTS KEY FACTS ON THE • This chapter focuses on coabuse of cannabis and MONOAMINERGIC TARGET SYSTEM amphetamine-like substances (ALS). • Monoamines refer to the particular neurotransmitters • Cannabis (main psychoactive compound dopamine, norepinephrine and serotonin. Δ 9 -Tetrahydrocannabinol, Δ 9 -THC) is consumed • These neurotransmitters are involved in mediating a by 2.9–4.3% of the global population aged 16–64 wide range of physiological and homeostatic functions in the world. such as cognition, memory, learning, mood, and behavior. • Cannabis consumption is frequently associated • These neurotransmitters are synthesized within with simultaneous use of other psychoactive particular neurons, and exert an effect when they are compounds such as alcohol, cocaine, and ALS released into the synapses, where they are able to act (ie, amphetamine, methamphetamine, and on specifi c receptors. 3,4-methylenedioxymethamphetamine). • The dopamine transporter (DAT), serotonin • New psychoactive substances (NPS), such as transporter (SERT), and the norepinephrine transporter cathinones and its derivatives, are frequently (NET) transport monoamines in or out of a cell. coabused with cannabis. • ALS may increase the activity of dopamine, • Cannabis + ASL coabuse enhances the subjective norepinephrine, or serotonin by either increasing effects of the drugs in humans, counteracts release, blocking reuptake, inhibiting metabolism, or the dysphoric symptoms of “coming down” acting directly on a receptor. from 3,4-methylenedioxymethamphetamine or methamphetamine (MDMA and METH), and/or improves and mellows the drug experience. KEY FACTS ON NEW PSYCHOACTIVE • Both pharmacological and genotype animal SUBSTANCES (NPS) studies support the role of the cannabinoid type • NPS are known in the drug market under the names of 1 receptor (CB1R) in the rewarding and addictive “designer drugs,” “legal highs,” “herbal highs,” “bath properties of MDMA. salts,” or “research chemicals.” • Preclinical and clinical studies investigating the • NPS have become a global phenomenon, and they effects of cannabis + ASL and their interaction have affected all regions of the world; 70 (out of 80) in METH/MDMA-induced neurotoxicity have countries and territories (88%) examined by UNODC reported confl icting fi ndings: cannabis might (2014) have reported the emergence of NPS. exacerbate or attenuate METH/MDMA induced • The number of NPS on the global market more than neurotoxicity. doubled over the period 2009–13. Legislation has not Handbook of Cannabis and Related Pathologies. http://dx.doi.org/10.1016/B978-0-12-800756-3.00066-1 Copyright © 2017 Elsevier Inc. All rights reserved. e101 CC0330.indd0330.indd 110101 114/12/164/12/16 22:43:43 PPMM e102 e10. CANNABIS AND THE USE OF AMPHETAMINE-LIKE SUBSTANCES RNS Reactive nitrogen species been established, making their sale easy and offi cially ROS Reactive oxygen species legal in almost all countries. SERT Serotonin transporter • The most popular of these drugs are based on the TH Tyrosine hydroxylase substance cathinone (2-amino-1-phenylpropanone) TTAR1 Activate trace amine associated receptor 1 and its synthetic analogs. TUNEL Terminal deoxynucleotidyl transferase • The chemical structure of NPS is similar to that of VMAT-2 Vesicular monoamine transporter-2 amphetamine, as well as their physiological and psychological actions. INTRODUCTION KEY FACTS ON POLYDRUG USE • Research on polydrugs use is typically done on Cannabis is the most widely consumed illicit drug relatively small convenient samples (eg, street- worldwide, with an estimated global use by 2.9– based, emergency rooms, and club patrons), where 4.3% of the population aged 16–64 ( UNODC, 2010 ) multiple drugs are frequently used consecutively or ( Fig. e10.1 ). simultaneously, often for their perceived counteracting While the prevalence of illicit drugs such as cocaine, or complementary effects. amphetamine-like substances (ALS) [ie, amphetamine • It is associated with a higher risk of developing (AMPH), methamphetamine (METH), and 3,4-methy- psychiatric and health problems. lenedioxymethamphetamine (MDMA)] appeared to remain stable between 2009 and 2011, since 2009 the ex- tent of cannabis and opioids use has increased. Cannabis LIST OF ABBREVIATIONS consumption is frequently associated with simultaneous and/or concurrent use of other psychoactive compounds Δ 9 -THC Δ 9 -Tetrahydrocannabinol such as alcohol, cocaine, and ALS ( Gouzoulis-Mayfrank 5HT Serotonin & Daumann, 2006 ). ADHD Attention-defi cit/hyperactivity disorder A growing body of clinical and preclinical studies has AMPH Amphetamine highlighted the simultaneous use of MDMA, also called ec- ALS Amphetamine-like substances stasy, and cannabis ( Parrott, Milani, Gouzoulis-Mayfrank, BDNF Brain-derived neurotrophic factor & Daumann, 2007 ). Strote, Lee, & Wechsler (2002) , survey- CB1-KO Cannabinoid type 1 receptor knockout mice ing a sample of over 10,000 US college students, reported a CB1R Cannabinoid type 1 receptor prevalence of ecstasy use of 4.7%, with 92% of consumers CB2-KO Cannabinoid type 2 receptors knockout mice also consuming cannabis. Wish, Fitzelle, O’Grady, & Hsu CB2R Cannabinoid type 2 receptor (2006) confi rmed that 98% of recreational MDMA users CPP Conditioned place preference in a sample of East Coast College students also consume DA Dopamine cannabis. Moreover, the presence of a metabolite of the Δ9 DAT Dopamine transporter main psychoactive compound -tetrahydrocannabinol Δ9 DEA Drug Enforcement Administration ( -THC), 11-nor-9 carboxy-THC, was found in urine sam- dUTP 2 Ј -deoxyuridine 5 Ј -triphosphate ples collected from 198 ecstasy users between 2005 and ECS Endocannabinoid system 2008 ( Black, Cawthon, Robert, & Moser, 2009 ). FDA Food and Drug Administration In Europe, the prevalence of couse of MDMA + can- fMRI Functional magnetic resonance technique nabis ranges from 73% to 100% in different countries GFAP Glial fi brillary acidic protein ( Sala & Braida, 2005 ), and is higher in males and in MAO Monoamine oxidase regular cannabis users than in women and occasional MDMA 3,4-Methylenedioxymethamphetamine METH Methamphetamine MJ Marijuana NE Norepinephrine NET Norepinephrine transporter nNOS Neuronal nitric oxide synthase NO Nitric oxide NPS New psychoactive substances pCREB Phosphorylated cAMP response element– binding protein FIGURE e10.1 Estimated number of people who used cannabis at PKA Protein kinase A least once in the past year, and its prevalence among the population PKC Protein kinase C aged 15–64, by region. Source: UNODC (2010) . IV. CANNABIS, ORGANS, TISSUES AND NON-CNS ASPECTS CC0330.indd0330.indd 110202 114/12/164/12/16 22:43:43 PPMM AMPHETAMINE-LIKE SUBSTANCES: AMPH, METH, MDMA, AND CATHINONES e103 cannabis consumers ( ESPAD, 2000 ). Due to its low cost, are complex, and data regarding their coadministra- wide availability, and high potential for abuse, METH tion in human and animal studies are contradictory is the second most frequently abused recreational drug ( Mohamed, Ben Hamida, Cassel, & de Vasconcelos, 2011 ; among adolescents, and is often coabused with cannabis Schulz, 2011 ). ( Gonzalez, Rippeth, Carey, & Heaton, 2004 ). Δ 9 -THC and other cannabis derivatives act via canna- Several psychosocial and functional reasons can ac- binoid type 1 receptors (CB1R) on the endocannabinoid count for the high percentage of concurrent use of Δ 9 -THC system (ECS), while the ALS, including MDMA, METH and METH or MDMA. Cannabis is often considered a and the cathinones, act by increasing synaptic levels of “gateway drug,” and its consumption might predict a the monoamines dopamine (DA), serotonin (5HT), and signifi cantly higher risk for subsequent use of heavy il- norepinephrine (NE). licit drugs such as ALS. However, numerous reports have For a detailed description of the ECS and the mecha- failed to support this theory, while other studies point to nism of action of Δ 9 -THC and other cannabinoids, see social, environmental, and genetic factors to explain the designated Chapters of this book. couse of cannabis and other drugs ( Parrott et al., 2007 ). In the following paragraphs, we will briefl y describe MDMA and METH are psychostimulant drugs that the ALS, including cathinones, their molecular pharma- induce euphoria, increased sociability, and empathy cology, and the pharmacological/neurobiological effects ( Parrott, 2013 ), while cannabis produces relaxation and induced by ALS + cannabis. feelings of happiness ( Green, Kavanagh, & Young, 2003 ). One of the main reasons for using cannabis in associa- tion with MDMA or METH is that the combination of AMPHETAMINE-LIKE SUBSTANCES: the two drugs enhances the subjective drug effects, and AMPH, METH, MDMA, counteracts the dysphoric symptoms of the ecstasy or AND CATHINONES METH “coming down” ( Schulz, 2011 ). Indeed, MDMA abusers often consume cannabis in the immediate post- Amphetamine (AMPH) is the parent compound of ecstasy period as a symptomatic relief against the nega- a class of molecules with similar chemical structures tive physiological and emotional states (eg, anhedonia, and biological properties, referred to as amphetamines depression) that follow ecstasy’s “high.” Many ecstasy ( Fig. e10.2 ) ( Fleckenstein, Volz, Riddle, & Gibb, 2007 ). users also report taking cannabis in