Transcript 5-HT2a – receptor agonist

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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„Fourth drive“
(Ronald K. Siegel)
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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?
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Recreational drug use
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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
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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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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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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)
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• 5-HT1 – 5-HT7 receptors in CNS
1. Stimulants („uppers“) dopamine/serotonin/norepinephrin releasing drugs
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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)
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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)
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3. Common psychoactives
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Opiates and opioids
morphine, heroin
hydrocodone, oxycodone
Cannabis and cannabinoids
Cocaine and analogues
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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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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)
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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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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!
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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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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;
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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)
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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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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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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
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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);
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- 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
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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)
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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!!!
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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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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
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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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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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Novel Recreational Herbal Drugs of Abuse
• Hawaiian Baby Woodrose
(Argyreia nervosa)
- Effect of ergine (LSA) – LSD-like
- „Tropical stones“ (seeds
of HBW)
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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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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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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)
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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“)
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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
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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)
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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
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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
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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“
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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)
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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)
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
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„Legal smoke blends“ with CB1-agonists
• „Herbal“ mixtures – synthetic Cannabinoid
Receptor Agonists JWH class – „Spice“, „Smoke“,
„Jamaican Gold“, „Ninja“, „Monkees go bananas“
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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
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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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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!
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• Treatment of overdose: opioid antagonist - naloxone