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Transcript
produce visual hallucinations and out of body experiences alterations in cortical functioning Also affect mood, thinking and physiologicalprocesses At least 90 different species of plant and many synthetic agents can produce these effects Distinguish them by the NT system that they work on (primarily) many occur in nature; other newer ones are synthetically produced Prior to 1960 (or so) – these were primarily restricted to religious rituals and most people were not even really aware of them Most psychedelics resemble one of 4 NT ◦ ACh, catecholamines (NE, DA) and 5HT ANTICHOLINERGIC ◦ Scopolamine CATECHOLAMINERGIC ◦ Mescaline ◦ DOM, MDA, DMA, MDMA (ecstasy), etc ◦ Myristicin, elemicin 5HT like ◦ Lysergic acid diethylamide (LSD) ◦ Dimethyltryptamine (DMT) ◦ Psilocybin, psilocin, bufotenine, Ololiuqui,etc GLUTAMINERGIC NMDAR ANT ◦ Phencyclidine (Sernyl) (PCP) ◦ Ketamine (Ketalar) ◦ Dextromethorphan OPIOID KAPPA R AG ◦ Salvinorin A from Salvia plants Serotonin-like drugs – includes lysergic acid diethylamide (LSD) psilocybin, psilocin dimethyltryptamine (DMT) bufotenine 5HT acting psychedelics produce characteristic syndrome ◦ disturbances in thinking, illusions, elementary and complex visual hallucinations believe that these psychedelics interact with 5-HT2A receptors LSD – agonist DMT, bufotenine – partial agonist ?? why doesn’t 5HT have psychotomimetic effects? What about SSRIs? naturally occurring compounds exist that resemble the indole ring investigating therapeutic use of compounds obtained from ergot fungus LSD belongs to class of agents called ergot alkaloids Grew on rye (and some other grain) when weather conditions were right Types of ergot poisoning convulsive ◦ characterized by twisting and contorting body in pain, trembling and shaking, muscle spasms, confusions, seizures, delusions and hallucinations gangrenous ergotism ◦ Due to decreased blood flow, infections occur in the extremities, accompanied by burning pain and loss of extremities. explanation for witch trials…. Joan of Arc Saint Anthony’s Fire On August 15, 1951 one in twenty of the 4000 inhabitants of a village in France called Pont Saint Esprit (Bridge of the Holy Spirit) went mad. They had hallucinations, writhed in agony in their beds, vomited, ran crazily in the streets and suffered terrible burning sensations in their limbs. Joan of Arc Saint Anthony’s Fire ◦ dreaded illness in the Middle Ages LSD – ◦ during mid 1960’s – 1970’s – LSD – History ◦ ◦ ◦ ◦ synthesized in 1938; Albert Hoffman (Sandoz)- swiss chemist looking for possible therapeutic uses of ergot fungus early animal studies – not much ◦ first human experience 1943 although arguments can be made for a much earlier time LSD 25 had strong uterine effect and animals became stuporous but restless ◦ nothing of special interest – set back on shelf…… ◦ 5 years later – made new batch and must have gotten tiny amount on fingers ◦ tried it again under a more controlled condition using a 0.25 mg dose (10X the dose for most to show an effect) most potent drug in existence ◦ 10 – 300 ug Uses of LSD – 1953 - 1966 ◦ ◦ ◦ ◦ LSD used as adjunct to psychotherapy possible treatment for alcoholics treating cancer patients possible truth serum 1966- Sandoz recalled LSD and withdrew sponsorship for work with LSD NIMH – stopped LSD research (in house) in 1968; stopped funding in 1974 NIAAA – stopped supporting psychedelic research in 1975 Recreational Use of LSD ◦ early to mid 1960’s Pharmacology of LSD – ◦ drug is odorless, colorless, tasteless ◦ extremely potent (25 – 100 ug) but no OD death reported in humans rats – behavioral effects at 0.04 mg/kg and LD50 ~ 16 mg/kg (400X the behaviorally effective dose) Pharmacokinetics ◦ ◦ ◦ ◦ absorption rapid – oral route most common ½ life ~ 3 hrs Effect usually lasts ~ 8-12 hours metabolized in liver tolerance – develops very rapidly recovery is also usually rapid (so weekly use of same dose is possible) Cross tolerance – LSD with psilocybin, mescaline Sympathomimetic (activates sympathetic NS) and so autonomic signs are often first to appear ◦ dilated pupils, elevated temperature, BP and salivation LSD experience◦ ◦ ◦ ◦ ◦ mostly visual/perceptual changes altered sense of time synethesia – mixing of senses depersonalization typical lasts 6 – 9 hours Adverse Reactions ◦ panic reaction ◦ flashbacks quite variable and unpredictable Bufo Marinus, also known as the cane toad, skin and glandular secretions toad secretions have been used since ancient time…… Psilocybin ◦ long history in religious and ceremonial use ◦ indole isolated by Abby Hoffman and then synthesized Morning Glory Seeds -Hoffmann analyzed seeds -found several active alkaloids as well as d-lysergic acid amide -dangers: pesticides, substances coated on seeds in US; coatings on seeds can cause nausea, vomiting, headaches, increased BP, probably need 100s for species common in US Heavenly Blue NE and DA receptors important site of action for a large group of psychedelic drugs structurally similar to catechol NT and amph differ from nt by one or more methoxy group (-OCH3) exert amphetaminelike psychostimulant actioons; can enhance energy, endurance, sociability and sexual arousal psychedelic actions probably due to augmentation of 5HT neurotransmissions (5HT2A) Peyote – common plant in southwest US and Mexico Spineless cactus with small crown or button mescal buttons (not mescal liquour from agave cactus, mescal beans) dates back 5000 or more years ◦ Aztecs used in spiritual ceremonies (Native American Church) ◦ Members of Native American Church exempt from federal criminal penalities for religious use (predates CSA) mescaline identified in 1918 pharmacokinetics: ◦ mescaline rapidly absorbed orally levels increased in brain 1-2 hrs acute psychotomimetic state 3.5 – 4 hrs ◦ effects can persist for ~ 10 hrs ◦ does not appear to be metabolized ◦ imaging studies – hyperfrontal pattern of activity (right hemisphere) Synthetic amphetamine derivatives ◦ large group of synthetic hallucinogens chemically related to amphetamines; ◦ structurally related to mescaline and methamphetamine ◦ exs. DOM –dimethyoxymethamphetamine 100X more potent than mescaline (but less potent than LSD) high incidence of OD – use not common – toxic MDMA – Ecstasymethlenedioxymethamphetamine ◦ potent and selective serotonin neurotoxin ◦ neurotoxic – issues re raves nutmeg and mace ◦ common household spices ◦ ingestion of large amounts – confusion disorientation, impending doom, depersonalization ◦ structural resemblance to mescaline ◦ many unpleasant side effects including vomiting, nausea and tremors ◦ if people try it once – they don’t usually try again PCP (phencyclidine) ◦ developed as an IV anesthetic- Sernyl – Parke Davis ◦ monkey studies suggested that it was a good analgesic but did not produce muscle relaxation OR sleep – ◦ a dissociative anesthetic ◦ several patients were unmanageable as they emerged from the anesthetic; ◦ studies showed patients becoming angry or uncooperative; reduction in sensitivity to pain in combination could contribute to violent behavior PCP (phencyclidine) ◦ few reports of intense visual experiences and many more reports of body image changes ◦ reports of disorganized thinking, suspiciousness and lack of cooperation Recreational Use of PCP ◦ early 1970’s – PCP crystals sprinkled onto oregano, parsley, etc and sold as marijuana ◦ can be made inexpensively and relatively easily PCP receptor – discovered in 1979 ◦ appears to antagonize GLU ◦ endogenous ligand – as yet unknown Other PCP like drugs ◦ Ketamine ◦ related veterinary product Other PCP like drugs ◦ Ketamine ◦ related veterinary product ◦ 1999 – widespread reports of ketamine abuse resulted in ketamine receiving Schedule III designation ◦ not as strong an effect as PCP an analgesic and a drug of abuse common ingredient in more than 140 OTC cough suppressants high doses produce hallucinations highest age group for abuse potential - from salvia plant (magic mint, diviner’s sage, Sally-d) potato family contains all naturally occurring agents in this category ◦ atropine, scopolamine ◦ atropine – belladonna – active ingredient in deadly nightshade. ACh antagonist – comes from belladona (Deadly nightshade) Jamestown weed, jimsonweed, stinkweed, devil’s apple, moonflower, mandrake scopolamine containing plants have been used and misused for centuries Professional and amateur poisoners used deadly nightshade as a source of poison Ibogaine - psychoactive indole alkaloid from roots of Tabernanthe iboga Howard LotsofPreclinical data reduces selfadministration of both cocaine and morphine, as well as attenuates symptoms of morphine WD mechanism of anti-addictive action of ibogaine not well defined NMDA R antagonist; kappa agonist; mAChR activity has hallucinogenic effects in humans