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New psychoactive substances: exploring new frontiers of health protection Gilberto Gerra Chief Drug Prevention and Health Branch Dark clouds at the horizon World Drug Report 2016 database (UNODC): lifetime • Ketamine: 15-64 years old: 0.02% - 4.0% Youth : 0.19% - 4.7% • Synthetic cannabinoids 15-64 years old: 0.3% - 2.5% Youth : 1.10% - 13.2% • Misc. NPS (Salvia Divinorum, Mephedrone, MDVP, Piperazines, BZP) 15-64 years old: 0.1% - 13.5% Youth : 1.7% - 19.9% NPS use prevalence: uncertain figures Eurobarometer/ EMCDDA NPS 8% lifetime NPS 3% last year 0.0% lifetime to 9.7% lifetime in Europe Mephedrone 1.9% last year in UK Synthetic cathinones 0.2% Finland 1.2% of individuals in the US, age 13–34, use of novel psychoactive substance lifetime - tryptamines - psychedelic phenethylamines - synthetic cannabinoids Palamar et al., 2015 . aged 14 and over / lifetime 1.3% of Australians synthetic cannabinoids 0.4% of Australians new psychoactive substances 7.0% of Australians methamphetamines lifetime 2.1% of Australians methamphetamines previous 12 months Australian Institute of Health and Welfare, 2014 Mephedrone-associated fatalities 90 cases; Schifano et al., 2012 Fatalities involving mephedrone (National Programme on Substance Abuse Deaths database): 30 cases Loi et al., 2015 Deaths involving heroin and morphine in England and Wales have increased by 64%, from 579 deaths in 2012 to 952 in 2014 Wise, 2015 Office for National Statistics Do not forget old drugs Changes in patterns of injecting drug use in Hungary: a shift to synthetic cathinones. heroin mephedrone decreasing heroin use and the appearance of mephedrone injecting Péterfi et al., 2014 NPS: "Internet drugs/designer drugs/legal highs" in Sweden Among 189 cases of drug intoxications at emergency departments and intensive care units 50 substances identified: - synthetic cannabinoid receptor agonists ("Spice") - piperazines - substituted phenethylamines - synthetic cathinones - hallucinogenic tryptamines - piperidines Helander et al., 2014 New psychoactive substances as adulterants of controlled drugs. A worrying phenomenon? 173 samples believed to be MDMA, amphetamine, ketamine, cocaine, mescaline, or methamphetamine. The NPS adulterant most frequently observed 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine (2C-B) - 69 different combinations of substances were detected: - 20 involving a controlled drug combined with an NPS - 49 involving one or more NPS that substituted the controlled drug Giné et al., 2014 Tryptamines: monoamine alkaloid found in plants, fungi and animals Binding serotonin receptors – hallucinogenic effects Psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine) α-methyltryptamine N,N-diisopropyltryptamine 4-hydroxy-N-methyl-N-ethyltryptamine Mephedrone, 4-methylmethcathinone(4-MMC) or 4-methylephedrone: Releasing dopamine/norepinephrine Dopamine transporter inhibitor Stimulant effects Teeth grinding, cardiovascular problems, behavioural undercontrol Bath salts containing substituted cathinones White crystals often resemble legal bathing products cathinone mephedrone Dizziness Double vision Euphoria Blurred vision Finding it hard to express emotions Feeling sick and vomiting Nightmares Illusions Hallucinations Changed body image Impaired memory and attention Ketamine is a NMDA antagonist Dissociative anaesthetic Useful drugs in shock/surgery patients because of blood pressure maintained Phenethylamine, β-phenethylamine, or phenylethylamine a natural monoamine alkaloid amine in the brain Monoamines uptake inhibitors. Stimulant effects Phenethylamine Piperazine organic compound GABA (γ-aminobutyric acid) receptor agonist Serotonin agonist Piperazines Clozapine Olanzapine 4-Bromo-2,5-dimethoxy-1- benzylpiperazine(2C-B-BZP) 1-Benzylpiperazine (BZP) 2,3-Dichlorophenylpiperazine (DCPP) 4-Chlorophenylpiperazine(pCPP) Sold as ecstasy Stimulant / hallucinogenic effects Adv Pharmacol. Bath salts, mephedrone, and methylenedioxypyrovalerone as emerging illicit drugs that will need targeted therapeutic intervention. Glennon, 2014 The actions of these agents resemble those of central stimulants: - dopamine, norepinephrine, and/or serotonin reuptake inhibitors - dopamine, norepinephrine release Effects of neurological and/or cardiovascular nature a broad class of agents/variety of actions to be evaluated on a case-by-case basis Treatment of synthetic cathinone intoxication requires more "basic science" research At this time, treatment is mostly palliative J Neurochem. 3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter. Anneken et al., 2015 Bath salts that are substrates for the DAT and release DA (METHY, MEPH) accentuate METH neurotoxicity Bath salts that are non-substrate of the DAT (MDPV) are neuroprotective, but do cause hyperthermia Am J Drug Alcohol Abuse. "Bath salt" ingestion leading to severe intoxication delirium: two cases and a brief review of the emergence of mephedrone use. Kasick, 2012 J Emerg Med. Bath salts intoxication: a case series. Imam et al., 2013 intense mephedroneinduced psychosis - Antipsychotics - Benzodiazepines - mechanical ventilation - intravenous hydration - hospitalizations and intensive care Addict Sci Clin Pract. Designer drugs 2015: assessment and management. Weaver et al., 2015 constellation of psychiatric and medical effects - anxiety - agitation - psychosis - tachycardia - deaths evaluating substance use in young adults or in anyone presenting with acute neuropsychiatric complaints - Treatment of acute intoxication: care targeting signs and symptoms - Long-term treatment lack of evidence to guide treatment Br J Pharmacol. Differential effects of cathinone compounds and MDMA on body temperature in the rat, and pharmacological characterization of mephedrone-induced hypothermia. Shortall et al., 2013 MDMA decreased 5-HT and/or 5-hydroxyindoleacetic acid (5-HIAA) MDMA reduced striatal homovanillic acid (HVA) levels cathinone and meth-cathinone increased striatal HVA and 5-HIAA Different effects on body temperature. Clin Toxicol. Treatment of cocaine cardiovascular toxicity: a systematic review. Richards et al., 2016 Benzodiazepines GABA-active agents Calcium channel blockers Nitric oxide-mediated vasodilators Alpha-adrenoceptor blocking drugs Alpha-1 blockers Alpha-2-adrenoceptor agonists (dexmedetomidine). Beta-blockers β/α-blockers (labetalol and carvedilol) Crit Rev Toxicol. Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): inter-individual differences due to polymorphisms and drug-drug interactions. Rietjens et al., 2012 Carvedilol Ketanserin Haloperidol Benzodiazepines Intravenous hydration Aggressive cooling Correction of electrolytes Dtsch Med Wochenschr. Fatal brain edema after ingestion of ecstasy and benzylpiperazine. Balmelli et al., 2001 Excessive rehydration The patient had severe hypervolaemic hypotonic hyponatraemia Measurement of serum sodium and brain CT scan is recommended in all patients with altered mental status after MDMA consumption J Psychoactive Drug Psychological Burden and Gender Differences in Methamphetamine-Dependent Individuals in Treatment. Simpson et al., 2016 Women reported experiencing problems because of METH use at a younger age Women were also more likely to have injected METH in the past year they reported greater severity of drug problems compared to men METH-dependent women had greater psychological burden, reported more use of an emotional-coping strategy CNS Drugs. Methamphetamine psychosis: epidemiology and management. Glasner-Edwards and Mooney, 2014 The pharmacological treatment of acute methamphetamine-induced psychosis may include the use of antipsychotic medications as well as benzodiazepines Treating anxiety Behavioral therapy J Addict Med. Utilizing a Two-stage Design to Investigate the Safety and Potential Efficacy of Monthly Naltrexone Plus Once-daily Bupropion as a Treatment for Methamphetamine Use Disorder. Mooney et al., 2016 Long term treatment naltrexone (slow release/Vivitrol) plus extended-release oral bupropion (Wellbutrin) smartphone-assisted medication adherence platform Drug Alcohol Rev. A potential role for N-acetylcysteine in the management of methamphetamine dependence. McKetin et al., 2016 Long term treatment to restore homeostasis to brain glutamate system reducing craving has also antioxidant properties that protect against methamphetamine-induced toxicity Int J Neuropsychopharmacol. Subjective and Cardiovascular Effects of Intravenous Methamphetamine during Perindopril Maintenance: A Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study. Verrico et al., 2016 Long term treatment Angiotensin II is known to facilitate the effects of norepinephrine which contributes to methamphetamine's subjective effects angiotensin-converting enzyme (ACE) inhibitor perindopril reduces methamphetamine's effects Addict Biol. A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment. Pei et al., 2016 Tyramine, β-phenylethylamine, tryptamine, octopamine are biogenic amines present in trace levels in mammalian nervous systems. Curr Psychiatry Rep. Adverse Effects of Synthetic Cannabinoids: Management of Acute Toxicity and Withdrawal. Cooper, 2016 unpredictable and severe nature of acute intoxication effects of long-term chronic use symptoms relief with: - benzodiazepines - atypical antipsychotics - quetiapine Int J Cardiol. Can your heart handle the spice: A case of acute myocardial infarction and left ventricular apical thrombus. Shah et al., 2016 Case Rep Crit Care. The Wide and Unpredictable Scope of Synthetic Cannabinoids Toxicity. Orsini et al., 2015 - acute hypoxemic/hypercapnic respiratory failure - acute congestive heart failure - myocardial stunning - non-ST-segment elevation myocardial infarction Brain Res Bull. brainresbull.2015.10.013. [Epub ahead of print] The behavioral profile of spice and synthetic cannabinoids in humans. Müller et al., 2015 Most of the observed effects are related to sympathomimetic-cardiac effects and neuropsychiatric manifestations Clinical treatment is primarily based on - intensive therapy - supportive therapy Clin Toxicol (Phila). A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Tait et al., Caldicott, 2016 Major complications: myocardial infarction ischemic stroke and emboli acute kidney injury generalized tonic-clonic seizures psychiatric presentations first episode psychosis paranoia self-harm/suicide ideation hyperemesis Most frequently result in tachycardia, agitation and nausea symptomatic care - intravenous fluids - benzodiazepines - anti-emetics J Emerg Med. Repeated Thrombosis After Synthetic Cannabinoid Use. Raheemullah and Laurence, 2016 Thrombo-embolic events after smoking synthetic cannabinoids: - kidney infarcts - pulmonary emboli - ischemic stroke - both venous and arterial thrombosis, activation of coagulation or inflammatory pathways WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? Australas Psychiatry. Signs and symptoms associated with synthetic cannabinoid toxicity: systematic review. Courts et al., 2016 tachycardia, hypertension, nausea/vomiting agitation, irritability, paranoia drowsiness, aggression hallucinations clinicians in emergency services should consider synthetic cannabinoid toxicity when evaluating young adult male patients presenting with unexplained agitation or cardiovascular symptoms. Focusing on: Intoxication emergency treatment Chronic/long term treatment Prevention programs / reliable information - Disco club personnel /owners - Rave party organizers - Web interactions - Low threshold interventions Peer programs Hydratation Drug testing Control mechanism CND / MS request for WHO investigation/evaluation CND approval after WHO report International control National control 16 substances under control in 58th and 59th CND Sessions Under control at the international level: 58th session CND, 2015 AH-7921 25B-NBOMe (2C-B-NBOMe) 25C-NBOMe (2C-C-NBOMe) 25I-NBOMe (2C-I-NBOMe) 4-methylmethcathinone) N-benzylpiperazine (BZP) JWH-018, AM-2201 3,4-methylenedioxypyrovalerone (MDPV) methylone (beta-keto-MDMA). 59th session CND, 2016 acetylfentanyl MT-45 para-methoxymethylamphetamine (PMMA) α-pyrrolidinovalerophenone (α-PVP) para-methyl-4-methylaminorex (4,4’-DMAR) methoxetamine (MXE) phenazepam