Synthetic Cannabinoids and Synthetic Cathinones

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Keywords: Synthetic cannabinoids, synthetic cathinones, legal highs, recreative drugs. INTRODUCTION ..... "Legal highs" - new players in the old drama. Curr.
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New Designer Drugs (Synthetic Cannabinoids and Synthetic Cathinones): Review of Literature Olivier Cottencin1,2,*, Benjamin Rolland1,3 and Laurent Karila4 1 Department of Psychiatry and Addiction Medicine, CHU Lille, F-59037, Lille Cedex, France; 2UDSL, EA4559, 59000, Lille, France; 3EA1046 Department of Medical Pharmacology, Faculty of Medicine, University Lille 2 59045 Lille France; 4Addiction Research and Treatment Center, Paul Brousse Hospital, Paris Sud-11 University, AP-HP, INSERM-CEA U1000, Villejuif, France

Abstract: New designer drugs (synthetic cannabinoids and synthetic cathinones) are new “legal highs” that are sold online for recreational public or private use. Synthetic cannabinoids are psychoactive herbal and chemical products that mimic the effects of cannabis when used. These drugs are available on the Internet or in head shops as incense or air fresheners to circumvent the law. Cathinone is a naturally occurring beta-ketone amphetamine analog found in the leaves of the Catha edulis plant. Synthetic cathinones are phenylalkylamine derivatives that may possess amphetamine-like properties. These drugs are sold online as bath salts. Designer drugs are often labeled as “not for human consumption” to circumvent drug abuse legislation. The absence of legal risks, the ease of obtaining these drugs, the moderate cost, and the availability via the Internet are the main features that attract users, but the number of intoxicated people presenting with emergencies is increasing. There is evidence that negative health and social consequences may affect recreational and chronic users. The addictive potential of designer drugs is not negligible.

Keywords: Synthetic cannabinoids, synthetic cathinones, legal highs, recreative drugs. INTRODUCTION Cannabis is the most commonly consumed illicit drug in the world, followed by cocaine. However, according to the European Drug Report for 2013 [1], there are fewer new users of heroin and less injectable drug use, and the use of cannabis and cocaine is decreasing in certain countries. However, there are concerns over synthetic stimulants and new psychoactive substances that are being sold both legally and illegally. In total, 73 new psychoactive substances were officially announced for the first time via the European Union (EU)’s early-warning system in 2012. The EU’s earlywarning system continues to receive reports of approximately one new substance per week as of 2013 [1]. Since 2009, new synthetic drugs have been developed: synthetic cathinones and synthetic cannabinoids, which are referred to as legal highs [3] and herbal highs [4], respectively. These drugs are mainly sold online as a legal alternative to controlled and regulated psychoactive substances [5]. Synthetic cathinones properties have properties that are close to those of amphetamines. These cathinones are derived from ephedrine (a sympathomimetic amine commonly used as a stimulant, appetite suppressant, concentration aid, and decongestant to treat colds). Synthetic cannabinoids’ main effect is functionally the same as that of the psychoactive ingredient in cannabis: 9tetrahydrocannabinol. These drugs do not contain tobacco or cannabis, and their consumption mimics cannabis’ psychic effects [6]. We present a review of the pharmacological and toxicological consequences of new synthetic agents abuse, focusing on synthetic cannabinoid and cathinone because of their medical and scientific *Address correspondence to this author at the Psychiatry and Addiction Medicine, University Hospital of Lille, Department of Psychiatry and Addiction Medicine, CHU Lille F-59037 Lille Cedex France; Tel/Fax: +33 320 44 5838; E-mail: [email protected]

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center of interest and their potential impact on public health. Literature searches were conducted from 2009 to 2013 using PubMed, Erowid, and governmental websites using the following key words alone or in combination: synthetic cathinones, mephedrone, MDVP, synthetic cannabinoid, and spice. We identified a total of 74 references from PubMed database for synthetic cathinone and 190 references for synthetic cannabinoid. After screening of titles and abstracts, we selected 48 articles that were relevant with current information about these drugs and we found 8 relevant European Monitoring Center for Drugs and Drug Abuse (EMCDDA) Reports or governmental websites. EPIDEMIOLOGY Today’s drug market appears to be more fluid and dynamic, and less structured around plant-based substances. An increasing number of new psychoactive substances can be found in Europe. The EU Early warning system continues to receive reports of around one new substance a week in 2013 [1]. Data on new psychoactive substances are based on notifications to the EU Early warning system, During 2012, 73 new psychoactive substances were notified by the Member States for the first time through the EU Early warning system: 30 of these substances were synthetic cannabinoid receptor agonists, 19 compounds did not conform to the readily recognized chemical groups (including plants and medicines), while there were also 14 new substituted phenethylamines reported [1]. After they are subjected to control measures, most new psychoactive substances tend to be rapidly replaced, making intervention measures particularly challenging in this area. Mephedrone, however, is a rare example of a new drug that may have made the crossover to become a sought-after substance on the illicit stimulant market [1]. Epidemiological data are currently limited and may suffer from methodological limitations, including a lack of common definitions (most users do not know which substances they have actually © 2014 Bentham Science Publishers

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taken) [2]. In the EMCDDA–Europol 2012 Annual Report, epidemiological data were collected on new drugs' use in Europe [2]. In 2010 a national survey of Spanish students (14-18) found overall lifetime use of "legal highs" of 0.7%: lifetime use of synthetic cannabinoids was 1.1% and 0,4 % for mephedrone. In England and Wales, the 2010/11 British Crime Survey found that among the general population (16–59) last year use of mephedrone (1.4 %) was at a level similar to that of ecstasy, but the same as that of cocaine (4.4%) among the 16–24 age group. And the 2011/12 survey found that mephedrone was the fourth most prevalent drug measured. In Northern Ireland, lifetime prevalence was estimated at 2 % and last year prevalence at 1 % for both mephedrone and ‘legal highs’. Lifetime prevalence levels were higher among those aged 15–24, reaching 6 % for both mephedrone and ‘legal highs. In Ireland, new psychoactive substances (last year use, 4 %) were the second most frequently reported illicit drugs after cannabis (6 %). As we can see, the use of new drugs actually concerns young population. But surveys have also examined targeted populations (such as nightclub patrons and dance music fans), which tend to include ‘early adopters’ of new drugs. The use of new drugs in these targeted populations can be very high. A survey of individuals attending ‘gay friendly’ nightclubs in south-east London in 2011 found that, among 313 participants, lifetime use of a ‘legal high’ was reported by 65.8 %. Lifetime use of mephedrone was reported by 63.8 % of the sample and lifetime use of ‘Spice/K2’ was 9.9 % [2]. SYNTHETIC CATHINONES Synthetic cathinones are referred to as designer drugs, club drugs, party drugs, designer party drugs, or synthetic drugs. These substances are mephedrone, methylone, methylenedioxypyrovalerone (MDPV), Energy-1, methedrone, flephedrone, buphedrone, butylone, and pentylone [5]. Cathinone is a stimulant alkaloid found in the leaves of the khat bush (Catha edulis). The plant grows in East Africa and southern Arabia, and the inhabitants of these regions frequently chew this plant because of its amphetamine-like effects [7]. Cathinone was discovered 50 years ago. The first synthetic cathinone appeared on the market for recreational drugs was methcathinone (-ketomethamphetamine or N-ephedrone methylcathinone), also called ephedrone. These drugs are substances whose chemical structure has been slightly modified from the chemical structure of existing molecules. Laboratories that manufacture these substances can substitute such drugs for substances classified as narcotics. These laboratories can then facilitate the drugs’ use and avoid being accused of the possession and use of illicit substances. These drugs can be bought on the Internet without any restriction, as the products are sold as chemicals that are “not for human consumption”, plant food, or bath salts to circumvent drug abuse legislation [8]. Thus, manufacturers will always be free of condemnation related to consumption and can prevent potential control by authorities [9]. Cathinone is chemically similar to ephedrine, cathine, and other amphetamines. The drug’s maximum effect occurs after 15 to 30 minutes. Cathinone’s metabolism is rapid, and only a small fraction of the molecule appears unchanged in the urine. Most cathinone is metabolized to norephedrine and is excreted in this form [5]. This substance has several “street names” (see Table 1). In 2012, five new synthetic cathinone derivatives were formally reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)'s Early Warning System (EWS), compared with eight reported in 2011 and 15 in 2010 [9, 10] The main vector is specialized Internet shopping sites and forums dedicated to these drugs. There is little information on the drugs’ pharmacological mechanisms and clinical effects; however, several substances have been were banned (such as the mephedrone

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and the Black Mamba). In general, these drugs have pharmacological properties similar to those of amphetamines and cocaine, but there is currently no focused research on the addiction potential or withdrawal syndromes related to synthetic cathinones [8]. However, a survey of 1,500 mephedrone users found that over 50% consider the drug to be addictive [11], and in another study, 25% of users reported urges or cravings to continue use [12]. Table 1.

Street name of synthetic drugs

Synthetic cathinones Mephedrone

4-MMC, Meow Meow, M-Cat, Bubbles

Methylone

Explosion, M1

Methylen-dioxypyrovalerone (MDPV)

Magic, Super Coke, MDPK, Maddie, Black Rob, MTV, PV

Energy-1

NRG1

4-Methylmethcathinone

4-MEC

Mixtures of 4-MEC and others cathinones

NRG-2

Synthetic cannabinoids

Spice, Spice Gold, Spice love, Spice Silver, Gorilla, Sence, Yucatan, Fire, Chill X, Genie, Algerian Blend, Smoke

1. Mephedrone Mephedrone is the best known because of media coverage of accidents or deaths associated with this drug’s use in many countries, including Sweden and the UK [13]. This substance is the fourth most commonly used drug (after cannabis, ecstasy, and cocaine) and the most commonly used legal high [5]. In 2010, mephedrone became the first substituted cathinone to benefit from a formal risk assessment. The drug has served as a model and was evaluated according to the new operational guidelines for risk assessment (damage and gravity), which allow an evidence-based, timely assessment when there is a lack of information [14]. Mephedrone use was first detected in November 2007 and was reported via the EMCDDA’s EWS in March 2008 [10]. Mephedrone (4-methylephedrone or 4-methylmethcathinone MMC (4-MMC)) is a water-soluble, white or colored (yellowish, beige, or brown) hydrochloride salt that is available on the Internet [15]. The oral (swallowing powder, capsules, or tablets) and intranasal routes are the predominant routes of administration, but intramuscular, intravenous, and rectal routes of administration have been reported. Slam, referring to the intravenous route, has been primarily reported in the homosexual population at festive events of a sexual nature [16]. Information regarding epidemiological data and the effects of mephedrone are limited to unconfirmed user reports and clinical case series. The dose usually consumed, regardless of the route of administration, is between 0.5 and 1 g. The price varies from 9 to 17  per gram. [5]. There are signs that synthetic cathinones, including mephedrone, may have carved a space in the illicit stimulants market in some countries. More generally, mephedronerelated mortality and morbidity continue to be reported in Europe, although at relatively low levels. Some countries also report the injection of mephedrone, MDPV and other synthetic cathinones, among groups of problem drug users and drug treatment clients (Hungary, Austria, Romania, United Kingdom) [1]. The acute psychotropic effects of mephedrone depend on the patient and the dose. The effects last for between 2 and 5 hours. The

New Designer Drugs (Synthetic Cannabinoids and Synthetic Cathinones)

psychic effects are intermediate between the effects of ecstasy and cocaine and are associated with euphoria, elevated mood, alertness, a sense of well-being, better self-esteem, empathogenic effects, a pleasurable rush, a sense of being sped up, enhanced music appreciation, disinhibition, tachypsychia, motor excitation, a reduced perception of tiredness, and mild sexual stimulation. Higher-dosage and more prolonged mephedrone use can cause more severe unwanted effects [5]. The main adverse psychiatric effects reported by users are hallucinations, paranoia, anxiety, dysphoria, depression, insomnia, cognitive disorders (i.e., impaired short-term memory or impaired attention and concentration), delusions, and suicidal ideations (especially with the intravenous route) [14, 17, 18]. Main psychiatric adverse effects are summarized in Table 2. The most frequent adverse effects are tachycardia, hypertension, agitation, fatigue, goose bumps, facial flushing, restlessness, mydriasis, a loss of appetite, increased sweating (“mephedrone sweat”), and abnormal vision. Dizziness, tremor, stupor, headache, chest pain, dyspnea, nausea, vomiting, abdominal pain, renal pain, nasal and throat irritation, sinusitis, trismus, and bruxism can also be observed [17, 18]. Debruyne et al. also reported a negative impact on libido in regular users [13]. The addictive potential of mephedrone is not negligible, and case reports of dependence have been publicized by the UK National Drug Treatment Monitoring System. The phenomena of craving and tolerance, comparable with the effects of cocaine or amphetamines, were observed [19]. Withdrawal syndrome is characterized by tremor, shivers, increased or decreased temperature, and a strong feeling of paranoia [5]. A phase of descent that is physically and mentally painful for 48 hours has been reported, with impaired concentration, tiredness, anxiety, palpitations, and headache with "brainzap" (similar sensation to electric shocks) [5]. Studies have not determined the minimum lethal dose of mephedrone [12]. Deaths have been attributed to mephedrone use, alone or with the co-consumption of other illicit drugs, in many European countries (Sweden, UK, and Romania) [20]. Two cases of a fatal overdose of mephedrone were only confirmed during autopsies performed on a young woman aged 18 years in Sweden and a young adult in the UK in 2008 [21, 22]. Mephedrone was also strongly suspected in the deaths of 10 people in Europe [12]. A post-mortem toxicological analysis was positive for mephedrone, alcohol, ketamine, and cannabis [12]. Due to its potential acute and chronic toxicity, mephedrone is now forbidden in several countries in Europe [8]. 2. Methylone Methylone (3,4-methylenedioxy-N-methylcathinone) ß-ketone MDMA (ßk-MDMA) is a close structural analog of MDMA (ecstasy) [23]. The drug is often combined with other drugs, such as mephedrone (EMCDDA 2010). Methylone was first reported in 2004 as a liquid solution sold as a vanilla-scented room deodorizer [24], and this drug mainly exists in powder form and in tablets. The oral and intranasal routes are the predominant routes of administration. A study found methylone sold in plastic tubes containing 5 ml of liquid called Explosion via the Internet and in head shops [25]. The average price ranges from 10 to 20  per gram [24]. The acute consumption of this drug (average doses of 100 to 200 mg) causes a calm euphoria, alertness, restlessness, and a strong sense of empathy with mild stimulation [26] and could likely used to manage the lowering of other psychostimulants (found on users’ websites). The adverse effects are relatively similar to those of mephedrone. The somatic adverse effects include tachycardia, hypertension, hyperthermia, sweating, mydriasis, nystagmus, nausea, vomiting, trismus, and bruxism. Seizures and hyponatremia have been reported. The psychiatric adverse effects include ano-

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rexia, anxiety, derealization / depersonalization, impaired shortterm memory, psychosis, hallucinations, and suicidal ideations [24]. Methylone has been illegal in Sweden since 2007 and in the UK since April 2010 [27]. No deaths have been attributed to methylone use alone or to co-ingestion with other illicit drugs [5]. 3. Methylen-dioxy-pyrovalerone (MDPV) The clinical effects of MDPV are close to the effects of amphetamine. The drug was first identified in Germany in June 2007. MDPV is in the form of a white powder or a granular gray substance and is sold on the Internet as a chemical or as bath salts. This drug is usually consumed by the intranasal or oral route. The psychoactive effects of MDPV last between 2 and 7 hours, depending on the route of administration and the dependence of the users; consist of psychomotor excitement, hypervigilance, a reduction in appetite and sleep, and compulsive consumption; and can cause abuse or dependence [28]. The side effects are similar to those of other synthetic cathinones. MDPV can cause hyperthermia; rhabdomyolysis; bone pain; myalgia; hypersomnia; and heart, liver, and kidney problems. Panic attacks and delirium, with hallucinations have been reported [28]. Death and serotonin syndrome have also been reported [5]. This drug has been considered as a controlled substance in many European countries since 2009 and in certain U.S. states [29]. Deaths from the use of MDPV and other synthetic cathinones are currently not well documented in the medical literature (because of frequent polydrug intoxication) [8]. 4. Energy-1 Energy-1 (NRG1), whose chemical name is naphthylpyrovalerone (NPV), looks structurally similar to mephedrone and MDPV and is sold in powder form. The drug quickly appeared on the Internet after the ban of mephedrone and its derivatives in April 2010 in the UK. In fact, this synthetic drug is a mixture of the cathinones 4-fluoromethcathinone and MDPV and the MDPBP pentylone. The substance’s psychoactive effects and side effects are the result of the effects of different substances in the mixture [8]. SYNTHETIC CANNABINOIDS Since the discovery of 9-THC, synthetic cannabinoids have been synthesized for biomedical research because of their potential as new therapeutic agents [30]. Apart from dronabinol (THC), the only synthetic cannabinoid receptor agonist that has found for clinical use is nabilone. Nabilone is a THC derivative that is used for the treatment of nausea in cancer chemotherapy. However, since 2004, “street chemists” have been producing smokable herbal “K2” or “Spice” products as legal alternatives to marijuana [31]. The number of synthetic cannabinoids detected by the EU’s early-warning system continues to grow year after year. There were nine alerts reported in 2009, and 84 were announced by the EMCDDA as of May 2013 [1]. Synthetic cannabinoids are sold online and in head shops (specialized stores for the sale of legal psychoactive plant products). These drugs can be found for sale as incense or air fresheners under various names (see Table 1). Synthetic cannabinoids do not contain tobacco or cannabis, and smoking blends are sold in foil bags containing approximately 3 g of dry plant material, to which one or more cannabinoids are added, along with vitamin E [32]. The addition of the vitamin serves to obscure the analysis of cannabinoids. According to the EMCDDA, these bags are enough for approximately eight joints, and the bags cost (online) between 12 and 18  in Europe in 2011. It has been suggested that such drugs may have been manufactured in China [1], but the origin actually remains unclear. The exact composition is not known, although the package information lists vegetable ingredients that are considered inert [31]. One unique characteristic of these substances is their everchanging composition, and the “JWH” series of cannabinoids is the

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dominant set of cannabinoids detected in Spice [33] and other drugs, such as HU-210 or cyclohexylphenol (CP). JWH is a series of compounds synthesized by John W. Huffman, and HU is the abbreviation for Hebrew University [31]. Nevertheless, in many countries most synthetic cannabinoids (JWH-018, CP 47,497 and equivalents (C6, C8, and C9), and HU-210) are classified as narcotics. The pharmacokinetic and pharmacodynamic profiles of synthetic cannabinoids in humans are unknown. Case reports indicate oral and inhalational bioavailability, and no cases of parenteral or rectal routes of administration have been described [31]. These drugs have pharmacological action similar to that of cannabis (resin, herb, or oil): an experience of well-being and euphoria that are energizing and disinhibiting and are likely among the most desirable effects pursued by users [34]. Spice blends are also described as causing inconstant sensory changes; visual, tactile, and auditory perceptions; perceptual illusions; hallucinations; and a feeling of slowed time [28]. The potential harm of synthetic cannabinoid exposure is important, as the American Association of Poison Control Centers reported 53 calls in 2009 and over 6,000 in 2011 [35]. The adverse clinical effects are mainly anxiety, paranoia, headache, nausea, vomiting, convulsions, and induced psychosis [28]. Those effects are primarily reported in cases reports or cases series and can be classified into central effects, cardiovascular effects, and gastrointestinal effects [31]. The central effects are emotional alterations, such as psychosis with the acute exacerbation of cannabis-induced recurrent psychotic episodes [36] or an enhanced risk of psychosis relapse in vulnerable individuals [37, 38]. New-onset psychoses in healthy young men were observed by Hurst et al. [39]. Adverse psychic effects, such as anxiety [37, 38, 40, 41], agitation [42], and irritability, with Spice or K2 [40] were also reported. Other central effects are seizure activity [43, 44, 45] or generalized seizure [46, 47], cognitive impairment (memory changes and increased reaction time) [40], impaired motor coordination difficulties with complex tasks [28], sedation [44, 45], and confusion with SpicyXXX [44, 45]. The reported cardiovascular effects are tachycardia [42, 44, 45], tachyarrhythmia [46], cardiotoxicity [48], and chest pain, and acute myocardial infarction has been reported in healthy adolescents (16year-old boys) [49]. Gastrointestinal effects, such as nausea associated with agitation, tachycardia, drowsiness, vomiting, or hallucinations, were frequently reported [42]. Vomiting was described in a healthy 19-year-old boy along with a generalized convulsion while smoking “Happy Tiger Incense” [47]. Other effects were somnolence, dilated pupils, brisk reflexes, emesis [44, 45], and appetite changes (patients reporting both decreased and increased appetite) [40]. Although the acute adverse effects of synthetic cannabinoids were well documented by Seely et al. [31], there is no information about the chronic use and toxicity of synthetic cannabinoids. The authors hypothesized that the prolonged use of Spice may induce significant alterations in emotional processing and cognitive functioning because cannabinoids have important effects on processes known to influence emotional processing, sensory perception, and the elaboration of incoming sensory information [50, 51]. The addictive potential of these substances is not negligible [6, 32]. However, to the best of our knowledge, only one case report in Germany has described Spice tolerance, withdrawal, and drug dependence in a 20-year-old man after smoking “Spice Gold” daily for 8 months. During abstinence, he reported inner unrest, craving, nocturnal nightmares, copious sweating, headache, nausea, and tremor [52]. According to Seely et al. [31], Spice abusers can be grouped into three main categories based on previous drug use: 1) marijuana smokers; 2) occasional drug users seeking to avoid legal complica-

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tions; and 3) drug-naïve, curious experimenters. The researchers also found that most clinical case reports concern male teenagers and, to a lesser extent, young women. Additionally, the authors report a recent survey by Hu et al. [53] that investigated the prevalence of Spice use in college students and concomitant use with other drugs of abuse, such as nicotine and marijuana. The results showed that 8% of surveyed college students used Spice, and concurrent use with hookah tobacco (88%), marijuana (91%), or cigarettes (77%) was also prevalent among college students. Table 2.

Main psychiatric adverse effects of synthetic drugs

Synthetic Cathinones Mephedrone

Hallucinations, paranoia, anxiety, dysphoria, depression, insomnia, cognitive disorders (impaired short-term memory or attention and concentration), delusions, and suicidal ideations (intravenous route) [14, 17, 18]. Psychic descent (impaired concentration, tiredness, anxiety, palpitations, and headache) [5]. Addictive potential [19]

Methylone

Anorexia, anxiety, derealization/depersonalization, impaired short-term memory, psychosis, hallucinations, and suicidal ideations [24].

MDPV

Panic attacks, delirium (with hallucinations) [28], serotonin syndrome [5]

Synthetic Cannabinoids

Inconstant sensory change (visual, tactile, and auditory perceptions); perceptual illusions; hallucinations; and a feeling of slowed time [28]. Psychosis with acute exacerbation of cannabis-induced recurrent psychotic episodes [36] or enhanced risk of psychosis relapse in vulnerable individuals [37, 38], paranoia and induced psychosis [28], new-onset psychoses in healthy young men [39]. Anxiety [28, 37, 38, 40, 41], agitation [42], and irritability (with Spice or K2) [40]. Cognitive impairment (memory changes and increased reaction time) [40], impaired motor coordination difficulties with complex tasks [28], sedation [44, 45], and confusion with SpicyXXX [44, 45]. Addictive potential [6, 32] (but only one case of Spice tolerance reported [52])

DISCUSSION The addiction landscape has to take synthetic cathinones and synthetic cannabinoids into account. The absences of legal risk, the ease of obtaining drugs, the low cost, and the rapid diffusion of these new drugs over the Internet are the main features that attract consumers. These new drugs are legally sold as soon as previous compounds are forbidden, which is especially true of synthetic cathinones. Users should be aware that just because a substance is being advertised as legal does not make the drug safe or actually legal. In fact, the use of synthetic drugs most often occurs in the context of polydrug use and festivity. Several users of stimulant drugs seem to use these new materials to replace cocaine or amphetamines. The addictive potential of these substances appears significant. In the first meeting with a patient, practitioners must assess the use of synthetic drugs and health and social consequences. Even if, current studies about the use and the long-term effects of synthetic

New Designer Drugs (Synthetic Cannabinoids and Synthetic Cathinones)

cathinones in humans do not show conclusive evidence [5], prevention and awareness programs must be developed and use social networks and the Internet. Because, concerning synthetic cannabinoids, some clinical reports led to the suggestion that they could precipitate psychosis in vulnerable individuals, similarly to cannabis [31], and it is possible to postulate that prolonged use of Spice may induce significant alterations in emotional processing and cognitive functioning [31]. To our knowledge, there are no synthetic cathinones human brain-imaging current studies. Blum et al. [55] reported the case of a 21 year old man presenting with delayed induced psychosis, whose case allows the hypothesis that cathinones, when consumed by humans, may induce specific inflammation and/or neurotoxic pathways involving the neuro-glial-microglia which may help explain the clinically observed delayed response. Unfortunately, most of patients presenting with polydrug consumption, do not allow formal conclusions. However, because cathinones are known to act as releasing agents at the human dopamine transporter (hDAT), Cameron et al. [54] investigated mephedrone and MDPV at hDAT expressed in Xenopus laevis oocytes. They found that mephedrone was found to have the signature of a dopamine-releasing agent similar to methamphetamine or methcathinone while MDPV behaved as a cocaine-like reuptake inhibitor of dopamine [54]. We are not able to know if those studies could easily be translatable in humans. Concerning synthetic cannabinoid, Kamat et al. [56] reported a case report of an 18-year-old man who inhaled a substance containing synthetic cannabinoids and 1 hour later developed a severe global headache. Imaging revealed a perimesencephalic subarachnoid haemorrhage and angiogram suggested that a small superior cerebellar artery aneurysm was the cause. Again, it is difficult to conclude on the relationship between synthetic cannabinoids use and intracranial haemorrhage. Treatment, which is still unclear, is the main goal that must be addressed for this new and potentially addictive problem. For the moment, treatment is primarily supportive and symptomatic and includes a drug plan coupled with psychotherapy in a structured program of care [5]. Unfortunately, blood or urine tests for these new drugs are not readily available in routine clinical practice. As Prosser and Nelson [8] noticed, many other substances such as ethanol and other drugs of abuse were reported or found on drug screening from patients seeking medical care after synthetic cathinone use. And Seely et al. [31] reported that most synthetic cannabinoids are not currently found using routine toxicology screening tests. Then, health care providers, especially those working in emergency departments, should be always on alert for Spiceinduced toxicity despite negative drug-screening results. There is an important lack of epidemiological, animal, and clinical data concerning designer drugs. There is evidence that negative health and social consequences may occur in recreational and chronic users. The methods of controlling street drugs cannot compete with the Internet. Interventions for drug prevention and harm reduction in response to the use of these drugs should be implemented on the Internet and in recreational settings. In parallel, as we can read in EMCDDA-Europol Report [2], the network now includes not only new forensic science and toxicological laboratories, but also a range of health and law enforcement professionals, as well as many academic researchers. The EU-EWS is now reinforced by the Reitox national focal points (French Network for Information on Drug and Drug Addiction), the technical expertise built up by members of the network, the clear operating guidelines and the coordination provided by the EMCDDA and Europol which could help in efficiency and effectiveness to prohibit these new synthetic drugs [2].

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Designer drugs have become a visible part of the American, Australian, and EU’s drug scene. The Internet has become a new marketplace for such drugs and plays a crucial role in the increase in the popularity of these new drugs [5]. DECLARATION OF INTEREST Olivier Cottencin was investigator in a clinical trial on Nalmefene in 2010 (Lundbeck), on Baclofen currently (Ethypharm), and participated to firm symposia (for Lundeck, Otsuka, Reckitt Benckiser, Bouchara Recordati, Janssen) • Benjamin Rolland was investigator in a clinical trial on Nalmefene in 2010 (Lundbeck), on Baclofen currently (Ethypharm), and has participated as an unpaid speaker for the Institut de Recherche Scientifique sur les Boissons (IREB), which receives funding from the alcohol industry. • Laurent Karila has received consulting fees from Sanofi Aventis, BMS Otsuka, Lundbeck, Gillead, Shering Plough, Eutherapie, Merck/Serono, Astra Zeneca, Bouchara Recordati, and Reckitt Bensicker Pharmaceuticals.



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Received: July 15, 2013

Accepted: August 26, 2013

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