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.

1. Recreational drugs
ass. prof. S. Zakharov, M.D., Ph.D.
Charles University in Prague
First Faculty of Medicine
Department of Occupational Medicine
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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. 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. 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)
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5. 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
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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. 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. 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. 3. Common psychoactives
• Opiates and opioids
- morphine, heroin
- hydrocodone, oxycodone
• Cannabis and cannabinoids
• Cocaine and analogues
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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)
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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. 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
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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. 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
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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. 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)
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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!
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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)
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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. 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. Cathinones
• Khat (Catha edulis) – tropical
East Africa, Arabian Peninsula;
• Fresh leaves – stimulating
amphetamine-like effect;
• Legal in UK,Netherlands,Israel
• http://ekhat.org/our-new-
shop-buy-khat-online-now
prices of khat in our site:
• 100gr – £33.99
• 200gr – £38.99
• 400gr – £53.99 21

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. 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. 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
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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. 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“
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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)
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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. 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
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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
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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,
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aggression, confusion)

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. 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. 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. 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. 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. 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. 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. 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. 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%
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feces, 20-35% urine (acid metabolites)

41. 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

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. 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. 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
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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
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