Lecture 9 Hallucinogens 2020 PDF

Psychopharmacology Detail from The Hallucinogenic Toreador, Salvador Dali (1968-1970) The Hallucinogens  Hallucinogens: An Introduction ❖Diverse group with different properties ❖a/k/a psychedelic, psychotomimetic, psychodysleptic, psycholytic ❖Hallucination-pr...

Psychopharmacology Detail from The Hallucinogenic Toreador, Salvador Dali (1968-1970) The Hallucinogens  Hallucinogens: An Introduction ❖Diverse group with different properties ❖a/k/a psychedelic, psychotomimetic, psychodysleptic, psycholytic ❖Hallucination-producing (perhaps not true hallucinations) ❖Much studied for their psychotherapeutic value Characteristics of Hallucinogenic Drugs (Hollister, 1994) ❖Primary Effect: Changes in thought, perception, and mood ❖ Minimal cognitive effects (such as memory impairment) ❖ Not characterized by excessive stimulation or lowered NS activity (stupor or narcosis) ❖ Minimal ANS side effects (may cause some sympathetic activity) ❖ No physical dependence ❖ Minimal addictive craving  Two Types of Classification ❖1. By the Neurotransmitter 2. By the Effect They Produce System They Affect Psychedelics (“Classic Hallucinogens”) ❖Serotonin: LSD, psilocybin, lysergic ❖ Perception-altering acid amide, DMT ❖ Examples: LSD, Psilocybin, Mescaline ❖ Primarily Serotonergic; typically agonist. ❖Norepinephrine: mescaline, DOM (STP), MDMA (Ecstasy) Dissociatives ❖ Can produce analgesia, amnesia and catalepsy (trance state) ❖Acetylcholine: atropine, ibotenic ❖ Produce a sense of detachment from surrounding environment acid scopolamine, hyoscyamine ❖ Examples: Ketamine, PCP, Nitrous Oxide ❖Glutamate: PCP, ketamine ❖ Primarily Antiglutamatergics (Glutamate Antagonists) ❖What’s missing????? Deliriants ❖ Delirium (extreme confusion and inability to control one's actions) ❖ Examples: Atropa belladonna (deadly nightshade), Datura stramonium ❖ Primarily Anticholinergics (Acetylcholine Antagonists)  Psychedelic (Classical) Hallucinogens Hallucinogens are substances which produce hallucinations Psychedelic (Humphrey Osmond): “Mind Provides Insight, Primarily manifesting” (from Greek: “psyche” Serotonergic Understanding, (mind), and “delos” (manifesting) Awareness, a New Perspective LSD Psilocybin MDMA Harmine LAA Mescaline Great Potential Value as DMT Cannabis Psychotherapeutic Agents Psychedelic Drugs are Conscious-Altering Substances Psychedelic (Classical) Hallucinogens: LSD ❖ Synthetic chemical derived from ergot One Famous Example (Perhaps): ❖ A parasitic fungus which grows on grains The Salem Witchcraft Trials ❖ Highly toxic ❖ History (1692-1693) ❖ Produces ergotism (St. Anthony’s Fire) ❖ Two girls started showing extreme symptoms- fits, ❖ reduction in blood flow to extremities convulsions, strange utterances. ❖Accused Tituba (West Indian slave) ❖ tingling sensation on skin, convulsions ❖Accusations spread. The trials resulted in the executions of ❖ disordered thinking, hallucinations twenty people. ❖ Ergotism has happened repeatedly ❖ Possible Cause ❖ Ergot poisoning! ❖ Rye bread was main crop ❖ Weather conditions were ideal for infection  The Modern History of LSD ❖ The hero of our tale: Albert Hoffmann ❖ Chemist studying lysergic acid for its medicinal value ❖ 1938- creates LSD-25 (25th variation of lysergic acid) ❖ 1943- accidentally comes in contact with LSD-25 ❖ 1953- Sandoz patent ❖ Interest quickly spreads ❖ Psychiatrist Humphrey Osmond ❖ Writer Aldous Huxley (The Doors of Perception) ❖ Clinical Psychologist Timothy Leary  The Modern History of LSD Dr. Timothy Leary: Our other LSD Hero A Brief Timeline ❖ Clinical Psychologist at Harvard University ❖ Self-Research into LSD properties ❖ LSD Advocate for the “Acid Generation” ❖ “Turn on, Tune In, Drop Out” ❖ Marijuana Possession Arrest ❖ Software Executive ❖ Died in 1997  LSD: Acute Effects Acute Effects ❖ Minor sympathetic nervous system activity ❖ Emotional changes ❖ Hallucinations (psychedelic trip; synesthesia) ❖ Extreme variability Description ❖ A lot of work! (8 draining hours) ❖Perhaps most powerful psychoactive drug ❖ Is both serotonergic agonist and antagonist ❖ Rapidly absorbed ❖ A quite safe drug in terms of toxicity ❖ Typically sold in powder pellets or as a liquid on a blotter  LSD: Adverse Effects No evidence of long-term toxicity Does NOT produce Has strong potential to long-term psychosis produce a “bad trip” (Time Dilation, Paranoia, Mood Does NOT produce Swings, Hallucinations, etc.) chromosomal damage Does NOT produce Does produce flashbacks violent behavior ❖Disturbed perception or distorted sensory experience ❖Can be pleasant or distressing ❖Can last for minutes to years ❖May be basis for Hallucinogen Persisting Perception Disorder (HPPD) Risk of Dependence is Quite Low  Psychedelic (Classical) Hallucinogens: MDMA Methylenedioxymethamphetamine (Ecstasy, XTC, Essence) Origin and History ❖Developed and patented by Merck in 1912 All MDMA Statistics from The DEA.Org ❖Has similar chemical structure to epinephrine (thus, sympathetic nervous system activity) ❖Used widely in psychotherapeutic settings starting in the 1970s ❖1985- re-classified as a Schedule I drug ❖Street use was popular in 1960s, increased in use in 1980s, and peaked in 1990-2000s. Considered to be the second most used illicit drug  MDMA: Physical Effects MDMA has strong stimulant properties and fairly low toxicity levels Risks Hypertension, Dehydration, Hyperthermia All MDMA Statistics from The DEA.Org Fatal complications are due to stimulant effects, not the hallucinogenic effects  MDMA: Neurotransmitter Effects MDMA Affects Three Major Neurotransmitter Systems Norepinephrine Dopamine Serotonin Re-uptake Inhibitor Re-uptake Inhibitor Re-uptake Inhibitor Direct Serotonin Releaser ❖ Stimulant Effects ❖ Increased ❖ Alters mood, appetite, sleep ❖ Increases Heart Rate energy/activity ❖ Triggers Oxytocin release and Blood Pressure ❖ Stimulates which increases ❖ Increases blood reward pathway ❖ Sexual arousal vessel constriction ❖ Trust and metabolic heat ❖ Emotional closeness generation (risk of ❖ Social bonding hyperthermia) ❖ Empathy Induces changes in brain chemistry ❖ Impairs transporter mechanism which produces reuptake ❖ Unclear whether this is temporary or permanent  MDMA: Psychological Effects Isn’t Increasing Empathy a Good Thing? May be useful in clinical/therapeutic settings ❖ Trauma Victims/PTSD ❖ Individual facing impending death ❖Enhanced tactile sensations ❖ Psychological conditions (anxiety, depression, etc.) ❖Enhanced mood Psychotherapeutic use dates to 1970s - 1980s ❖Cognitive insights ❖Perceptual distortions ❖Heightened self-awareness ❖Empathy and understanding Ongoing MAPS clinical trials ❖ Started in 2008 ❖ Currently in Phase III of Clinical Trials ❖ Goal is FDA approval for PTSD by 2022 Psychedelic (Classical) Hallucinogens: Mescaline and DOM Derived from peyote plant. Used for over 3000 years in Mexico Agonist Can produce DOM severe GI (2,5-dimethoxy-4-methylamphetamine) disruptions ❖Synthetic derived from mescaline (1963) ❖ Frequently used in combination with LSD ❖ Street name: STP (Serenity, Tranquility, Peace) ❖ Perceptual Effects: blurred vision, multiple Origin and History images, distorted shapes, slowed time perception ❖Active ingredient isolated in 1897 ❖ Reputation for producing bad trips ❖First synthesized in 1919 ❖ 7-8-hour trips, but up to 14-20 hours LSD’s Little Brother! Effects are similar to LSD, but more sensual Psychedelic (Classical) Hallucinogens: Psilocybin Psychedelic agent produced in more than 200 mushroom species Origin and History ❖ Earliest use dates to 9000BC in Northern Africa ❖ 1959: Active ingredient of Psilocybe Mexicana was identified and named by… ❖ Effects were studied scientifically in 1960s by… ❖ Produces 4-5-hour trip like LSD, but far less potent Magic ❖ Research was banned from the 1970s to 2018 Mushrooms ❖ Current FDA clinical trials for treatment of depression. Lyme Nicotine Depression disease Dependency Opioid Alcohol PTSD Addiction Dependency 2019: FDA provides “breakthrough therapy” status. Clinical trials are ongoing.  Other Classical Hallucinogens Drug Lysergic Acid Amide Dimethyltryptamine Harmine (DMT) Morning Glory seeds. Resin of tree bark and nuts bark of Banisteriopsis Source (identified by…??) of numerous trees vine (South America) 1/10 to 1/30 potent as LSD Usually inhaled or smoked. Induces strong trance Effect Quite potent effects state 6-10 hours Minutes: (“the 1-2 hours Time Frame businessperson’s LSD”)  Dissociative Hallucinogens Hallucinogens are substances which produce hallucinations Phencyclidine Ibogaine (PCP) Ketamine ❖Glutamate antagonists typically ❖Dissociation: Feeling detached from world affecting NMDA receptors ❖Depersonalization: Feeling disconnected ❖Main effects: Dissociation, or detached from one's body and thoughts Hallucinogenic, Euphoriant ❖Derealization: The World is “Not Real” Dissociatives produce feelings of detachment from the environment and self.  Dissociatives: PCP and Ketamine Phencyclidine (PCP or Angel Dust) Ketamine (Special K) ❖Developed as a surgical anesthetic ❖Developed in 1952 as a ❖Reclassified as Schedule 1 dissociative anesthetic in ❖Taken orally, IV, inhaled, or smoked humans and animals ❖ Effects ❖Current Schedule 3 as ❖ remarkably unpredictable anesthetic or for chronic ❖ dissociative effects pain management ❖ mania, paranoia, depression, ❖2019: FDA approved anxiety, psychosis, hallucinations Spravato (s-enantiomer of ❖can last two weeks ketamine) for depression  Dissociatives: Ibogaine Derived from Tabernanthe iboga (iboga), a shrub native to Africa Origin and Effects ❖First extracted from iboga plant in 1901 ❖Produces mild stimulant effects ❖Promotes empathy ❖24 to 48 hours time frame (often physically and mentally exhausting) ❖Structurally related to Serotonin but affects many NT systems and pathways. Used in treatment of addiction to many drugs (But, not in the U.S.!)  Dissociatives: Ibogaine Used in treatment of addiction to many drugs Anti-addiction Effects ❖ Complete alleviates symptoms of opioid withdrawal following administration ❖ Eliminates cravings for future use ❖ Much studied for treating addiction: opioids, cocaine, alcohol, nicotine ❖ Clinical trials in Europe, Canada, but not US ❖ Clinics established in many locations: UK, Canada, France, Caribbean, Mexico, Brazil, etc.  Hallucinogens: Deliriants Hallucinogens are substances which produce hallucinations Atropine Henbane Benadryl Datura Amanita muscaria Atropa mushrooms belladonna Delirium (Acute Confusional State) A serious disturbance in mental abilities resulting in confused thinking, reduced attention (awareness of the environment), and disruptions of consciousness. Anticholinergic (ACh antagonists) drugs which produce a state of Delirium.  Hallucinogens: Deliriants Principally Affect the Muscarinic ACh Receptor Sites. Cognitive effects Physical effects Delirium, drowsiness, confusion, Low blood pressure, heart rhythm temporary memory loss, disturbances, hyperthermia, dry restlessness, convulsions, mouth, dry eyes, blurred vision, psychotic manifestations, vivid temporary blindness, constipation. and unpleasant hallucinations Effects are Generally Unpleasant and Unlikely to be Repeated.  Examples of Deliriants Drug Source Effect Image Atropa belladonna (deadly Plant native to Europe, North Produces “living dreams”. nightshade, banewort, naughty Africa, Western Asia. Potential for delirium and man’s cherries). Atropine source. Naturalized in North America. psychosis. Datura (jimson weed, Hell’s North through South America Potential for psychosis and Bells, Devil’s weed, Angel’s temporary blindness up to trumpet, Devil’s trumpet). Source two weeks of Scopalamine. Henbane: from Anglo-Saxon Found globally Used to flavor German hennbana (killer of hens) pilsners until 1516 (Stinking nightshade) Amanita muscaria mushrooms Northern Hemisphere, Central “Nectar of the Gods”; used (contains ibotenic acid) America by Berserkers