Download 11/3/2014 Psychedelic Drugs Continued

11/3/2014
Psychedelic Drugs Continued
Serotonergics
Psilocybin/psilocin, N,N‐dimethyltryptamine
Psilocybin/psilocin, N,N
dimethyltryptamine (DMT), mescaline
(DMT), mescaline
Psychostimulants
methylenedioxymethamphetamine (MDMA)
Dissociatives
phencyclidine (PCP), ketamine
Other
myristicin, elemicin, salvinoria
Psilocybin / Psilocin
Use dates back to pre‐historic times (artifacts 200 AD)
Natural product present in >200 species of mushrooms
0.5 – 2% of dry weight of mushrooms with significant variability in concentration across species, within species, and amongst different parts of the mushroom
1958 – Psilocybin and psilocin identified by Albert Hoffman psilocybin
psilocin
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Psilocybin / Psilocin Pharmacokinetics
Psilocybin rapidly hydrolyzed in vivo to active metabolite psilocin
(chemical hydrolysis occurs under acidic or basic solutions)
(chemical hydrolysis occurs under acidic or basic solutions)
Half‐life 1‐3 hours, effects generally last 3‐8 hours
Less potent than LSD – milligram versus microgram doses 0.25‐0.30 mg/kg (above this, negative experiences increase)
Generally orally administered, dosed by mushroom mass or volume
Psilocybin / Psilocin
Mechanisms
Effects attributed primarily to partial agonist activity at 5HT2A receptors in pre‐frontal cortex
Additional activity at 5HT2C and 5HT1A receptors
Effects
Subjective effects similar to LSD
Tolerance builds if used repeatedly within a short time period
Not considered to cause physical or psychological dependence
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Psilocybin Potential Therapeutic Utility
• Cluster headaches
• Alcoholism
• Obsessive compulsive disorder (OCD)
• Depression
• Anxiety (end‐stage cancer studies)
Psilocybin down‐regulates 5HT2A receptors resulting in a reduced response to serotonin
N,N‐Dimethyltryptamine (DMT)
Present in various plant species (at least 50 species)
Occurs in trace amounts in animals including humans
Proposed neurotransmitter though insufficient evidence to‐date
DMT in salt form (water soluble) or free‐base form (can be smoked)
Unstable in solution
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N,N‐Dimethyltryptamine (DMT)
DMT can produce powerful psychedelic experiences: "The feeling of doing DMT is as though one had been struck by noetic lightning. The ordinary world is almost instantaneously replaced, not only with a hallucination, but a hallucination whose alien character is its utter alienness. Nothing in this world can prepare one for the impressions that fill your mind when you enter the DMT sensorium."
‐‐ Terence McKenna
DMT Pharmacokinetics
Short‐lived effects – generally less than 30 minutes (half‐life ca. 15 min)
Businessman s LSD
LSD”
“Businessman’s
Smoked, snorted or injected when used by itself
Psychedelic threshold dose 0.2 mg/kg
DMT is rapidly metabolized by monoamine oxidase (MAO) enzymes
First‐pass metabolism precludes oral bioavailability unless taken with MAO inhibitor p
p
y
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Ayahuasca – Traditional South American Religious Ceremonial Beverage
Brew made from plants containing DMT (e g Psychotria) and
Brew made from plants containing DMT (e.g. Psychotria) and MAO inhibitor of the harmine class (e.g. Banisteriopsis caapi vine)
Catecholamines – Mescaline and MDMA
Phenethylamine confers stimulant activity
Methylenedioxy confers
Phenethylamine confers hallucinogen‐like properties
stimulant activity
Methoxy groups confer
hallucinogen‐like properties
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Mescaline
Mescaline produced by peyote and other Cactaceae cacti –
Mescaline produced by peyote and other Cactaceae
cacti drug content variable across plants.
drug content variable across plants
Mescaline can be readily synthesized in the laboratory
Common psychedelic doses of pure mescaline 200 mg – 400 mg (10‐20 g peyote buttons)
Effects 10‐12 hours
Peyote Use Dates Back >5,000 Years
US – Mescaline and peyote plants listed as Schedule I
Exception granted for “bona fide religious ceremonies” within the Native American Church
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Methylenedioxymethamphetamine – Prototypical Psychostimulant
1912 – Synthesized by Merck (potential appetite suppressant, reduce bleeding)
1970s – Examined in psychotherapy (Alexander Shulgin credited with introduction of drug)
1980s – Increased recreational use 1985 – Classified as Schedule I
Other psychostimulants with similar effects: 2C‐B, DOM, MDA, DMA, MDE, AMT, 5‐MeO‐DIPT Alexander Shulgan – “Godfather of Psychedelics”
Discovered, synthesized, and personally bioassayed over 230 psychoactive compounds
Examined psychedelic, empathogenic and entactogenic properties along with wife Ann Shulgan
Alexander Shulgan
(1925 – 2014)
Ann Shulgan
(1931 ‐
)
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Alexander Shulgan – “Godfather of Psychedelics”
Personal experiences described along with synthetic protocols
Tryptamines
I Have Known And Loved (1997)
Phenethylamines
I Have Known And Loved (1991)
MDMA Effects
Increases serotonin dopamine norepinephrine levels via release and/or reuptake inhibition
Increases serotonin, dopamine, norepinephrine levels via release and/or reuptake inhibition
• Users report increased feelings of empathy, insight, enhanced communication
• Adverse reactions are generally physical – including increased heart rate and blood pressure, fatigue, insomnia, muscle tension, loss of motor coordination, and hyperthermia
• Malignant hyperthermia of great concern when used at Malignant hyperthermia of great concern when used at “raves”
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MDMA Effects
Malignant hyperthermia Drastic and uncontrolled increase in skeletal muscle oxidative metabolism, which overwhelms the body’s capacity to supply oxygen, remove carbon dioxide, and regulate body temperature. Condition can lead to circulatory collapse and death if not treated quickly.
Dantrolene can block MDMA‐precipitated malignant hyperthermia
http://en.wikipedia.org/wiki/Malignant_hyperthermia
SENATE BILL 12‐020 (State of Colorado Legislation)
IMMUNITY FROM CERTAIN CRIMINAL OFFENSES WHEN A PERSON REPORTS IN GOOD FAITH AN EMERGENCY DRUG OR ALCOHOL OVERDOSE EVENT
http://www.colorado.gov/ccjjdir/Resources/Resources/Leg/EnablingBills/SB12‐020.pdf
http://www.ccjrc.org/
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Ketamine and PCP ‐ Dissociative Psychedelics
Ketamine and PCP act as antagonists of glutaminergic NMDA receptors
Ketamine and PCP act as antagonists of glutaminergic
NMDA receptors
May also
* block acetylcholine receptors
* block dopamine reuptake
* induce dopamine release
* act as partial agonist at dopamine 2 receptors N
Cl
O
ketamine
phencyclidine (PCP)
Ketamine and PCP Effects ‐ “Dissociative Anesthetics”
Analgesia, amnesia and
a ges a, a es a a d
sensory distortions
N
Cl
ketamine
PCP:
O
phencyclidine (PCP)
Withdrawn from human use; currently approved for veterinary use only
Ketamine: Deemed safer than PCP; restricted medical use
* Anesthesia in children (less likely to experience hallucinations than adults)
* Pain relief
* Bronchospasm treatment
* Fast‐acting anti‐depressant (off‐label use)
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Myristicin and Elemicin, Present in Nutmeg and Mace
Myristicin
Precursor to MMDA (MDMA analog)
Elemicin
Precursor to mescaline
Myristicin and elemicin: monoamine oxidase inhibitors (MAOIs), anticholinergics
Raw nutmeg containing myristicin and elemicin can cause an excited and confused state with headaches, nausea, vomiting, tachycardia, dizziness, dry mouth, bloodshot eyes, memory disturbances, hallucinogenic effects, anxiety, paranoid ideation. Effects and after effects last up to several days.
Salvinorin A From Salvia Divinorium ‐ Most Potent Naturally Occurring Hallucinogen
Used for centuries by the Mazatecs (Mexico)
Leaves chewed, brewed or smoked
Doses generally 200‐500 mcg
Short‐acting – ca. 30 minutes
Currently legal though under investigation
Kappa opiod agonist
Mechanism distinct from seratonergic psychedelics though
similar effects
Salvinorin A
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