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When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex”

When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex” Send Orders for Reprints to [email protected] 762 Current Neuropharmacology, 2017, 15, 762-770 RESEARCH ARTICLE a,* a b c c Raffaele Giorgetti , Adriano Tagliabracci , Fabrizio Schifano , Simona Zaami , Enrico Marinelli and Francesco Paolo Busardò a b Section of Legal Medicine, Università Politecnica delle Marche, Ancona, Italy; Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, College Lane Campus, University of Hertfordshire, Hatfield, Herts, AL10 9AB, UK; Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy Abstract: Background: The term “chemsex” was coined to indicate the voluntary intake of psychoactive and non psychoactive drugs in the context of recreational settings to facilitate and/or to enhance sexual intercourses mostly among men who have sex with other men (MSM). Objective: The authors aimed to review the mechanisms of action, the toxicity and the pattern of use and abuse of substances involved in “chemsex” practice together with the sociocultural background underlying it and the health-related consequences that they may have. Results: Gamma-hydroxybutyrate, gamma-butyrolactone,1,4-butanediol, mephedrone, methamphetamine, A R T I C L E H I S T O R Y   sildenafil, tadalafil, vardenafil and alkyl nitrites have been described in their role of “chemsex drugs” Received: May 17, 2016 including pharmacological action and in their implication to impair capacities to chose sexual Revised: June 17, 2016 partners and consensual sex. Moreover, it has been demonstrated that sexual activity over protracted Accepted: November 04, 2016 length of time under the influence of chemsex drugs can result in rectal trauma or penile abrasions and a DOI: significant increase of the risk of transmission of sexual transmitted diseases, especially in case of 10.2174/1570159X15666161117151148   condomless intercourses, which are frequent in this context, representing therefore a serious health threat. Conclusion: One of the major problems to establish health policy priority interventions for chemsex is the lack of available epidemiological data on the issue. Finally, social actions should be taken in order to break down the barriers that currently exist among chemsex drug users in accessing services, including the shame and stigma often associated with drug use. In conclusion, more specific resources to face high risks of infections and HIV transmission are required in bisexual and homosexual individuals having SUID: sex under the influence of drugs. Keywords: Chemsex, GHB, mephedrone, crystal meth, erectile dysfunction agents, viagra, poppers. 1. INTRODUCTION that those MSM, who are aware of being HIV positive and take anti HIV medication (e.g. Highly Active Anti-Retroviral The term “chemsex”, coming from the contraction of Therapy, HAART) more commonly use “chemsex” drugs “chemical sex” was coined to indicate the voluntary intake of than the ones who are HIV negative or with an unknown certain psychoactive and non psychoactive drugs in the status [3-5]. This is mainly done to potentiate physical context of sex parties and sexual intercourses with the performance impaired by the disease and to counteract the intention of facilitating and/or enhancing the sexual encounter effects of consequent pharmacological treatment [6]. mostly among men who have sex with other men (MSM) Whereas in the nineties of the last century the most [1]. common abused drugs in the “party and sex” contest were: According to different studies, mainly homosexual and cannabis, ecstasy, amphetamine and cocaine, more recently bisexual male partygoers use one or more drugs in “chemsex” has been associated to new psychoactive drugs combination to facilitate prolonged sexual sessions possibly and sex enhancers such as, γ-hydroxybutyric acid (GHB) and with multiple sexual partners [2], although MSM are more congeners, mephedrone, methamphetamine (commonly prone to use sex enhancer drugs in comparison to non-MSM. called crystal methamphetamine or chrystal meth), erectile A serious harmful behaviour related to this latter evidence is dysfunction agents and alkyl nitrites (or poppers) [5, 6]. Within the framework of neuropharmacological, chemical and toxicological aspects of new psychoactive *Address correspondence to this author at the Section of Legal Medicine, substances, the authors aimed to review the mechanisms of Università Politecnica delle Marche, Ancona, Italy; Tel: +390715964727; E-mail: [email protected] action, the toxicity and the pattern of use and abuse of 1570-159X/17 $58.00+.00 ©2017 Bentham Science Publishers When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex” Current Neuropharmacology, 2017, Vol. 15, No. 5 763 substances involved in “chemsex” practice together with the to obtain an energy boost thereby increasing libido, sociocultural background underlying it and the health-related facilitating muscle relaxation, providing more self-assurance consequences that they may have on sexual behaviours in and in general facilitating sexual sessions [7]. Indeed, homosexual and bisexual users, including the risk of GHB acts in the central nervous system inducing a biphasic acquiring sexually transmitted infections. time profile with an initial stimulant-like effect related to the simultaneous rise of plasma concentrations with a 2. LITERATURE SEARCH preponderant disinhibiting action and a later sedative effect unrelated to GHB kinetics [12]. This latter peculiar effect has The following databases were searched: Pubmed and made GHB one of the most used substance in drug- Scopus (from 1980 to 2016) using key-words: chemsex; facilitated sexual assaults, also in the settings of MSM with gamma-hydroxybutyrate; GHB; gamma-butyrolactone; GBL; associated risk of sexually transmitted infection including 1,4-butanediol; mephedrone, methamphetamine; crystal HIV [6]. After GHB ingestion, its performance and behavioural meth, erectile dysfunction agents, viagra, sildenafil, tadalafil, effects begin approximately 10-30 min. later and according vardenafil, alkyl nitrites, poppers. to the dose can last from 1 to 6 hours. The dose-effect curve These key-words were searched alone or in association for GHB is quite high, so that small increases in doses cause with the main keyword: chemsex. disproportionate increases in behavioural effects and toxicity. The effect duration can also be influenced by combinations Several textbooks, non-indexed sources and government with other drugs taken at the same time. For recreational websites were also looked through. This search strategy purposes, a fixed GHB dosage could be problematic and detected about 1000 sources, which were screened to find improper dosage (overdose and poisoning) can lead to those deemed the most relevant for the current review. About serious side effects and even death [7]. 60 articles were more deeply examined and the main findings from the reported studies are here presented. Another important aspect worthy of attention is that, differently from several other drugs of abuse where 3. RESULTS adulteration practices are well known, little information Table 1 summarized the “chemsex” drugs” described in relating to GHB adulteration is currently available and GHB this review with their principal characteristic features. used for non-medical purposes is most commonly synthesized illicitly from GBL. In this context, a recent case of intoxication 3.1. Gamma-hydroxybutyric Acid (GHB) and Congeners in the context of “chemsex” involved MSM who consumed GHB adulterated with sildenafil by the drug dealer with the GHB, a potent central nervous system depressant acting declared intention to enhance expected sexual effects [13]. both as a precursor and a metabolite of the chief inhibitory Chest pain, a severe headache and tachycardia, shortness of neurotransmitter gamma-aminobutyric acid (GABA), is quite breath and dizziness”, never experienced so far after GHB commonly encountered during forensic examination of use, were attributed to sildenafil (the adulterant) rather than living and deceased subjects in recreational and sex scenes the claimed active ingredient (GHB). Hence, the illegal (Fig. 1) [7]. GHB prodrugs or precursors, mainly gamma market, hypothesizing a synergic action of GHB and butyrolactone (GBL) and 1,4 butanediol (1,4-BDL), are rapidly sildenafil, aimed to increase the promised GHB effect by converted into GHB within the body after ingestion and for adding another pharmacologically active compound, with the this reason are present in the illegal market together with risk of causing serious health hazard as in this case. illicit GHB [8]. GBL is considered more pharmacologically potent than GHB due to its more rapid absorption thanks to 3.2. Mephedrone its lipophilic property and greater bioavailability and a major duration of action, although its effects last less [9]. GHB Mephedrone (4-methylmethcathinone; 4-methylephedrone; interacts with GABAergic neurotransmission and this molecule 4-MMC; 2-(methylamino)-1-(4-methylphenyl)propan-1-one] is considered a GABA-B agonist. Neurons releasing GABA falls within the category of designer drugs and is structurally are predominantly located in the hippocampus, cortex similar to cathinone, the main active constituent of the Khat and amygdala. GHB receptors are localized in these sites, plant (Catha edulis) [14-17]. Mephedrone was synthesized in pre- and postsynaptic cells. GHB exerts most of its for the first time in 1929 as a ring-substituted cathinone and effects through binding to the GABA-B receptors, which are its chemical structure is strictly linked to that of the metabotropic transmembrane receptors linked via G-proteins phenethylamine family [14]. to potassium channels, although also dopamine and serotonin neurotransmission is thought to be implicated. GHB firstly Similarly to methamphetamine and cathinone, mephedrone inhibits the dopamine release, however the dopamine later is powerfully able to stimulate dopamine release and block increases according to the dose turnover [10]. GHB is known its re-uptake through its interaction with the dopamine with numerous street names: Liquid X, Liquid E, Liquid transporter [18]. Furthermore it presents some affinity for various Ecstasy, Easy Lay, G, Vita-G, G-Juice, Georgia Home Boy, serotonin receptor subtypes, so that serotonergic signalling may Great Hormones, Soap, Gook, Gamma, and is available in mediate more of mephedrone effects [18]. Hence his subjective colourless, odourless liquid or white powder, tablet and effects result in temporary improvements in mental and/or capsule forms [11]. In certain contexts, such as rave parties physical function, with distinctive emotional and social effects, and gay nightclubs, GHB has been reported to be used by similar to those of 3,4 methylenedioxymetamphetamine men who look for intentional sex with other men, alone or in (Ecstasy MDMA). Among the most common effects induced combination with other psychoactive drugs with the intention by mephedrone in users, there are: euphoria, stimulation, 764 Current Neuropharmacology, 2017, Vol. 15, No. 5 Giorgetti et al. Table 1. Drugs used in “chemsex” with their street names, chemical structures, preparations and route of administration. Chemical Structure Common Name Street Names Preparations Route of Administration Gamma- GHB, "G" (most common), Gamma- White crystalline Usually oral; Hydroxybutyric OH, Liquid E, Fantasy, Georgia Home powder: sodium or intravenous acid Boy, Grievous Bodily Harm, Liquid X, potassium salt, Liquid Ecstasy, Scoop, Water, clear liquid Everclear, Great Hormones at Bedtime, solution: GHB salt GBH, Soap, Easy Lay, Salty Water, dissolved in water G-Riffick, Cherry Meth, and Organic Quaalude, Jib Gamma- GBL, Blue Nitro, Blue Nitro Vitali Colorless oily Oral Butyrolactone ty, Firewater, G3, Gamma G, liquid G.H. Revitalizer, Insom-X, Invigor ate, Paint Stripper, Remforce, Renewtrient, Revivarant, Serenity 2, Thunder, Verve, Weigth Belt Cleaner, revivarant, revivarant G, blue moon, BLO, GH-gold (GHG), genx (genex), verve (verv), liquid go ld, N-force, pure raine, reactive, rejoov, rejuv+nite, regenerize, remedy GH, thunder, X-12 1,4-butanediol BlueRaine, Dream On, Fubar, Colorless viscous Oral Pine Needle Oil, Rejuv@Nite, liquid Thunder, Cleaner, Enliven, Inner G, One Comma Four, One Four Bee, One Four B-D-O, Revitalize Plus, Serenity, SomatoPro, Soma Solution, Sucol B, Thunder Nectar, Weight Belt Cleaner, White Magic Mephedrone 4-MMC, meow meow, m-CAT, Tablets, powder Oral, bounce, bubbles, mad cow insufflation, IV, rectal, smoking Methamphetamine Crystal meth, Batu, Blade, Cristy, Clear chunky Snorted, hydrochloride Crystal, Crystal glass, Glass, Hot ice, crystals smoking, IV Ice, Quartz, Shabu, Shards, Stove top, Tina, Ventana Sildenafil Viagra*, blue diamond, vitamin V, the Tablet, mouth Oral, blue pill spray Sublingual Tadalafil Cialis* Tablet Oral When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex” Current Neuropharmacology, 2017, Vol. 15, No. 5 765 (Table 1) contd…. Chemical Structure Common Name Street Names Preparations Route of Administration Vardenafil Levitra* Tablet Oral Amyl nitrite Amy, high-tech, kix, liquid gold, locker Transparent liquid Inhalation room, poppers, ram, rave, rush, snappers, thrust, TNT Butyl nitrite Poppers Oily liquid Inhalation Cyclohexyl nitrite Poppers Inhalation Isobutyl nitrite Poppers Colorless liquid Inhalation Isopropyl nitrite Poppers Clear pale yellow Inhalation oil Pentyl nitrite Poppers Inhalation *Commercial name. an elevation of mood, an improved mental function and mild It is sold by illegal market, but also by internet web sites sexual stimulation [6]. as “plant food” as a white or slightly yellowish powder or fine crystals with street names, including “4-MMC”, “MMCAT”, For its “entactogenic effects” the substance is mainly “bubbles”, “Crab”, “meow meow”, and “M-Cat”[20-22]. abused in nightclubs and parties alone or in combination with other “chemsex” drugs such as crystal methamphetamine Cases of mephedrone related fatalities have been and GHB, and due to its short duration of action and to a described in literature, demonstrating the high potential harm tolerance mechanism, users frequently take repeated doses to of this substance, alone or in combination with other drugs keep the desired effects [1, 2, 14]. Several sources report its of abuse, the latter representing the most common scenario implication in chemsex of MSM, since as self-reported, it especially in chemsex context [14, 23]. can trigger feelings of sexual arousal, increase the longevity 3.3. Erectile Dysfunction Agents (Sildenafil, Tadalafil of sex and facilitate a higher number of sexual partners [19]. and Vardenafil) Nevertheless, similarly to all the other psychostimulant and sex enhancing drugs used in the setting of chemsex, users Erectile dysfunction, is “the inability of the male subject seldom realize the serious health hazard of possible increase to achieve and/or maintain an erection sufficient to conduct a of sexually transmitted diseases [19]. sexual intercourse”. The erection induction involves the production of cyclic guanosine monophosphate (cGMP), mainly stimulated by nitric oxide in the penis corpus cavernosum. Type V phosphodiesterases, enzymes which break the phosphodiester bond in the corpus cavernosum, transform cGMP into inactive metabolites by putting an end to the erection. The phosphodiesterase V inhibitors have proved decisive in the treatment of erectile dysfunction [24]. The first drug to be marketed was the sildenafil citrate in 1998, with the trade name of Viagra . It was followed by vardenafil, a structural modification of the progenitor molecule. In fact, the chemical structure of vardenafil differs from that of sildenafil only for the different position of a nitrogen atom and the substituent for the alkyl piperazine ring, that instead of being a methyl Fig. (1). Dose-related effects of GHB. group, it is an ethyl group, without any modification of phar- 766 Current Neuropharmacology, 2017, Vol. 15, No. 5 Giorgetti et al. macokinetic properties and pharmacodynamics. Furthermore, narcolepsy has been banned since several decades due to the vardenafil significantly increases the time it takes from the high abuse liability and the sever health challenges cause by beginning of vaginal penetration to ejaculation and can the drug use [33]. therefore be also used in the treatment of premature Methamphetamine is a selective agonist of trace amine- ejaculation [25]. Finally, tadalafil has been- to date - the last associated receptor 1 (TAAR1), whose activation increases drug of phosphodiesterase type 5 inhibitors to have appeared cyclic adenosine monophosphate production and inhibits the on the market. Unlike sildenafil and vardenafil, the active reuptake of dopamine, norepinephrine and serotonin by ingredient has the longest half-life (approximately 17 hours), reversing the direction of their transporters [34]. In this way, allowing a more prolonged effect, estimated at around 36 the substance induces a substantial release of those neuro- hours [26]. transmitters in the CNS synapses exerting its euphoric, The huge volume of sales and the patent expiry of empathogenic, and hallucinogenic properties on users [34]. sildenafil production opened in fact the market on electronic Involvement of crystal meth in “chemsex” scenarios has sites of international standing and in stores specializing in been reported since more than one decade as sole substance erotic articles and pornographic materials offering drugs at or in association with the other typical club drugs here competitive prices compared to those of legally registered described. Smoking, snorting or injecting are the most pharmaceutical specialties. The belief that these drugs can common ways of consumption, often in combination with increase libido and improve sexual performance prompted mephedrone and GHB [6]. Whereas GHB is a nervous their recreational use in the context of ‘ChemSex’, to sustain system depressant, even if euphorizing at low doses, long-lasting sexual activity and reverse the impotence-inducing mephedrone and crystal meth are stimulants. All three can effects of other substances (e.g., cocaine, antidepressants and trigger feelings of excitement and among many users can HAART) [27, 28]. In this context, recent epidemiological also facilitate intense feelings of sexual arousal [35]. studies also showed that phosphodiesterase V inhibitors use increased in communities of men having sex with men (MSM) Recreational use of crystal meth has been recently reported and in people living with HIV with a simultaneous consumption in both homosexual and bisexual men as sexual desire of other “chemsex “ drugs such as methamphetamine (crystal enhancer and inhibition reducer [36]. However, as above methampheratine or chrystal meth) alkyl nitrites (poppers), reported for erectile dysfunction agents, methamphetamine ketamine, GHB/GBL (gamma-hydroxybutyric acid/γ- use in this context has been shown to contribute to a rise in butyrolactone) [6, 29]. These two occurrences have posed a high-risk sexual behaviours as well as in the incidence of serious concern regarding users health and safety. First, there HIV [37] with possible interaction with HAART [38]. is an increased risk of drug-drug interaction which can lead Apart from these severe health related consequences in to an enhanced cardiotoxicity caused by erective dysfunction the use of crystal meth in chemsex context, the main concern drugs [6]. Second, since the use of sildenafil, tadalafil and related to the use of methamphetamine are the long-term vardenafil has also been associated with high-risk sexual consequences on brain due to the damage to dopamine and behaviour, this fact has been linked to HIV seroconversion serotonin release in nerve terminals, gliosis, and apoptosis in MSM [30]. Nevertheless, the recreational use of [34]. Not only these, but other mechanisms such as hyper- phosphodiesterase V inhibitors in association with others thermia, glutamate release, reactive oxygen species, reactive “chemsex” does not solely occur within the environments of nitrogen species seem to be involved in its neurotoxicity. MSM, but a non negligible portion of recreational users are heterosexual men [31]. Motivations for use are similar to those Among the described substances implicated in the of MSM: curiosity, increased erectile rigidity, counteracting context of chemsex, methamphetamine is doubtless the most the effects of drugs/alcohol that may attenuate erection, dangerous compound for both its additive and neurotoxic increase erectile sensation, increased libido, enhance self- effects and health consequences both in case of healthy and esteem, decrease performance anxiety, impress/satisfy sexual frail individuals. partner). However, also the associated risks are very similar: 3.5. Alkyl Nitrites (poppers) a vast majority of users buy these drugs without any medical advice on internet with the risk of : Alkyl nitrites are a chemical class of substances colloquially known as “poppers” (Rush, Bolt, Locker Room, - consuming a product which cannot contain the Bullet, Aroma of Men, Dr. Bananas, Cum, Heart-On), whose declared substance and in the reported amount [32]. basic pharmacological action of the nitrites is relaxation of - incurring in non desirable side effects such as vascular smooth muscles [39]. The route of administration is coronary heart diseases. inhalation of the vapour of the volatilized organic liquid. Indeed, for their rapid onset, short-acting potent vasodilators, - being more prone to unprotected sexual intercourses disinhibiting effect, poppers have been consumed in with increased risk of sexually transmitted infections recreational and sexual settings since the 1970s [40]. [31]. In the 1990s the popularity of alkyl nitrites significantly 3.4. Methamphetamine increased for both heterosexual and homosexual sexual intercourses. Interestingly, among the “chemsex” drugs, Methamphetamine (also called meth, crystal meth, chalk these ones are frequently used by youngsters too, for the and ice), the N methyl derivative of amphetamine is an misperception of the products harmlessness. Nitrites have extremely additive psychoactive drug discovered at the end th been reported by many women to be useful for abandonment of 19 century. Its medical use as anorectic drug and in When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex” Current Neuropharmacology, 2017, Vol. 15, No. 5 767 to a full sexual experience. Furthermore, anal penetration public health concerns raised by chemsex phenomenon and becomes easier, probably from a combination of nitrites different sources have demonstrated that the most involved actions on the anal sphincter and decreased pain perception subjects in this type of practice are MSM and bisexual men, [40]. These two actions plus mild hallucinatory sensations especially within HIV positive individuals. (eg. “visions of bright colours, often containing symbolic An extensive epidemiological survey on HIV-diagnosed representations of the sexual moment”) made the products adults (2248 MSM, 373 heterosexual men and 637 women) highly popular in gay discos to enjoy at most music, lights, recruited from UK clinics in 2011-2012 showed that half of other drugs and social-sexual excitement [40]. MSM (1138, 50.6%) reported use of recreational drugs and a Among poppers, the most common sold are: amyl nitrite quarter of them simultaneously consumed at least three types (isoamyl nitrite, isopentyl nitrite), but also cyclohexyl nitrite, of drugs [47-49]. This was objectively shown in cities such isobutyl nitrite (2-methylpropyl nitrite), isopropyl nitrite (2- as London, Berlin, San Francisco, Los Angeles and Sydney, propyl nitrite), and less frequently butyl nitrite. but the phenomenon is spreading internationally with the concurrent boom of crystal methamphetamine and mephedrone Pharmacologically, alkyl nitrites act inducing relaxation use and high risk sexual practices [50-53]. of vascular smooth muscles, with an indirect effect on heart, by systemic arterioles relaxation resulting in a decrease of In this concern, British gay men using crystal blood pressure, reflex tachycardia and a drop in the activity methamphetamine, mephedrone or GHB/GBL either of the left ventricle. The peak action in blood pressure occurs immediately before or during sex self-reported to have been in 30 seconds, with an average increase of 30 mm of systolic the victim of non-consensual sex (3 out of 30 interviewed), pressure, returning to normal within two minutes. When in a situation where consciousness was impaired by the using these substances individuals feel different sensations setting and drug use itself and led them to unwittingly take like warmth, dizziness and an altered heartbeat and facial risks of transmitted infections of physical traumas [54, 55]. blush. This response can range from high pleasure to Indeed, sexual activity over protracted length of time moderate nausea and headaches according to the scenario under the influence of chemsex drugs can result in rectal and the expectations [40]. trauma or penile abrasions and a significant increase of the Since these illicitly used products are unregulated in the risk of transmission of sexual transmitted diseases, especially majority of countries, the implications on user health and in case of condomless intercourses, which are frequent in associated risks can be extremely serious. this context, representing therefore a serious health threat [6]. Pharmacologically, alkyl nitrites can interact with other drugs, such as prescription vasodilators, like erectile dysfunction Recent attention has also been posed on sexually agents (sildenafil, tadalafil and vardenafil), also frequently transmissible enteric infections among the pathogens whose used in “chemsex” scenarios and this can result in a transmission may be associated with chemsex. An example dangerous decrease of blood pressure and the possibility of a is represented by Shigella flexneri, which is one of the four stroke or a heart attack [27]. species of Gram-negative bacterium of the genus Shigella that can cause severe bacillary dysentery in humans. In a Among the most common side effects due to poppers study conducted in a small community of British patients, headaches have been reported as acute side effects, whereas 80% were sexually active MSM, with multiple partners, several cases of retinal toxicity, retinopathy and toxic found through social media networking sites and 60% 42 maculopathy have been described as long-term effect [41- were also HIV-positive and looking for positive partners for 45]. The mechanisms of toxicity remain unclear with the unprotected sex with the use of “chemsex drugs” [56, 57]. hypotheses of a modulation of retinal cell phototransduction All these evidences require careful consideration in the or of an increase in light toxicity susceptibility [43]. As a light of health policy interventions and harm reduction consequence of retinal toxicity, a prolonged visual loss as a practices since MSM engaged in “chemsex” with impaired result of damage to foveal photoreceptors shortly after capacities to chose sexual partners and consensual sex inhaling poppers has been described [42]. should need more specific resources to face high risks of Recently, an animal study focused on the action of some infections and HIV transmission [54]. alkyl nitrites (isobutyl nitrite, isoamyl nitrite, and butyl Another final concern worthy of attention is represented nitrite) on the central nervous system and of their possible by the interaction between drugs implicated in chemsex and abuse potential [46] Mice treated with the test substances (50 HIV medications not only in terms of drug-drug interaction mg/kg, i.p.) showed a significantly increased drug-paired but also for the adherence to the therapy by HIV-positive place preference. Furthermore, greater levels of dopamine individuals engaging in chemsex. Lower rates of adherence were released by striatal region synaptosomes in response to to HIV medications, especially in case of poly-drug use have isobutyl nitrite treatment. Therefore, according to these been demonstrated together with drug-drug interactions. About findings alkyl nitrites could lead to psychological dependence this, an exaggerated response to GHB has been observed in a and dopaminergic effects. HIV positive individual treated with protease inhibitors such as ritonavir or efavirenz, which inhibit CYP450 enzymatic 4. SOCIOCULTURAL BACKGROUND system blocking in this way GHB first pass metabolism. Very recently, different journals have published editorials, On the other hand, GHB/GBL consumption may precipitate letters to the editor, short communications etc. focusing on seizure-like activity in HIV-positive patients with predisposing 768 Current Neuropharmacology, 2017, Vol. 15, No. 5 Giorgetti et al. [5] Theodore, P.S.; Durán, R.E.; Antoni, M.H. Drug use and sexual seizure disorders or with opportunistic infections that may risk among gay and bisexual men who frequent party venues. AIDS lower seizure threshold (e.g. toxoplasmosis, cryptococcal Behav., 2014, 18(11), 2178-2186. [http://dx.doi.org/10.1007/ meningitis) [58]. s10461-014-0779-y] [PMID: 24770947] [6] Bracchi, M.; Stuart, D.; Castles, R.; Khoo, S.; Back, D.; Boffito, M. CONCLUSION Increasing use of party drugs in people living with HIV on antiretrovirals: a concern for patient safety. AIDS, 2015, 29(13), The “chemsex” phenomenon firstly coined on the 1585-1592. [http://dx.doi.org/10.1097/QAD.0000000000000786] [PMID: 26372268] London gay scene and rapidly diffused to many other larger [7] Busardò, F.P.; Jones, A.W. GHB pharmacology and toxicology: cities had brought with it numerous concerns. They derive acute intoxication, concentrations in blood and urine in forensic not only from the actual risk of harm due to the metabolic cases and treatment of the withdrawal syndrome. Curr. pathways of different involved drug, but also for the specific Neuropharmacol., 2015, 13(1), 47-70. [http://dx.doi.org/10.2174/ features of the recreational drugs used including the amount 1570159X13666141210215423] [PMID: 26074743] [8] Corkery, J.M.; Loi, B.; Claridge, H.; Goodair, C.; Corazza, O.; of consumed compound, the route of administration, drug Elliott, S.; Schifano, F. Gamma hydroxybutyrate (GHB), gamma bioavailability, drug pharmacokinetics, drug half life and butyrolactone (GBL) and 1,4-butanediol (1,4-BD; BDO): A finally polydrug use [6]. Moreover, special attention should literature review with a focus on UK fatalities related to non- be paid to the possible interaction between drugs implicated medical use. Neurosci. Biobehav. Rev., 2015, 53, 52-78. [http://dx. in chemsex and HIV medications (e.g. HAART) not only in doi.org/10.1016/j.neubiorev.2015.03.012] [PMID: 25843781] [9] Brunt, T.M.; van Amsterdam, J.G.; van den Brink, W. GHB, GBL terms of drug-drug interaction, but also for the adherence to and 1,4-BD addiction. Curr. Pharm. Des., 2014, 20(25), 4076- the therapy by HIV-positive individuals engaging in chemsex. 4085. [http://dx.doi.org/10.2174/13816128113199990624] [PMID: 24001290] As reported in different Sections, serious health threat [10] Hutchins, D.A.; Rayevsky, K.S.; Sharman, D.F. The effect of can be also represented by the significantly higher hazard of sodium -hydroxybutyrate on the metabolism of dopamine in the sexually transmitted diseases and enteric infections. brain. Br. J. 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When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex”

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Send Orders for Reprints to [email protected] 762 Current Neuropharmacology, 2017, 15, 762-770 RESEARCH ARTICLE a,* a b c c Raffaele Giorgetti , Adriano Tagliabracci , Fabrizio Schifano , Simona Zaami , Enrico Marinelli and Francesco Paolo Busardò a b Section of Legal Medicine, Università Politecnica delle Marche, Ancona, Italy; Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, College Lane Campus, University of Hertfordshire, Hatfield, Herts, AL10 9AB, UK; Unit of Forensic Toxicology (UoFT), Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy Abstract: Background: The term “chemsex” was coined to indicate the voluntary intake of psychoactive and non psychoactive drugs in the context of recreational settings to facilitate and/or to enhance sexual intercourses mostly among men who have sex with other men (MSM). Objective: The authors aimed to review the mechanisms of action, the toxicity and the pattern of use and abuse of substances involved in “chemsex” practice together with the sociocultural background underlying it and the health-related consequences that they may have. Results: Gamma-hydroxybutyrate, gamma-butyrolactone,1,4-butanediol, mephedrone, methamphetamine, A R T I C L E H I S T O R Y   sildenafil, tadalafil, vardenafil and alkyl nitrites have been described in their role of “chemsex drugs” Received: May 17, 2016 including pharmacological action and in their implication to impair capacities to chose sexual Revised: June 17, 2016 partners and consensual sex. Moreover, it has been demonstrated that sexual activity over protracted Accepted: November 04, 2016 length of time under the influence of chemsex drugs can result in rectal trauma or penile abrasions and a DOI: significant increase of the risk of transmission of sexual transmitted diseases, especially in case of 10.2174/1570159X15666161117151148   condomless intercourses, which are frequent in this context, representing therefore a serious health threat. Conclusion: One of the major problems to establish health policy priority interventions for chemsex is the lack of available epidemiological data on the issue. Finally, social actions should be taken in order to break down the barriers that currently exist among chemsex drug users in accessing services, including the shame and stigma often associated with drug use. In conclusion, more specific resources to face high risks of infections and HIV transmission are required in bisexual and homosexual individuals having SUID: sex under the influence of drugs. Keywords: Chemsex, GHB, mephedrone, crystal meth, erectile dysfunction agents, viagra, poppers. 1. INTRODUCTION that those MSM, who are aware of being HIV positive and take anti HIV medication (e.g. Highly Active Anti-Retroviral The term “chemsex”, coming from the contraction of Therapy, HAART) more commonly use “chemsex” drugs “chemical sex” was coined to indicate the voluntary intake of than the ones who are HIV negative or with an unknown certain psychoactive and non psychoactive drugs in the status [3-5]. This is mainly done to potentiate physical context of sex parties and sexual intercourses with the performance impaired by the disease and to counteract the intention of facilitating and/or enhancing the sexual encounter effects of consequent pharmacological treatment [6]. mostly among men who have sex with other men (MSM) Whereas in the nineties of the last century the most [1]. common abused drugs in the “party and sex” contest were: According to different studies, mainly homosexual and cannabis, ecstasy, amphetamine and cocaine, more recently bisexual male partygoers use one or more drugs in “chemsex” has been associated to new psychoactive drugs combination to facilitate prolonged sexual sessions possibly and sex enhancers such as, γ-hydroxybutyric acid (GHB) and with multiple sexual partners [2], although MSM are more congeners, mephedrone, methamphetamine (commonly prone to use sex enhancer drugs in comparison to non-MSM. called crystal methamphetamine or chrystal meth), erectile A serious harmful behaviour related to this latter evidence is dysfunction agents and alkyl nitrites (or poppers) [5, 6]. Within the framework of neuropharmacological, chemical and toxicological aspects of new psychoactive *Address correspondence to this author at the Section of Legal Medicine, substances, the authors aimed to review the mechanisms of Università Politecnica delle Marche, Ancona, Italy; Tel: +390715964727; E-mail: [email protected] action, the toxicity and the pattern of use and abuse of 1570-159X/17 $58.00+.00 ©2017 Bentham Science Publishers When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex” Current Neuropharmacology, 2017, Vol. 15, No. 5 763 substances involved in “chemsex” practice together with the to obtain an energy boost thereby increasing libido, sociocultural background underlying it and the health-related facilitating muscle relaxation, providing more self-assurance consequences that they may have on sexual behaviours in and in general facilitating sexual sessions [7]. Indeed, homosexual and bisexual users, including the risk of GHB acts in the central nervous system inducing a biphasic acquiring sexually transmitted infections. time profile with an initial stimulant-like effect related to the simultaneous rise of plasma concentrations with a 2. LITERATURE SEARCH preponderant disinhibiting action and a later sedative effect unrelated to GHB kinetics [12]. This latter peculiar effect has The following databases were searched: Pubmed and made GHB one of the most used substance in drug- Scopus (from 1980 to 2016) using key-words: chemsex; facilitated sexual assaults, also in the settings of MSM with gamma-hydroxybutyrate; GHB; gamma-butyrolactone; GBL; associated risk of sexually transmitted infection including 1,4-butanediol; mephedrone, methamphetamine; crystal HIV [6]. After GHB ingestion, its performance and behavioural meth, erectile dysfunction agents, viagra, sildenafil, tadalafil, effects begin approximately 10-30 min. later and according vardenafil, alkyl nitrites, poppers. to the dose can last from 1 to 6 hours. The dose-effect curve These key-words were searched alone or in association for GHB is quite high, so that small increases in doses cause with the main keyword: chemsex. disproportionate increases in behavioural effects and toxicity. The effect duration can also be influenced by combinations Several textbooks, non-indexed sources and government with other drugs taken at the same time. For recreational websites were also looked through. This search strategy purposes, a fixed GHB dosage could be problematic and detected about 1000 sources, which were screened to find improper dosage (overdose and poisoning) can lead to those deemed the most relevant for the current review. About serious side effects and even death [7]. 60 articles were more deeply examined and the main findings from the reported studies are here presented. Another important aspect worthy of attention is that, differently from several other drugs of abuse where 3. RESULTS adulteration practices are well known, little information Table 1 summarized the “chemsex” drugs” described in relating to GHB adulteration is currently available and GHB this review with their principal characteristic features. used for non-medical purposes is most commonly synthesized illicitly from GBL. In this context, a recent case of intoxication 3.1. Gamma-hydroxybutyric Acid (GHB) and Congeners in the context of “chemsex” involved MSM who consumed GHB adulterated with sildenafil by the drug dealer with the GHB, a potent central nervous system depressant acting declared intention to enhance expected sexual effects [13]. both as a precursor and a metabolite of the chief inhibitory Chest pain, a severe headache and tachycardia, shortness of neurotransmitter gamma-aminobutyric acid (GABA), is quite breath and dizziness”, never experienced so far after GHB commonly encountered during forensic examination of use, were attributed to sildenafil (the adulterant) rather than living and deceased subjects in recreational and sex scenes the claimed active ingredient (GHB). Hence, the illegal (Fig. 1) [7]. GHB prodrugs or precursors, mainly gamma market, hypothesizing a synergic action of GHB and butyrolactone (GBL) and 1,4 butanediol (1,4-BDL), are rapidly sildenafil, aimed to increase the promised GHB effect by converted into GHB within the body after ingestion and for adding another pharmacologically active compound, with the this reason are present in the illegal market together with risk of causing serious health hazard as in this case. illicit GHB [8]. GBL is considered more pharmacologically potent than GHB due to its more rapid absorption thanks to 3.2. Mephedrone its lipophilic property and greater bioavailability and a major duration of action, although its effects last less [9]. GHB Mephedrone (4-methylmethcathinone; 4-methylephedrone; interacts with GABAergic neurotransmission and this molecule 4-MMC; 2-(methylamino)-1-(4-methylphenyl)propan-1-one] is considered a GABA-B agonist. Neurons releasing GABA falls within the category of designer drugs and is structurally are predominantly located in the hippocampus, cortex similar to cathinone, the main active constituent of the Khat and amygdala. GHB receptors are localized in these sites, plant (Catha edulis) [14-17]. Mephedrone was synthesized in pre- and postsynaptic cells. GHB exerts most of its for the first time in 1929 as a ring-substituted cathinone and effects through binding to the GABA-B receptors, which are its chemical structure is strictly linked to that of the metabotropic transmembrane receptors linked via G-proteins phenethylamine family [14]. to potassium channels, although also dopamine and serotonin neurotransmission is thought to be implicated. GHB firstly Similarly to methamphetamine and cathinone, mephedrone inhibits the dopamine release, however the dopamine later is powerfully able to stimulate dopamine release and block increases according to the dose turnover [10]. GHB is known its re-uptake through its interaction with the dopamine with numerous street names: Liquid X, Liquid E, Liquid transporter [18]. Furthermore it presents some affinity for various Ecstasy, Easy Lay, G, Vita-G, G-Juice, Georgia Home Boy, serotonin receptor subtypes, so that serotonergic signalling may Great Hormones, Soap, Gook, Gamma, and is available in mediate more of mephedrone effects [18]. Hence his subjective colourless, odourless liquid or white powder, tablet and effects result in temporary improvements in mental and/or capsule forms [11]. In certain contexts, such as rave parties physical function, with distinctive emotional and social effects, and gay nightclubs, GHB has been reported to be used by similar to those of 3,4 methylenedioxymetamphetamine men who look for intentional sex with other men, alone or in (Ecstasy MDMA). Among the most common effects induced combination with other psychoactive drugs with the intention by mephedrone in users, there are: euphoria, stimulation, 764 Current Neuropharmacology, 2017, Vol. 15, No. 5 Giorgetti et al. Table 1. Drugs used in “chemsex” with their street names, chemical structures, preparations and route of administration. Chemical Structure Common Name Street Names Preparations Route of Administration Gamma- GHB, "G" (most common), Gamma- White crystalline Usually oral; Hydroxybutyric OH, Liquid E, Fantasy, Georgia Home powder: sodium or intravenous acid Boy, Grievous Bodily Harm, Liquid X, potassium salt, Liquid Ecstasy, Scoop, Water, clear liquid Everclear, Great Hormones at Bedtime, solution: GHB salt GBH, Soap, Easy Lay, Salty Water, dissolved in water G-Riffick, Cherry Meth, and Organic Quaalude, Jib Gamma- GBL, Blue Nitro, Blue Nitro Vitali Colorless oily Oral Butyrolactone ty, Firewater, G3, Gamma G, liquid G.H. Revitalizer, Insom-X, Invigor ate, Paint Stripper, Remforce, Renewtrient, Revivarant, Serenity 2, Thunder, Verve, Weigth Belt Cleaner, revivarant, revivarant G, blue moon, BLO, GH-gold (GHG), genx (genex), verve (verv), liquid go ld, N-force, pure raine, reactive, rejoov, rejuv+nite, regenerize, remedy GH, thunder, X-12 1,4-butanediol BlueRaine, Dream On, Fubar, Colorless viscous Oral Pine Needle Oil, Rejuv@Nite, liquid Thunder, Cleaner, Enliven, Inner G, One Comma Four, One Four Bee, One Four B-D-O, Revitalize Plus, Serenity, SomatoPro, Soma Solution, Sucol B, Thunder Nectar, Weight Belt Cleaner, White Magic Mephedrone 4-MMC, meow meow, m-CAT, Tablets, powder Oral, bounce, bubbles, mad cow insufflation, IV, rectal, smoking Methamphetamine Crystal meth, Batu, Blade, Cristy, Clear chunky Snorted, hydrochloride Crystal, Crystal glass, Glass, Hot ice, crystals smoking, IV Ice, Quartz, Shabu, Shards, Stove top, Tina, Ventana Sildenafil Viagra*, blue diamond, vitamin V, the Tablet, mouth Oral, blue pill spray Sublingual Tadalafil Cialis* Tablet Oral When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex” Current Neuropharmacology, 2017, Vol. 15, No. 5 765 (Table 1) contd…. Chemical Structure Common Name Street Names Preparations Route of Administration Vardenafil Levitra* Tablet Oral Amyl nitrite Amy, high-tech, kix, liquid gold, locker Transparent liquid Inhalation room, poppers, ram, rave, rush, snappers, thrust, TNT Butyl nitrite Poppers Oily liquid Inhalation Cyclohexyl nitrite Poppers Inhalation Isobutyl nitrite Poppers Colorless liquid Inhalation Isopropyl nitrite Poppers Clear pale yellow Inhalation oil Pentyl nitrite Poppers Inhalation *Commercial name. an elevation of mood, an improved mental function and mild It is sold by illegal market, but also by internet web sites sexual stimulation [6]. as “plant food” as a white or slightly yellowish powder or fine crystals with street names, including “4-MMC”, “MMCAT”, For its “entactogenic effects” the substance is mainly “bubbles”, “Crab”, “meow meow”, and “M-Cat”[20-22]. abused in nightclubs and parties alone or in combination with other “chemsex” drugs such as crystal methamphetamine Cases of mephedrone related fatalities have been and GHB, and due to its short duration of action and to a described in literature, demonstrating the high potential harm tolerance mechanism, users frequently take repeated doses to of this substance, alone or in combination with other drugs keep the desired effects [1, 2, 14]. Several sources report its of abuse, the latter representing the most common scenario implication in chemsex of MSM, since as self-reported, it especially in chemsex context [14, 23]. can trigger feelings of sexual arousal, increase the longevity 3.3. Erectile Dysfunction Agents (Sildenafil, Tadalafil of sex and facilitate a higher number of sexual partners [19]. and Vardenafil) Nevertheless, similarly to all the other psychostimulant and sex enhancing drugs used in the setting of chemsex, users Erectile dysfunction, is “the inability of the male subject seldom realize the serious health hazard of possible increase to achieve and/or maintain an erection sufficient to conduct a of sexually transmitted diseases [19]. sexual intercourse”. The erection induction involves the production of cyclic guanosine monophosphate (cGMP), mainly stimulated by nitric oxide in the penis corpus cavernosum. Type V phosphodiesterases, enzymes which break the phosphodiester bond in the corpus cavernosum, transform cGMP into inactive metabolites by putting an end to the erection. The phosphodiesterase V inhibitors have proved decisive in the treatment of erectile dysfunction [24]. The first drug to be marketed was the sildenafil citrate in 1998, with the trade name of Viagra . It was followed by vardenafil, a structural modification of the progenitor molecule. In fact, the chemical structure of vardenafil differs from that of sildenafil only for the different position of a nitrogen atom and the substituent for the alkyl piperazine ring, that instead of being a methyl Fig. (1). Dose-related effects of GHB. group, it is an ethyl group, without any modification of phar- 766 Current Neuropharmacology, 2017, Vol. 15, No. 5 Giorgetti et al. macokinetic properties and pharmacodynamics. Furthermore, narcolepsy has been banned since several decades due to the vardenafil significantly increases the time it takes from the high abuse liability and the sever health challenges cause by beginning of vaginal penetration to ejaculation and can the drug use [33]. therefore be also used in the treatment of premature Methamphetamine is a selective agonist of trace amine- ejaculation [25]. Finally, tadalafil has been- to date - the last associated receptor 1 (TAAR1), whose activation increases drug of phosphodiesterase type 5 inhibitors to have appeared cyclic adenosine monophosphate production and inhibits the on the market. Unlike sildenafil and vardenafil, the active reuptake of dopamine, norepinephrine and serotonin by ingredient has the longest half-life (approximately 17 hours), reversing the direction of their transporters [34]. In this way, allowing a more prolonged effect, estimated at around 36 the substance induces a substantial release of those neuro- hours [26]. transmitters in the CNS synapses exerting its euphoric, The huge volume of sales and the patent expiry of empathogenic, and hallucinogenic properties on users [34]. sildenafil production opened in fact the market on electronic Involvement of crystal meth in “chemsex” scenarios has sites of international standing and in stores specializing in been reported since more than one decade as sole substance erotic articles and pornographic materials offering drugs at or in association with the other typical club drugs here competitive prices compared to those of legally registered described. Smoking, snorting or injecting are the most pharmaceutical specialties. The belief that these drugs can common ways of consumption, often in combination with increase libido and improve sexual performance prompted mephedrone and GHB [6]. Whereas GHB is a nervous their recreational use in the context of ‘ChemSex’, to sustain system depressant, even if euphorizing at low doses, long-lasting sexual activity and reverse the impotence-inducing mephedrone and crystal meth are stimulants. All three can effects of other substances (e.g., cocaine, antidepressants and trigger feelings of excitement and among many users can HAART) [27, 28]. In this context, recent epidemiological also facilitate intense feelings of sexual arousal [35]. studies also showed that phosphodiesterase V inhibitors use increased in communities of men having sex with men (MSM) Recreational use of crystal meth has been recently reported and in people living with HIV with a simultaneous consumption in both homosexual and bisexual men as sexual desire of other “chemsex “ drugs such as methamphetamine (crystal enhancer and inhibition reducer [36]. However, as above methampheratine or chrystal meth) alkyl nitrites (poppers), reported for erectile dysfunction agents, methamphetamine ketamine, GHB/GBL (gamma-hydroxybutyric acid/γ- use in this context has been shown to contribute to a rise in butyrolactone) [6, 29]. These two occurrences have posed a high-risk sexual behaviours as well as in the incidence of serious concern regarding users health and safety. First, there HIV [37] with possible interaction with HAART [38]. is an increased risk of drug-drug interaction which can lead Apart from these severe health related consequences in to an enhanced cardiotoxicity caused by erective dysfunction the use of crystal meth in chemsex context, the main concern drugs [6]. Second, since the use of sildenafil, tadalafil and related to the use of methamphetamine are the long-term vardenafil has also been associated with high-risk sexual consequences on brain due to the damage to dopamine and behaviour, this fact has been linked to HIV seroconversion serotonin release in nerve terminals, gliosis, and apoptosis in MSM [30]. Nevertheless, the recreational use of [34]. Not only these, but other mechanisms such as hyper- phosphodiesterase V inhibitors in association with others thermia, glutamate release, reactive oxygen species, reactive “chemsex” does not solely occur within the environments of nitrogen species seem to be involved in its neurotoxicity. MSM, but a non negligible portion of recreational users are heterosexual men [31]. Motivations for use are similar to those Among the described substances implicated in the of MSM: curiosity, increased erectile rigidity, counteracting context of chemsex, methamphetamine is doubtless the most the effects of drugs/alcohol that may attenuate erection, dangerous compound for both its additive and neurotoxic increase erectile sensation, increased libido, enhance self- effects and health consequences both in case of healthy and esteem, decrease performance anxiety, impress/satisfy sexual frail individuals. partner). However, also the associated risks are very similar: 3.5. Alkyl Nitrites (poppers) a vast majority of users buy these drugs without any medical advice on internet with the risk of : Alkyl nitrites are a chemical class of substances colloquially known as “poppers” (Rush, Bolt, Locker Room, - consuming a product which cannot contain the Bullet, Aroma of Men, Dr. Bananas, Cum, Heart-On), whose declared substance and in the reported amount [32]. basic pharmacological action of the nitrites is relaxation of - incurring in non desirable side effects such as vascular smooth muscles [39]. The route of administration is coronary heart diseases. inhalation of the vapour of the volatilized organic liquid. Indeed, for their rapid onset, short-acting potent vasodilators, - being more prone to unprotected sexual intercourses disinhibiting effect, poppers have been consumed in with increased risk of sexually transmitted infections recreational and sexual settings since the 1970s [40]. [31]. In the 1990s the popularity of alkyl nitrites significantly 3.4. Methamphetamine increased for both heterosexual and homosexual sexual intercourses. Interestingly, among the “chemsex” drugs, Methamphetamine (also called meth, crystal meth, chalk these ones are frequently used by youngsters too, for the and ice), the N methyl derivative of amphetamine is an misperception of the products harmlessness. Nitrites have extremely additive psychoactive drug discovered at the end th been reported by many women to be useful for abandonment of 19 century. Its medical use as anorectic drug and in When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex” Current Neuropharmacology, 2017, Vol. 15, No. 5 767 to a full sexual experience. Furthermore, anal penetration public health concerns raised by chemsex phenomenon and becomes easier, probably from a combination of nitrites different sources have demonstrated that the most involved actions on the anal sphincter and decreased pain perception subjects in this type of practice are MSM and bisexual men, [40]. These two actions plus mild hallucinatory sensations especially within HIV positive individuals. (eg. “visions of bright colours, often containing symbolic An extensive epidemiological survey on HIV-diagnosed representations of the sexual moment”) made the products adults (2248 MSM, 373 heterosexual men and 637 women) highly popular in gay discos to enjoy at most music, lights, recruited from UK clinics in 2011-2012 showed that half of other drugs and social-sexual excitement [40]. MSM (1138, 50.6%) reported use of recreational drugs and a Among poppers, the most common sold are: amyl nitrite quarter of them simultaneously consumed at least three types (isoamyl nitrite, isopentyl nitrite), but also cyclohexyl nitrite, of drugs [47-49]. This was objectively shown in cities such isobutyl nitrite (2-methylpropyl nitrite), isopropyl nitrite (2- as London, Berlin, San Francisco, Los Angeles and Sydney, propyl nitrite), and less frequently butyl nitrite. but the phenomenon is spreading internationally with the concurrent boom of crystal methamphetamine and mephedrone Pharmacologically, alkyl nitrites act inducing relaxation use and high risk sexual practices [50-53]. of vascular smooth muscles, with an indirect effect on heart, by systemic arterioles relaxation resulting in a decrease of In this concern, British gay men using crystal blood pressure, reflex tachycardia and a drop in the activity methamphetamine, mephedrone or GHB/GBL either of the left ventricle. The peak action in blood pressure occurs immediately before or during sex self-reported to have been in 30 seconds, with an average increase of 30 mm of systolic the victim of non-consensual sex (3 out of 30 interviewed), pressure, returning to normal within two minutes. When in a situation where consciousness was impaired by the using these substances individuals feel different sensations setting and drug use itself and led them to unwittingly take like warmth, dizziness and an altered heartbeat and facial risks of transmitted infections of physical traumas [54, 55]. blush. This response can range from high pleasure to Indeed, sexual activity over protracted length of time moderate nausea and headaches according to the scenario under the influence of chemsex drugs can result in rectal and the expectations [40]. trauma or penile abrasions and a significant increase of the Since these illicitly used products are unregulated in the risk of transmission of sexual transmitted diseases, especially majority of countries, the implications on user health and in case of condomless intercourses, which are frequent in associated risks can be extremely serious. this context, representing therefore a serious health threat [6]. Pharmacologically, alkyl nitrites can interact with other drugs, such as prescription vasodilators, like erectile dysfunction Recent attention has also been posed on sexually agents (sildenafil, tadalafil and vardenafil), also frequently transmissible enteric infections among the pathogens whose used in “chemsex” scenarios and this can result in a transmission may be associated with chemsex. An example dangerous decrease of blood pressure and the possibility of a is represented by Shigella flexneri, which is one of the four stroke or a heart attack [27]. species of Gram-negative bacterium of the genus Shigella that can cause severe bacillary dysentery in humans. In a Among the most common side effects due to poppers study conducted in a small community of British patients, headaches have been reported as acute side effects, whereas 80% were sexually active MSM, with multiple partners, several cases of retinal toxicity, retinopathy and toxic found through social media networking sites and 60% 42 maculopathy have been described as long-term effect [41- were also HIV-positive and looking for positive partners for 45]. The mechanisms of toxicity remain unclear with the unprotected sex with the use of “chemsex drugs” [56, 57]. hypotheses of a modulation of retinal cell phototransduction All these evidences require careful consideration in the or of an increase in light toxicity susceptibility [43]. As a light of health policy interventions and harm reduction consequence of retinal toxicity, a prolonged visual loss as a practices since MSM engaged in “chemsex” with impaired result of damage to foveal photoreceptors shortly after capacities to chose sexual partners and consensual sex inhaling poppers has been described [42]. should need more specific resources to face high risks of Recently, an animal study focused on the action of some infections and HIV transmission [54]. alkyl nitrites (isobutyl nitrite, isoamyl nitrite, and butyl Another final concern worthy of attention is represented nitrite) on the central nervous system and of their possible by the interaction between drugs implicated in chemsex and abuse potential [46] Mice treated with the test substances (50 HIV medications not only in terms of drug-drug interaction mg/kg, i.p.) showed a significantly increased drug-paired but also for the adherence to the therapy by HIV-positive place preference. Furthermore, greater levels of dopamine individuals engaging in chemsex. Lower rates of adherence were released by striatal region synaptosomes in response to to HIV medications, especially in case of poly-drug use have isobutyl nitrite treatment. Therefore, according to these been demonstrated together with drug-drug interactions. About findings alkyl nitrites could lead to psychological dependence this, an exaggerated response to GHB has been observed in a and dopaminergic effects. HIV positive individual treated with protease inhibitors such as ritonavir or efavirenz, which inhibit CYP450 enzymatic 4. SOCIOCULTURAL BACKGROUND system blocking in this way GHB first pass metabolism. Very recently, different journals have published editorials, On the other hand, GHB/GBL consumption may precipitate letters to the editor, short communications etc. focusing on seizure-like activity in HIV-positive patients with predisposing 768 Current Neuropharmacology, 2017, Vol. 15, No. 5 Giorgetti et al. [5] Theodore, P.S.; Durán, R.E.; Antoni, M.H. Drug use and sexual seizure disorders or with opportunistic infections that may risk among gay and bisexual men who frequent party venues. AIDS lower seizure threshold (e.g. toxoplasmosis, cryptococcal Behav., 2014, 18(11), 2178-2186. [http://dx.doi.org/10.1007/ meningitis) [58]. s10461-014-0779-y] [PMID: 24770947] [6] Bracchi, M.; Stuart, D.; Castles, R.; Khoo, S.; Back, D.; Boffito, M. CONCLUSION Increasing use of party drugs in people living with HIV on antiretrovirals: a concern for patient safety. AIDS, 2015, 29(13), The “chemsex” phenomenon firstly coined on the 1585-1592. 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Published: Jul 1, 2017

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