Hallucinogens (Psychedelics) PDF

15 Hallucinogens (“Psychedelics”) and Dissociative Anesthetics Psychedelics • proposed the term "psychedelic" in 1956 • ”Mind-manifesting” •from "mind” (psyche) and "manifest"(delos) • "clear, euphonious and uncontaminated by other associations" Sir Humphry Osmond, MD https://collections.nlm.nih...

15 Hallucinogens (“Psychedelics”) and Dissociative Anesthetics Psychedelics • proposed the term "psychedelic" in 1956 • ”Mind-manifesting” •from "mind” (psyche) and "manifest"(delos) • "clear, euphonious and uncontaminated by other associations" Sir Humphry Osmond, MD https://collections.nlm.nih.gov/catalog/nlm:nlmuid-101424752-img Psychedelics https://hopkinspsychedelic.org/ Psychedelics https://www.nytimes.com/interactive/2023/04/03/magazine/roland-griffiths-interview.html?searchResultPosition=1 Psychedelics https://www.nytimes.com/2023/10/17/obituaries/roland-griffiths-dead.html Psychedelics https://www.nytimes.com/2023/01/03/health/psychedelic-drugs-mushrooms-oregon.html?smid=nytcore-ios-share&referringSource=articleShare Psychedelics https://www.denverpost.com/2022/11/08/colorado-results-prop-122-legalizing-psilocybin-psilocin-mushrooms/ Psychedelics https://www.fda.gov/regulatory-information/search-fda-guidance-documents/psychedelic-drugs-considerations-clinical-investigations Hallucinogens, PCP, and Ketamine Hallucinogenic Drugs ▪Mescaline ▪Psilocybin a 3 Mmaghroom ▪LSD synthetic ▪Ayahuasca “What a long, strange trip it’s been” Truckin’, Grateful Dead Hallucinogenic Drugs 5 Criteria: 1. Main effect is on thought, perception, and mood 2. Minimal intellectual or memory impairment 3. Stupor or psychostimulation is not an integral part of drug action 4. Autonomic side effects are not disabling 5. Little or no dependence liability Do withdraw Hallucinogenic Drugs “Tripping” • produces unusual perceptual and cognitive distortions ▪ “The girl with kaleidoscope eyes” Lucy in the Sky with Diamonds • novel, stimulating, or even spiritually up-lifting Mescaline • Found in several species of cactus • Peyote cactus (Lophophor williamsii) native to the US southwest and northern Mexico ▪ used for thousands of years by Native Americans for religious and healing boner rituals 299mn basis • Aldous Huxley molecular ▪ AP ▪ tried mescaline in 1953— from Humphry Osmond ▪ The Doors of Perception (1954) Psilocybin ”Magic mushrooms” • several different species (Psilocybe cubensis—most common) • produce alkaloids with hallucinogenic properties • dried mushrooms (1-5 g) eaten raw or cooked or made into tea ▪ “shrooming” • main compound is psilocybin (prodrug) metazoized ▪ converted to psilocin • actual psychoactive agent Psilocybin •Aztec and Mayans: religious rituals (veladas) around psilocybin mushrooms •Largely ingored by the West until 1938 ▪ “re-discovered” by Harvard botanist Richard Schultes in the Mazatec people •1957 Life Magazine article by R. Gordon Wasson “Seeking the Magic Mushroom” about a Mazatec ritual •1960—Timothy Leary eats “magic mushrooms” in Mexico ▪ founds ▪ Marsh the Harvard Psilocybin Project Chapel Experiment ▪ Concord Prison Experiment— reduced recidivism to 20% from 60% LSD Lysergic acid diethylamide (LSD-25) • Synthesized in 1938 by Albert Hoffman at Novartis (Sandoz) • synthetic compound based on fungal alkaloids (from ergot ▪ wanted to generate a new circulatory and respiratory stimulant (analeptic) ▪ psychedelic properties were not recognized until 1943 (4/16) ▪ LSD had arrived in the United States in 1949 • originally perceived as a psychotomimetic>>capable of producing a model of psychosis under LSD ppl usually don't have features of psyundelics plycosis Albert Hoffman LSD World’s first acid trip (4/16) From the book My Problem Child (1979) written by Hofmann: The following description of this incident is from the report that I sent to Professor Stoll: "Last Friday, April 16,1943. I have been forced to interrupt my work in the laboratory right in the middle of the afternoon and proceed home, being affected by a remarkable restlessness, combined with a slight dizziness. At home I lay down and sank into a hallucinogenic-like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly loud), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. About two hours later this condition faded away" LSD Bicycle Day LSD • A typical neuropharmacologist (e.g., ”My Friend”) on 4/21 LSD: A whose who Kary Mullis, Noble Laureate for the Invention of PCR: • "Back in the 1960s and early '70s I took plenty of LSD. A lot of people were doing that in Berkeley back then. And I found it to be a mind-opening experience. It was certainly much more important than any courses I ever took." • "What if I had not taken LSD ever; would I have still invented PCR?" He replied, " I don't know. I doubt it. I seriously doubt it.” Steve Jobs: • “Doing LSD was one of the two or three most important things I have done in my life.” Francis Crick: • Told his Cambridge fellow, Dick Kemp, that he surprisingly had “perceived the double-helix shape while on LSD.” Michel Foucault • Foucault wrote Wade and Stoneman a few months later to tell them “it was the greatest experience of his life, and that it profoundly changed his life and his work…. He wrote us that he had thrown volumes two and three of his History of Sexuality into the fire and that he had to start over again.” Phil Jackson: • “In his book Maverick: More Than a Game, Jackson says that an LSD-induced vision that he had in Malibu in May of 1973 helped him to see basketball in a new way that boosted his coaching performance. He said that the experience— which he called one of the peak experiences of his life–gave him a new love for the sport and a deeper appreciation of team play.” (http://www.maps.org/news-letters/v21n1/v21n1-3to6.pdf) Dock Ellis (June 12, 1970): Who? A no no on acid LSD and DNA LSD or Photo 51? Rosalind Franklin LSD • Sandoz first marketed the drug in 1947 for neurosis: uncovering repressed feelings ▪ made it freely available for research in 1950s • 1000’s of papers describing its therapeutic potential in psychotherapy • Sidney Cohen M.D.: psychiatrist>>>promoted its use in psychotherapy guided sessions Housewife on Acid • Non-medical (illicit) use exploded with the hippie culture in the 1960s • backlash occurred amid growing anecdotal accounts and scientific reports of LSDrelated problems recreational use was banned in 1967 LSD • very potent and orally active single dose in crystalline form is barely visible • Larger amounts are dissolved in water>>>droplets containing singledose units are applied to a sheet of paper (a “blotter”) and dried paper is divided into individual squares or “tabs” • War on Drugs: Mandatory minimums Ayahuasca (and DMT) • rapidly diffusing from aboriginal and mestizo society into mainstream culture • orally active tryptamine-based hallucinogen • prepared by boiling the bark or crushed stems of Banisteriopsis caapi and leaves of Psychotria viridis ▪ leaves of both species contain substantial concentrations of DMT (a structural analogue of 5HT and other tryptamine psychedelics) ▪ Banisteriopsis contains high concentrations of b-carboline alkaloids • potent MAO inhibitors • protect the DMT from degradation in the liver and gut Hallucinogens in popular culture https://www.nytimes.com/2021/11/25/travel/psychedelic-retreat-ayahuasca.html?referringSource=articleShare Hallucinogens in popular culture https://michaelpollan.com/about/ Which of the following hallucinogenic drugs is a prodrug? A) Psilocybin B) Mescaline C) LSD D) DMT Pharmacology of Hallucinogenic Drugs Pharmacology of Hallucinogenic Drugs • Hallucinogens vary widely in potency: ▪ LSD: most potent; mescaline: least • Psychedelic effects begin ~30 to 90 minutes after ingestion • LSD “trip”>>> 6 to 12 hours • DMT (smoked): felt within seconds, peak over a few minutes, and are gone within an hour Pharmacology of Hallucinogenic Drugs AADC • Most hallucinogenic drugs: have either a serotonin-like or a catecholamine-like structure • serotonin-like (indoleamine) hallucinogens: ▪ LSD, psilocybin, psilocin, DMT, and synthetic tryptamines https://link.springer.com/chapter/10.1007%2F7854_2016_472 • Contains a detailed synthesis manual for 55 psychedelic compounds! Pharmacology of Hallucinogenic Drugs • Phenethylamine hallucinogens: Mescaline: structurally similar to NE and AMPH amphetamine Pharmacology of Hallucinogenic Drugs • LSD binds with high affinity to at least eight different 5-HT receptor subtypes • Phenylethylamines: also bind to some 5-HT receptors ▪ common receptor subtypes are 5-HT2A and 5-HT2C • Suggests that these receptors may play a central role in producing hallucinations Pharmacology of Hallucinogenic Drugs pYhYaiciMP Fm Honey can't share what is goin on repair Ima in their ofmikg.gg • In humans, activation 5-HT2A receptors is the critical mechanism of action in generating hallucinations mind guy 5-HT2A fAntagonists night at me D2 Antagonists • hallucinations are blocked by 5-HT2A antagonists nanffihi.fg.fi an psi—psilocybin pla—placebo Pharmacology of Hallucinogenic Drugs Wacker et al., 2017, Cell 168, 377–389 is psychdelicexpneeded • • • forpsychological breakthrough high brain permeability Neither had psychedelic activity, in contrast to classic 5HT2AR agonists both had potent antidepressant activity and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose maybeableto activate 5472A andhave psychologic breakinnug wout psychedelicexp https://doi.org/10.1038/s41586-022-05258-z beneficial as somehave badtript make drugmore accessible Pharmacology of Hallucinogenic Drugs • Can not use animal models to study hallucinogens: ▪ Can not assess if an animal is experiencing a change of consciousness can discriminate drug suciesully • Can be trained in drug discrimination tasks to recognize the subjective effects of hallucinogens vs. saline ▪ Selective antagonists of 5-HT2A receptors blocks drug discrimination Pharmacology of Hallucinogenic Drugs • do not have high abuse potential no withdrawal symptoms and not an effective reinforcer • Dependence does occur in a very small number of users • Most hallucinogens produce rapid tolerance with repeated use shown in mice • down-regulation of 5-HT2A receptors seen in rats mescaline doesnot show this animals won'tselladmin Pharmacology of Hallucinogenic Drugs Negative effects (some users) • “bad trip” ▪ acute anxiety or panic ▪ Can be severe • Flashbacks—reexperiencing the hallucinations after drug use has stopped • psychotic reactions longtermacuteeffect some inair gointo permanentpsychoticstate hadair being diagnosed wpsychotic disorder Pharmacology of Hallucinogenic Drugs adishhpnc msn.FI are Pharmacology of Hallucinogenic Drugs Clinical Studies of Hallucinogenic Drugs ie naming exp Clinical Studies of Hallucinogenic Drugs Neurology, June 27, 2006 vol. 66 no. 12 1920-1922 Clinical Studies of Hallucinogenic Drugs increase anxiety i depp around cancer diagnosis 801 had relief sustainedeffect by Clinical Studies of Hallucinogenic Drugs Clinical Studies of Hallucinogenic Drugs Clinical Studies of Hallucinogenic Drugs • • 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The researchers strongly caution that their study results are not an endorsement of do-it-yourself psychedelic drug use for smoking cessation, but instead are specific to the controlled administration of the drug in the context of a treatment program involving cognitive behavioral therapy. https://hub.jhu.edu/2014/09/11/magic-mushrooms-smoking/ Clinical Studies of Hallucinogenic Drugs Clinical Studies of Hallucinogenic Drugs schedule being ability to study limits grow https://www.hopkinsmedicine.org/news/newsroom/news-releases/johns-hopkins-medicinereceives-fi Clinical Studies of Hallucinogenic Drugs Nature | Vol 609 | 29 September 2022 | S87 Clinical Studies of Hallucinogenic Drugs https://tonic.vice.com/en_us/article/mushrooms-are-the-safest-drug-you-can-take Clinical Studies of Hallucinogenic Drugs Microdosing (10 to 20 micrograms of LSD) https://www.cbc.ca/news/health/microdosing-pschedelics-study-1.4771647 Clinical Studies of Hallucinogenic Drugs • “It is unclear whether these benefits exist beyond the placebo effect. One source of uncertainty is that people who microdose psychedelic substances usually have a specific hope for what it will achieve. As a result, some of the findings might be explained by the placebo effect.” • “One way to tackle the question is with the help of placebo-based trials, in which some participants are given a microdose of a psychedelic, and others are given an inactive substance. “ • “The evidence that is beginning to emerge from such studies, however, doesn’t look promising.” Dissociative Anesthetics: PCP and Ketamine •Background and History •Pharmacology •Clinical and Basic Studies of Ketamine •Dextromethorphan PCP and Ketamine: Background and History Phencyclidine (PCP) • developed as an anesthetic • did not cause respiratory depression • Patients had atypical response: ▪ catatonic-like state (vacant stares, no facial expression) • Motor rigidity • Some patients experienced blurred vision and dizziness, hallucinations and severe agitation Clinical use stopped in 1965 in 1967, became an illicit street drug (“angel dust”, “hog”) ▪ powdered or pill ▪ taken orally, intranasally (snorted), injected, or applied to cigarettes and smoked prolonged delirium catatonic line 979 like floatingsive s e PCP and Ketamine: Background and History • Ketamine: developed as a safer alternative to PCP ▪ less potent and shorter-acting • anesthetic for certain procedures: ▪ Adults given an anesthetic dose lose all contact with their environment, but eyes are open and muscle tone remains • children do not! • used by veterinarians as a general sedative and immobilizing agent ▪ ▪ ▪ Ketalar, Ketaset, and Vetalar • Street supply usually comes from of medical or veterinary sources • sold on the street as “K,” “special K,” or “cat Valium” Injectable liquid that is converted to a powder >>>smoked or snorted half-life of ~2.5 hr Pharmacology Pharmacology of PCP and Ketamine • Noncompetitive antagonists of NMDA receptors ▪ binding site is inside the receptor’s ion channel ▪ Blockade in cortex and hipp likely contributes to cognitive deficits seen in users Pharmacology of PCP and Ketamine • Subjective effects of PCP: ▪ feeling detached from the body, floating sensation, numbness, a dreamlike state (dissociative anesthetic) • Affective reactions ▪ drowsiness and apathy, loneliness (social withdrawal), negativism or hostility, • Possible euphoria and inebriation • Cognitive disorganization (most subjects) ▪ difficulty concentratimg, disruption in abstract thinking, and halting speech • Effects of PCP>>>similar to symptoms of schizophrenia: • A psychotomimetic Pharmacology of PCP and Ketamine Subjective effects of Ketamine: • Doses in the anesthetic range produce a dissociated state with many subjective effects reported the “K-hole” can be either spiritually uplifting or terrifying Pharmacology of PCP and Ketamine • PCP and ketamine>>>highly reinforcing in primates and high abuse potential • Both activate midbrain DA cell firing and stimulate DA release Chronic use of ketamine or PCP: • Urological problems (e.g., bladder pain and incontinence) • Deficits in memory • Gray- and white-matter abnormalities in chronic ketamine users bilateral frontal and left temporoparietal reductions Pharmacology of PCP and Ketamine Control • repeated administration of high doses of ketamine causes apoptotic cell death in developing brains of rats and monkeys • Ketamine: a recommended anesthetic agent for pediatric procedures Ketamine— • Six 20mg/kg doses in 7 day old rat at 2hr intervals • Animals sac’d 6hrs after last dose Clinical and Basic Studies of Ketamine Pharmacology of PCP and Ketamine Ketamine (A miracle ADM?) • A serendipity>>>trying to model schizophrenia § Therapeutic dose produces transient cognitive dysfunction similar to cognitive symptoms of schizophrenia § Too high of a dose (into anesthetic range) loses its antidepressant effects • Alleviates depression but is not euphoric • Patients with high levels of comorbid anxiety are poor responders to SSRI but respond well to ketamine John Krystal, MD Pharmacology of PCP and Ketamine • Ketamine ▪ ▪ ▪ for Affective rapid Therapies (within hours) reduction in depression symptoms for 65 to 70 percent of treatmentresistant (TR) patients Disorders Subanesthetic doses Effects last weeks • Plasma half-life is 2.5 hours • antidepressant effects typically emerge ~4 hr after IV admin • Patients are maintained on regimens of 1x every two weeks to two months “Ketamine trips are known to help people disconnect from their bodies and their thoughts, and it worked that way for Reiger. After her first trip, she remembers feeling better than she had for years. "I immediately felt relief ... a lightness of the depression kind of lifting," says Reiger. And it all happened in less than an hour.” http://time.com/4876098/new-hope-for-depression/ Pharmacology of PCP and Ketamine Ketamine • Chronic stress causes excess extracellular glutamate § dendritic retraction, reduced dendritic arborization and spine density (A and B) stress-induced neuronal atrophy and normalization following ketamine treatment in PFC 24 hours posttreatment (C and D): Sub-anesthetic dose of ketamine reverses the chronic stress-induced structural deficits § § Rapid induction of BDNF • increased synaptogenesis and spine density • Similar effects to traditional antidepressants (ADMs) • Neuroadaptive state occurs much faster with ketamine Abdallah, et al., DEPRESSION AND ANXIETY 33:689–697 (2016) Pharmacology of PCP and Ketamine The Disinhibition Hypothesis • Ketamine’s antidepressant mechanism of action primarily depends on the antagonism of NMDARs on GABAergic interneurons preventing GABA release • The inhibition of GABA release prevents the inhibition of pyramidal glutamatergic neurons. This allows for the release of glutamate and the downstream effects of the subsequent glutamate surge • Glutamate binds to post-synaptic AMPARs, allowing for calcium influx • Calcium influx leads to the calciumdependent release of BDNF from the postsynaptic membrane Pharmaceuticals 2023, 16(5), 742; https://doi.org/10.3390/ph16050742 https://www.cnn.com/2019/03/05/health/esketamine-depression-nasal-spray-fda-bn/index.html https://www.nytimes.com/2022/03/11/well/mind/wellness-ketamine-mental-health.html?referringSource=articleShare https://www.ketaminewellnessinfusionspa.com/ Dextromethorphan Pharmacology of PCP and Ketamine • Dextromethorphan (the “DM” in Robitussin DM) • Antitussive agent: low doses>>>suppresses the cough reflex • High doses>>>noncompetitive antagonist of NMDA receptor • High doses of dextromethorphan: subjective effects similar to those observed with classical hallucinogens • can be extracted from cough syrup and repackaged in pills Experienced hallucinogen users What did we learn about drugs this semester? Lots of ways to get high at CVS! Opioid Psychomotor Stimulant Cocaine Dissociative anesthetic