Recreational Drugs


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This presentation aims to discuss the reason why Recreational drugs (also known as legal highs) were created and the problems and consequences behind these drugs.

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Recreational Drugs

  1. 1. Recreational drugs ass. prof. S. Zakharov, M.D., Ph.D. Charles University in Prague First Faculty of Medicine Department of Occupational Medicine 1
  2. 2. „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
  3. 3. 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 3
  4. 4. 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“)• – 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
  5. 5. Novel Recreational Drugs of Abuse• Production in Southeast Asia, China, packaging and distribution in Europe and USA.• Growth of popularity: earlier, now• 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
  6. 6. 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)• 5-HT1 – 5-HT7 receptors in CNS 6
  7. 7. 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
  8. 8. 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
  9. 9. 3. Common psychoactives• Opiates and opioids- morphine, heroin- hydrocodone, oxycodone• Cannabis and cannabinoids• Cocaine and analogues 9
  10. 10. 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
  11. 11. 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
  12. 12. Amphetamines, methamphetamines• Mechanisms of action (toxicity):i – enters the cell by passive diffusion orii – via membrane-bound dopamine reuptake transportes (DAT)iii – redistribution of DA from vesicles into the cytosol (VMAT-2)iv – promotes the activity of tyrosine hydroxylasev – blocking the presynaptic re-uptake of DA by DATvi – inhibiting MAO activity 12
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. MDA, MDMA („Extasy“), MDxx• MDA synthetised in 1910 (G.Mannish, W.Jacobson), MDMA in 1912 (A.Kollisch)• Recreational use from 1963• „Love drugs“, empathogens- entactogens (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
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. 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);- Rehydratation 20
  21. 21. Cathinones• Khat (Catha edulis) – tropical East Africa, Arabian Peninsula;• Fresh leaves – stimulating amphetamine-like effect;• Legal in UK,Netherlands,Israel• shop-buy-khat-online-nowprices of khat in our site:• 100gr – £33.99• 200gr – £38.99• 400gr – £53.99 21
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. 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
  28. 28. Novel Recreational Herbal Drugs of Abuse• Hawaiian Baby Woodrose(Argyreia nervosa)- Effect of ergine (LSA) – LSD-like- „Tropical stones“ (seeds of HBW) 28
  29. 29. 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
  30. 30. 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
  31. 31. 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, 31 aggression, confusion)
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. Deliriants: Solanaceae alkaloids(atropine, scopolamine, hyoscyamine)• Jimsonweed (Datura stramonium), Deadly nightshade (Atropa bella- donna), 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, benzodiazepi- nes, antidote physostigmine, 35
  36. 36. 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
  37. 37. 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
  38. 38. Dissociatives: Ketamine, Phencyclidine• „Non-classical hallucinogens“ – no effect on 5- HT2A receptors in CNS• Mechanisms of action: non-competitive NMDA- receptor antagonist (antagonizes glutamic acid – main excitatory neurotransmitter in CNS), D2- receptor 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
  39. 39. 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
  40. 40. 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)
  41. 41. Synthetic cannabinoids – CB1-agonists• Distinct chemical classes (THC-analogues, aminoalkylindoles, diarylpyrazoles, quinolines...)• Distinct legal status – many legal ones („legal highs“) – : 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
  42. 42. „Legal smoke blends“ with CB1-agonists• „Herbal“ mixtures – synthetic Cannabinoid Receptor Agonists JWH class – „Spice“, „Smoke“, „Jamaican Gold“, „Ninja“, „Monkees go bananas“ 42
  43. 43. 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
  44. 44. 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
  45. 45. 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!• Treatment of overdose: opioid antagonist - naloxone 45