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Recreational drugs ass. prof. S. Zakharov, M.D., Ph.D. Charles University in Prague First Faculty of Medicine Department of Occupational Medicine 1 „Fourth drive“ (Ronald K. Siegel) Satisfaction of hunger, thirst Need for safety (shelter) Sexual drive ? „Altered-mind“ states ? „We are perceiving creatures...“ (C. Castaneda) - Thirst for new impressions, sensations, feeling, emotions, experiences – ways of satisfaction? 2 Recreational drug use - Why? (Intention) – creating/enchancing recreational experience Where,when? – night clubs („party drugs“), psychonautics, spiritual communities, sport, army, sex... Problems: Legality? Addiction Tolerance Physical/psychical dependence Neurotoxicity General toxicity 3 Novel Recreational Drugs of Abuse („Legal Highs“) • New synthesized chemicals,not listed in Convention on psychotropic substances, sold by internet (in Czech republic – 3 websites with „legal highs“) • http://botanic.cz – psychoactive plants. • „clubbers drugs“ – use 40% of night clubs visiters • Each 2-3 months new „Legal High“ is marketed (absence of studies about toxicity, biometabolism, no lab methods of identification in human liquids) 4 Novel Recreational Drugs of Abuse • Production in Southeast Asia, China, packaging and distribution in Europe and USA. • Growth of popularity: earlier http://bythemg.com, now http://bythekg.com • Simple synthesis schemes (2-3 chemical reactions, common reagents (toluene, acetone...), high grade of chemical purity, low prices • Chemical structure is similar to the structure of forbidden „classical“ psychoactive substances 5 Molecules driving the human world • 1. Catecholamine neurotransmitter dopamine • Brain reward system: enjoyment, motivation, sociability • Production: substancia nigra, ventral tegmental area • D1-D5 receptors in CNS • Cannot cross the blood-brain barrier • 2. Monoamine neurotransmitter serotonin • Contributes to happiness, well-being, dominant behavior • Production: raphe nuclei (brainstem) 6 • 5-HT1 – 5-HT7 receptors in CNS 1. Stimulants („uppers“) dopamine/serotonin/norepinephrin releasing drugs • • • • • Amphetamines, methamphetamines („Pervitin“) MDMA („Extasy“), MDxx family Cathinones Piperazines Mitragynine (Kratom) * Empathogens-entactogens („love drugs“) • MDA, MDMA, MDxx family • 2C-x family • Tryptamines (AET, AMT) 7 2. Hallucinogens • 2.1. Psychedelics („classical hallucinogens“5-HT2a/2c receptors agonists): - Phenethylamines (mescaline, DOx, 2C-x) - Tryptamines (LSD, psilocybin, DMT, ibogaine) • 2.2. Deliriants: - Muscimol (Amanita muscaria) - Solanaceae alkaloids (atropine, scopolamine...) - Myristicin („Nutmeg“) • 2.3. Dissociatives: - Ketamine, Phencyclidine, Salvinorin - Dextromethorphan (opioid) 8 3. Common psychoactives • • • Opiates and opioids morphine, heroin hydrocodone, oxycodone Cannabis and cannabinoids Cocaine and analogues 9 Amphetamines, methamphetamines • Synthesized in 1887 – Amph. (L.Edeleanu, Germany), 1893 – Meth. (N. Nagayoshi, Japan) • 1933 – Benzedrine (A.), 1938 – Pervitin (M.) • World War II – for soldiers • 1971 – Schedule II drug (USA) • Recreational use „speed“,„meth“ • In nature – Acacia species (A. berlandieri, A. rigidula) 10 Amphetamines, methamphetamines • Recreational use: from 1937 (Minnesota, USA, students), 16-51 mln. of abusers worldwide • Psychological effects: euphoria, positive mood, decreased fatigue, reduced appetite, increased energy (self-esteem, self-confidence), alertness, sociability, psychomotor agitation, insomnia, increased libido, excessive feeling of power and invincibility, hallucinations • Routes of exposure: ingestion, injection, insufflation, inhalation (smoking), suppositoria (rectal, vaginal) 11 Amphetamines, methamphetamines • Mechanisms of action (toxicity): i – enters the cell by passive diffusion or ii – via membrane-bound dopamine reuptake transportes (DAT) iii – redistribution of DA from vesicles into the cytosol (VMAT-2) iv – promotes the activity of tyrosine hydroxylase v – blocking the presynaptic re-uptake of DA by DAT vi – inhibiting MAO activity 12 Amphetamines, methamphetamines • Neurotoxicity: - enhanced cytosol concentration of DA - increased oxidation - superoxide free radicals, peroxylnitrite (:NO3) - oxidative stress - mitochondrial injury, - neuronal apoptosis, nerve terminal degeneration • General toxicity - sympathomimetic toxidrome! 13 - - Sympathomimec toxidrome (amphetamines, methamphetame, MDMA…) Cardio: tachycardia, hypertension, palpitations, chest pain, ischemia/infarction; CNS: nistagmus, tremor, headache, paresthesia, numbness, hyperreflexia, muscle rigidity (bruxisme), seizures; Psychiatric: anxiety, paranoia, psychosis, confusion/desorientation, delirium, hallucinations; Respiratory: tachypnea, dyspnea, pulmonary hypertension 14 Sympathomimec toxidrome (amphetamines, methamphetame, MDMA…) - Metabolic: dehydratation (hypovolemia), lactic acidosis, hyperglycemia, hyper-K, hypo-Na, hyper-CK (rhabdomyolysis – renal insufficience); - Ocular: mydriasis, blurred vision, intraretinal hemorrhagia; - GI: nausea/vomiting, diarrhea, abdominal pain; 15 MDA, MDMA („Extasy“), MDxx • MDA synthetised in 1910 (G.Mannish, W.Jacobson), MDMA in 1912 (A.Kollisch) • Recreational use from 1963 • „Love drugs“, empathogensentactogens (induce feelings of empathy, love, emotional closeness to others) • Dose: 100-160 mg MDA, 75-120 mg MDMA • Overdose at 200-250mg (mainly in combination with excessive physical activity + strong alcohol) 16 MDA, MDMA („Extasy“), MDxx • Mechanisms of action: releasing agents for mainly serotonin (SSRA), than dopamine, norepinephrine - enter neuron via carriage by the monoamine transporters (DAT, SERT); inhibit VMAT... (like Meth). - indirect stimulation of oxytocin secretion (orgasm, hugging) - Mechanisms of toxicity: amphetamin-like + serotonin syndrome! 17 Acute recreational drug toxicity syndrom • Sympathomimetic toxidrome • Serotonin syndrome • Psychiatric symptoms („Amphetamine psychosis“) • Combination: „alcohol + legal high“ milder cardiovascular symptoms (softer „onset“ of MDMA after 1 glass of red vine), - better driving ability then after alcohol intake only) • Use less than 1 weekly (tolerance due to „receptor downregulation effect“) • Drink plenty of water (not Coca) -- - 18 Selective serotonin releasing agents (SSRA) • MDMA („Extasy“), MDxx, PMA („Chicken Powder“, „Dr. Death“) – effective releasers of 5-HT, reuptake inhibitors of 5-HT (risk in combination with SSRI, MAO-A and CYP450 inhibitors) • Serotonergic neurotoxicity - Serotonin syndrom: - Rapid increase in body temperature (hyperthermia) - Hypertension/hypotension, tachycardia, convulsions, seizures, coma - Dehydratation, rhabdomyolysis 19 Selective serotonin releasing agents (SSRA) • Treatment: intubation, external cooling (4º water, ice) - Internal cooling (i.v. Infusion of cooled saline, gastric lavage with „ice“ saline), - Treatment of convulsions and agitation: benzodiazepines (i.v. diazepam in bolus), phenytoin, thiopental; - Treatment of hypertension: alpha/beta blockers, nitroprusside; - Dantrolene (5-HT antagonist); 20 - Rehydratation Cathinones • Khat (Catha edulis) – tropical East Africa, Arabian Peninsula; • Fresh leaves – stimulating amphetamine-like effect; • Legal in UK,Netherlands,Israel • http://ekhat.org/our-newshop-buy-khat-online-now prices of khat in our site: • 100gr – £33.99 • 200gr – £38.99 • 400gr – £53.99 21 Cathinones • Chemically similar to Amph. • Substituted C.: „designer drugs“ - Mephedrone, Methylone, Naphyrone • Replacement of MDMA („party drugs“) – stimulants, entactogens (higher doses – worse cross the BBB-100-250mg) • Were „legal highs“ until 2010 • „Plant fertilisers“, „Bath salte“, „Miaow Miaow“ (Cat) 22 Piperidines • Pipradol, Methylphenidate, 2-DPMP (Legal!) (Desoxypipradol) • No polar functional groups (targets for metabol. enzymes),highly lipophilic • „Ivory wave“, „Purple Wave“, „Vanilla Sky“ – „bath salts“ – amphetamine-like „journey“ Soothing bath Salts – Relax and soak away IVORY WAVE, Concentrated bath salts, please only use as advised, PLEASE do not use this as SNUFF!!! 23 New Herbal Stimulants • Kratom (Mitragyna speciosa) - Native to Southeast Asia - Leaves contain alcaloid mitragynin interacts with opioid receptors - Stimulant-like effect in small doses, opiate-like effect in higher doses 24 Psychedelics: Phenethylamines (mescaline, DOx, 2C-x) • Mescaline – alkaloid in peyote cactus (Lophophora williamsii) • Activating of „hallucinogenous“ serotonin 5-HT2a receptor (5-HT2a – agonist) • Excitation of neurons in the prefrontal cortex - hallucinogen • In add. stimulates DA-receptors • Native Americans in Mexico use for over 3000 years (religious ceremonies) • Dried cactus legal in UK 25 Psychedelics: Tryptamines (LSD - 5-HT2a– agonist, DA–receptor agonist ) • LSD (Lysergic acid diethylamide) • Synthesized by A.Hofmann in 1938 (Sandoz Laboratories) • Recreational drug, entheogen, psychedelic therapy (non-addictive) • 1950s – CIA („mind control“, chemical warfare) • „Trip“ – eidetic imagery, altered sense of time, true hallucinations, „ego death“ (6-14 hours) • „Bad trip“ – the best treatment is an anxiolytic agent (diazepam) • „Flashbacks“ • Dosage: 100-500 ug (mkg) – „blotters“ 26 LSD (5-HT2a – receptor agonist) • Natural sources: • Fungus Claviceps purpurea (grows on the rye and other cereals) ergotamine • „Morning glory“ (Ipomoea tricolor, I. violacea) – ergine (LSA, lysergic acid amide) 27 Novel Recreational Herbal Drugs of Abuse • Hawaiian Baby Woodrose (Argyreia nervosa) - Effect of ergine (LSA) – LSD-like - „Tropical stones“ (seeds of HBW) 28 Psychedelics-synthetic „LSD mimics“: DOx, 2C-x families („designer amphetamines“) • DOx-family (20 chemicals): DOM (dimethoxy-methylamphetamine), DOB, DOC, DOI... – substituted Amph. derivates (highly selective to 5-HT2a/2b/2c receptors) • 2C-family (2C-I, 2C-B...) (Alexander Shulgin, 1974) – 5-HT2c receptor agonists (not 5-HT2a), visual hallucinations like „brain movies“ duration 2-5 hours, easier „comedown“ than from MDMA 29 Psychedelics: Tryptamines: Psilocin (Psilocybin) • Psychedelic mushrooms alkaloid (over 200 species – Psilocybe cubensis, P.semilanceata, P.cyanescens...) • Partial agonist at 5-HT2a • No efect at DA-R (unlike LSD) • Hallucinations, synesthesia (hearing colours, seeing sounds) • Effect lasts 3-8 hours 30 Psychedelics: Tryptamines: Psilocin (Psilocybin) • History: religious ceremonies (9000 BCE – Africa, 6000 BCE – Europe, Spain, Mayan and Aztec cultures in America) • Purified from P. mexicana in 1958 by A. Hofmann • Low toxicity (LD50 for rats 280 mg/kg – 1,7 kg of dried or 17 kg of fresh rooms for adult) • Recreational dosage: 10-50 mg (alkohol and tobacco enhance the effect)- „brain movies“ • Adverse reactions in 25% of cases (psychosis, panic attack, aggression, confusion) 31 Psychedelics: Tryptamines: DMT (Dimethyltryptamine) • Natural sources: 50 plant species, 4 animal species • Product of normal metabolism in humans and other mammals? • Ayahuasca (Amazonian Amerindian brew) – DMT (B. rusbyana, Psychotria viridis aj.)+ MAOI (harmala alcaloids of jungle vine Banisteriopsis caapi) • Agonist of 5-HT2a receptor („classical hallucinogen“) 32 Psychedelics: Tryptamines: DMT (Dimethyltryptamine) • Routes of exposure: ingestion (only with MAOI – othervise is metabolised in GIT), inhalation (smoking as „crack“ cocain), insufflation, injection (contacts with „alien entities“); • Short action when smoking („businessman´s trip“) 15 min, orally over 3 hours. • Intense erotic imagery and sensations, archetypal visions 33 Deliriants: Muscimol (Amanita muscaria) • Psychoactive alcaloid in Amanita muscaria, A.pantherina • Siberian shamans, Scandinavia. Possibly the Soma drink of India (Rig-Veda) • Selective agonist of the GABAA receptor (major inhibitory neurotransmitter in CNS) – like BD, barbiturates • Excreted unchanged by kidneys • Dosage: 10-15 mg (1 g of dried rooms) 34 Deliriants: Solanaceae alkaloids (atropine, scopolamine, hyoscyamine) • Jimsonweed (Datura stramonium), Deadly nightshade (Atropa belladonna), Mandrake (Mandragora officinarum)… • Potent combination of anticholinergic substances (competitive antagonists of muscarinic acetylcholine receptors) • Anticholinergic delirium, hyperthermia, dry mouth tachycardia; bizarre (violent) behavior; mydriasis, photophobia, blurred vision • Treatment: gastric lavage, activated charcoal, benzodiazepi35 nes, antidote physostigmine, Deliriants: Myristicin • Myristica fragrans („Nutmeg tree“) • Anticholinergic-like symptoms when consuming raw nutmegs (nausea, vomiting, dizziness, anxiety, headache, hallucinations and irrational behavior, myosis) • MDMA-like chemical structure + weak inhibitor MAO • extremely long time before peak (4-7 hours), effects last for 24-72 hours 36 Dissociatives: Ketamine („Vitamin K“, „Kitties“), Phencyclidine („Angel dust“) • Dissociation – reduce/block signals to the conscious mind from other parts of the brain (trances): - sensory loss (dissociation from the body), - depersonalization („out-of-body“, „near-death“ experiences), spiritual/psychonautic use - derealization (unreal world outside) Other effects: hallucinogenic, euphoric, anesthetic 37 Dissociatives: Ketamine, Phencyclidine • „Non-classical hallucinogens“ – no effect on 5HT2A receptors in CNS • Mechanisms of action: non-competitive NMDAreceptor antagonist (antagonizes glutamic acid – main excitatory neurotransmitter in CNS), D2receptor partial agonist • Problems of abuse: great neurotoxicity (much more than of „classical hallucinogens“) – cognitive impairment, memory loss, urinary tract diseases (ulcerative cystitis, „shrunken bludder“), abdominal „K-cramps“ 38 Cannabis and cannabinoids • Species: Cannabis sativa (North America), C. indica (!!!) (Indie), C. ruderalis (Russia) • Marijuana (flowers and subtending leaves and stalks of mature female plants) • Hashish (compressed stalked resin glands from the unfertilized buds) 39 Natural cannabinoids (over 85) • THC (Tetrahydrocannabinol) • Binds to the cannabinoid receptor CB1 in CNS (agonist) • Activate endogenous opioid pathways (μ1 OR) – precipitate dopamine release in nucl. accumbens • Analogous to the endogenous cannabinoids (2-AG – in human maternal milk!, anandamide, NADA, OAE...) • Effects: euphoria, relaxation, analgesia, alteration of senses, appetite stimulation („munchies“) • Bioavailability 10-35% (inhalation), 6-20% (oral), metabolism mostly hepatic, excretion 65-80% 40 feces, 20-35% urine (acid metabolites) Synthetic cannabinoids – CB1-agonists • Distinct chemical classes (THC-analogues, aminoalkylindoles, diarylpyrazoles, quinolines...) • Distinct legal status – many legal ones („legal highs“) – www.bythekg.com : JWH-250, AM-2201, AM-694, JWH-019, 2-DPMP. ATTENTION! JWH- 203 SALE OUT!! 5$ PER GRAM!! • JWH cannabinoids – synthesized by the John.W. Huffman research group at Clemson University (over 450 chemicals) • AM cannabinoids – synthesized by the A. Makriyannis research group at the University of Connecticut • HU cannabinoids – Hebrew University, Jerusalem 41 „Legal smoke blends“ with CB1-agonists • „Herbal“ mixtures – synthetic Cannabinoid Receptor Agonists JWH class – „Spice“, „Smoke“, „Jamaican Gold“, „Ninja“, „Monkees go bananas“ 42 Symptoms of „acute intoxication by smoking herbal products“ • Cardiovascular, neurological, psychiatric symptoms • Hallucinations, agitation, somnolence, insomnia, mydriasis • Tremor, seizures, myoclonus • Addiction/dependence and tolerance • Tachycardia, palpitations, chest pains • Dyspnoea • Nausea, vomitind • Hypokalemia 43 Cocaine and cocaine analogues • Stimulants (like Amph.) • Mechanism of action: only DA/SER/NOR reuptake inhibitors (not DA/SER releasers) • Natural source: Erythroxylum coca (Coca plant) • „Crack“ = cocaine+NaHCO3 (t°), smoking form (inhalation) • Withdrawal symptoms („crash“): depression, craving, itching, anxiety, insomnia, exhaustion, fatigue, nausea, vomiting 44 Opiates and opioids • Morphine, heroin, hydrocodone, oxycodone, methadone, tramadol... • Natural source of opiates – Opium poppy (Papaver somniferum) • Mechanisms of action: binding to specific opioid receptors (mimic endogenous opioids – endorphins, enkephalins...) • Activating the μ-opioid receptors in the CNS (analgesia, sedation, euphoria, physical dependence, respiratory depression) • Activating the k-opioid receptors in the CNS (myosis (pinpoint pupils), psychotomimetic effects). Respiratory depression! 45 • Treatment of overdose: opioid antagonist - naloxone