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I. Introduction A. Classification of psychotomimetics, psychedelics and hallucinogenic drugs

31:128 Psychopharmacology Professor A. K. Johnson Spring 2012 Unit 7: Outline Psychotomimetics and Hallucinogens. I. Introduction A. Classification of psychotomimetics, psychedelics and hallucinogenic drugs II. Cholinergic A. Background B. Prototypic agonist drugs 1. Muscarine

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I. Introduction A. Classification of psychotomimetics, psychedelics and hallucinogenic drugs

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  1. 31:128 PsychopharmacologyProfessor A. K. JohnsonSpring 2012 Unit 7: OutlinePsychotomimetics and Hallucinogens I. Introduction A. Classification of psychotomimetics, psychedelics and hallucinogenic drugs II. Cholinergic A. Background B. Prototypic agonist drugs 1. Muscarine 2. Physostigmine C. Pharmacological effects and mechanisms of action D. Prototypic antagonist drugs 1. Atropine 2. Scopolamine E. Pharmacological effects of mechanisms of action III. Catecholamine-like A. Introduction B. Prototypic drugs 1. Mescaline 2. Amphetamine derivatives 3. Myristin and elemicin IV. Serotonergic A. Introduction 2830/7.0a

  2. Psychotomimetics and Hallucinogens(continued) B. LSD C. Dimethyltryptamine (DMT) D. Psilocybin and psilocin E. Ololiuqui F. Harmine V. Dissociative Anesthetics A. Introduction 1. Phencyclidine 2. Ketamine B. Effects C. Pharmacokinetics D. Pharmacodynamics E. Side effects and toxicity F. Tolerance, dependence and abuse VI. Marijuana A. Introduction B. Effects (and therapeutic uses) C. Pharmacokinetics D. Pharmacodynamics E. Side effects and toxicity F. Tolerance, dependence and abuse 2830/7.0b

  3. Key Terms and Concepts Anticholinergic syndrome Hypnagogic Dissociative anesthetics LSD Dorsal raphe neurons Psychedelics Endocannabinoids Psychotomimetics Hallucinogens Important Drugs and Chemicals Amphetamine derivatives Anandamide Atropine Bufotenine Cannabinoid Dimethyltryptamine (DMT) Dronabinol Elemicin Harmine Ketamine (Ketalar) Lysergic acid diethylamide (LSD) Marijuana MDMA Mescaline Muscarine Myristin Ololiuqui (morning glory seed) Phencyclidine Physostigmine Psilocin Psilocybin Scopolamine 2830/7 KTC

  4. Psychotomimetics and HallucinogensStudy Questions • What is a psychedelic drug? • What differentiates a psychedelic drug from a behavioral stimulant? Discuss from both structural and behavioral viewpoints. • Describe the four classes of psychedelic drugs. • What are the differences between mescaline and LSD. • How does LSD exert psychedelic actions? • What is the psychedelic syndrome? • What are some of the problems associated with LSD use? • What is the mechanism of phencyclidine action? Discuss the state of psychosis it produces. • What properties characterize the clinical usefulness of phencyclidine and ketamine? • How are the effects of THC similar to those of the nonselective depressants? How are they dissimilar? • How are the effects of THC similar to those of the psychedelic drugs? How are the dissimilar? • How does the half-life of THC reflect a person's ability to become intoxicated more easily and with a smaller amount of drug after its repeated use? 2830/7 Qa

  5. Psychotomimetics and HallucinogensStudy Questions (continued) 13. Discuss some of the concerns and side effects that are associated with varying degrees of THC use by young people. 14. What does THC do to cognition? 15. Are there any potential long-term effects of marijuana on the brain? The body? Society? 16. Are there any potential long-term effects that might be associated with chronic use of marijuana? 17. Does dependence on marijuana develop? 18. Discuss the cannabinoid receptor, its location, and its endogenous neurotransmitter. 19. What are some of the potential therapeutic uses of cannaboid agonists? 20. Outline the endocannabinoid system, including its receptors and functions. 21. Describe the neurobiological effects of the hallucinogens. 22. What are features of LSD intoxication? 23. Which neurotransmitter receptors appear to be affected by LSD? 24. What is the mechanism of action of PCP and ketamine? 2830/7 Qb

  6. General Behavioral, Cognitive and Physiological Effects of A Psychedelic Drug - The main effect is on thought, perception and mood - There is only minimal intellectual or memory impairment - Stupor or psychomotor stimulation is not an integral part of the action of most psychedelic drugs - Autonomic side effects are not disabling - There is little or no dependence liability 2830/7.1-a

  7. • Cholinergic/Anticholinergic Drugs - (e.g., muscarine; scopolamine) •Catecholamine-Like Psychedelic Drugs - Mescaline - Amphetamine derivatives (DOM, MDA, DMA, MDMA, TMA, MDE) - Myristin, elemicin •Serotonin-Like Psychedelic Drugs - Lysergic acid diethylamide (LSD) - Dimethyltryptamine (DMT) - Psilocybin, psilocin, bufotenine - Ololiuqui (morning glory seeds) - Harmine •Psychedelic Anesthetic Drugs (Dissociative Anesthetics) - Phencyclidine (Sernyl) - Ketamine (Ketalar) •Marijuana A Classification Scheme for Psychedelic Drugs 2830/7.1

  8. Chemical Structures of Various Street Drugs 2830/7.2

  9. Structural Formulas of Acetylcholineand the Anticholinergic Psychedelic Scopolamine 2830/7.3

  10. • Acts at muscarinic receptors. •Also acts as an agonist on GABAA receptors and therefore has neurodepressant action •One of two active ingredients of the mushroom Amanita muscaria or “fly agaric mushroom” •Ingestion of muscarine produces a state best described as delirium (restlessness, ataxia and hallucinations in the strict medical sense of the word) •Muscarine also produces salivation, nausea, diarrhea, hypotension and shock •Antidote: atropine •The use of Amanita muscaria is becoming increasingly rare in Western culture Muscarine 2830/7.4

  11. Psychic Effects •Euphoria •Delirium •Anxiety •Excitement •Hallucinations (usually visual, formed, and frightening, with loss of insight) Somatic Effects •Mydriasis (dilation of the pupils) •Reduced secretions (saliva, bronchi, and nasal) •Loss of pupillary light reflexes •Decreased GI motility •Blurred vision (loss of accommodation) •Hyperpyrexia •Dry, flushed skin •Tachycardia with hyper/hypotension •Vasodilation •Urinary retention Toxic Effects •Myoclonus (muscle contraction) •Coma •Extensor posturing •Respiratory depression •Seizures •Circulatory collapse •Death The Anticholinergic SyndromeScopolamine; Deadly Nightshade, Atropa belladonnaDatura; Jamestown Weed; Zombi’s Cucumber, Datura stramonium 2830/7.5

  12. Structural Formulas of NorepinephrineAmphetamine, and Eight Catecholamine-Like Psychedelic Drugs 2830/7.6

  13. Catecholamine-Like Psychedelic Drugs Mescaline - Crown (bud or mescal button) of the Peyote Cactus - Chewed raw or cooked then eaten - SW U.S. and Northern Mexico Indians have used for between 5 and 6 K yr. - 1896 chemically identified and 1918 synthesized - 1950’s entered mainstream U.S. culture in large part due to A. Huxley (The Doors of Perception) Synthetic NE Derivatives (DOM, TMA, MDE, MDA and MDMA) - “Designer Psychedelics” - Effects similar to mescaline but generally more potent, although not as potent as LSD - These drugs produce a mix of catecholamine and serotonin related effects - MDMA (ecstasy; XTC) “club drug”; structurally resembles MDA; MDA is a metabolite of MDMA - MDMA produces euphoria, enhanced sensory processing, increased energy, sense of well-being and self confidence - However, MDMA produces increased heart rate, blood pressure, sweating and salivation - MDMA can result in a fatal syndrome of malignant hyperthermia - MDMA is a neurotoxin destroying serotonin nerve terminals and producing memory loss and mood disorders Myristin and Elemicin - The active ingredients in the spices nutmeg and mace - Usually brewed in tea - Induce feelings of nonreality, confusion, disorientation, impending doom, depersonalization, euphoria and visual hallucinations - Toxic effects include nausea, vomiting and tremors 2830/7.6a

  14. Structural Formulas of Serotonin and Six Serotonin-Like Psychedelic Drugs 2830/7.7

  15. Serotonin-Like Psychedelic Drugs Psilocybin and Psilocin - Source: Various species of mushrooms (“magic mushrooms”) grown around the world - Evidence of mushroom use to at least 3500 B.C.E. - Psilocybin is converted enzymatically to the psychoactive agent psilocin - Awareness of the use of mushrooms as psychedelic agents emerged in the mid 1950’s Harmine - Obtained from seeds of a Middle Eastern plant (Peganum harmala) and a South American tropical plant (Banisteriopsis caapi). - Produces visual distortions similar to LSD - Intoxication is usually accompanied by nausea and vomiting Lysergic Acid Amide (LAA) - Aztecs ingested morning glory seeds called ololuqui - The active ingredient was found by Albert Hoffman to be LAA - LAA is similar chemically to LSD but is only 1/10th to 1/13th as potent as LSD DMT and 5-Meo-DMT - DMT is derived from several different plants growing in S. American Amazon Rain Forest - SA Indians make a drink (ayahuasca) containing DMT along with another ingredient, which together make it psychoactive - Typically DMT is sold in powdered form and smoked - 5-Meo-DMT (“Foxy Methoxy”) is a synthetic form of DMT 2830/7.7a

  16. Serotonin-Like Psychedelic Drugs (Cont.) Lysergic Acid Diethylamide (LSD) History - Synthesized in 1938 by the Swiss Chemist Albert Hoffman at Sandoz Pharmaceuticals - The natural compound was obtained from ergot (Claviceps purpuera) a fungus - In 1943 Hoffman made the serendipitous discovery of the hallucinogenic effects of LSD by accidentally ingesting it in the laboratory - Was subjectively studied in the 1950’s as an adjunct to psychotherapy - Its use was promoted by A. Huxley and especially by Harvard professor Timothy Leary - In the mid 1960’s Sandoz withdrew and recalled the drug - The U.S. Government and governments throughout the world criminalized the drug in the 1960’s Pharmokinetics - Usually taken orally and is rapidly absorbed in about 60 min; peaks in blood in about 3 hr. - Dose range 25 to 300 µg; usually supplied by paper (“a blotter”), stamps or sugar cube - Easily crosses the blood-brain and placental barriers - Metabolized in the liver and excreted by the kidneys Physiological Effects - Slight increases in body temperature, heart rate and blood pressure; dilation of pupils; increased blood glucose; dizziness, drowsiness; nausea (the somatic phase) - Remarkably low life threatening toxicity: ED = 50 µg; Estimated LD = 14,000 µg 2830/7.7b

  17. Serotonin-Like Psychedelic Drugs (cont.) Lysergic Acid Diethylamide (LSD, cont.)) Psychological Effects - Doses of 25 to 50 µg produce alterations in perception, thinking, emotion, arousal and self-image; time is slowed and sensory input is distorted and false hallucinations occur (the sensory or perceptual phase) - A maximum drug effect with changes in mood, disrupted thought, true hallucinations and psychotic episode is referred to as the psychic phase and is considered a “bad trip” Tolerance and Dependence - Physiological and psychological tolerance develops rapidly and easily - Cross-tolerance occurs with other psychedelics - Physical dependence does not develop, few withdrawal signs Adverse Reactions and Toxicity - Chronic or intermittent psychotic states - Persistent or recurrent major affective disorder (e.g., depression) - Exacerbation of preexisting psychiatric illness - Disruption of personality or chronic brain syndrome, known as “burnout” - Hallucinogenic persisting perceptual disorder(HPPD) is characterized by periodic hallucinogenic imagery months or even years after LSD use (flashbacks) 2830/7.7c

  18. LSD Effects on Dorsal Raphe Neurons 2830/7.8

  19. Potential Sites of Action of the Hallucinogen LSD 2830/7.9

  20. Phencyclidine and Ketamine Are Knownas Dissociative Anesthetics 2830/7.10

  21. • Altered body image •Feelings of isolation/aloneness •Cognitive disorganization •Drowsiness and apathy •Negativism and/or hostility •Feelings of euphoria and inebriation •Hypnagogic (dreamlike) states Self-Reported and Observed Effectsof PCP in Controlled Studies 2830/7.11

  22. Anticipated Effects Untoward Effects Low Dose Dreamy, carefree state Impaired judgment Mood elevation Mood swings, panic Heightened or altered perception Partial amnesia Moderate Dose Inebriation Ataxia, motor impairment Dissociation, depersonalization Confusion, disorientation Perceptual distortions Preoccupation with abnormal Diminished pain sensitivity body sensations Amnesia Exaggerated mood swings Panic High Dose All of the above, hallucinations Catatonia, “blank stare,” delirium, drooling, severe motor impairment, psychotic behavior, hypertensive crisis, amnesia Signs and Symptoms of PCP Intoxication 2830/7.12

  23. The Binding Site for Phencyclidine (PCP)Is Thought to be Located Inside the CationChannel of the NMDA-Receptor Complex PCP Receptor 2830/7.13

  24. PCP-Like Drugs Stimulate Firing of VentralTegmental Area (A10) Dopaminergic Neurons 2830/7.14

  25. 6-Hydroxydopamine Lesions of the Nucleus Accumbens Block PCP-Induced Locomotor Activation 2830/7.15

  26. Marijuana (MJ) (Cannabis) Source and Most Active Component - MJ is derived from the plant Cannabis sativa - In1964 it was shown that virtually all of the pharmacological activity of MJ is due to (-)delta-9-tetrahydrocannabinol (THC) - The MJ plant is either male or female and the most concentrated THC comes from the resin glands of the female flower Pharmacokinetics - Smoking is highly effective in delivering THC – Within seconds it reaches the brain and blood levels peak about the time smoking is complete - THC is reasonably well absorbed from the GI tract but systemic delivery is unreliable because of the first pass effect - Metabolites are excreted in both the feces (2/3) and urine (1/3) 2830/7.15a

  27. Marijuana (Cont.) Pharmacodynamics - Two types of THC receptors– CB1 and CB2 - Both are G-protein coupled receptors - CB-1 are the receptors in the brain - Rimonbant is a CB-1 receptor antagonist - THC receptors are mostly on nerve axons and terminals of nearly every type of neurotransmitter - This suggests that CB receptor agonists act to modulate release - Most of the effects of agonist action at CB-1 receptors is to inhibit release - The effects of CB-1 agonist on axon terminals may be through affecting N-Type calcium channels 2830/7.15b

  28. Marijuana (Cont.) Psychological Effects Stages of Intoxication 1. - The Buzz is a transient stage where body, head, arms and legs tingle and there is a feeling of light headedness with a dry mouth and throat and a feeling of thirst 2. - The High produces euphoria and physical and mental excitement 3. - With a sufficiently high dose in the stage of Stoned the senses may be heightened and distorted with a relaxed, peaceful calm - May experience synesthesia - Loss of normal sense of time - Light aversion - With the peak of intoxication hallucinations may be experienced - Withdrawn and difficulty in interacting with others - Reflective with metaphysical or philosophical thoughts 4. - When Coming Down there may be hunger (“munchies”) and craving for sweet food and drink - Sleep with colorful dreams 2830/7.15c

  29. Marijuana (Cont.) Acute Toxicity - Vomiting, dizziness and headache - Possible intense fear and panic-like attack Withdrawal Syndrome - Decreased appetite - Sleep-related difficulties - Weight loss - Psychological changes including anger, aggression, irritability, restlessness, - strange dreams Many Questions About Chronic Toxicity - Concerns about persisting cognitive deficits and increased mental illness - Conflicting opinions and studies - Lack of prospective studies and data 2830/7.15d

  30. Basic Cannabinoid Structure and Numbering Systems 2830/7.16

  31. Low Dose (2 mg*) •Reduces anxiety •Mild euphoria (a little giddy) Medium Dose (5 mg) •Things become very amusing •Difficulty in completing thoughts •Slowing of perception of time •Increased awareness of internal state High Dose (10-15 mg) •Perceptual changes •Afterimages •Quiet •Slowing of time and movement •Seeing images with eyes closed •Marked motor impairment; may be unable to move *1 joint ≈ 1 mg Dose-Related Effects of Marijuana 2830/7.17

  32. • Memory impairments •Amotivational state •Paranoia •Lung and respiratory disease •Cardiac arrhythmias •Younger and younger users Concerns with Marijuana 2830/7.18

  33. Localization of Rat Brain Cannabinoid Receptorsby [3H]CP 55,940 Autoradiography 2830/7.19

  34. Structures of (left) Delta-9-Tetrahydrocannabinol (THC)and (right) Anandamide, an Endogenous Ligandof the Cannabinoid Receptor (i.e., endocannabinoid) 2830/7.20

  35. There are Several Proposed Signal Transduction Mechanisms of Cannabinoid Receptors 2830/7.21

  36. Retrograde Signaling by EndocannabinoidsReduces GABAergic Inhibition ofPyramidal Neurons in the Hippocampus 2830/7.22

  37. Dronabinol (Marinol) – Synthetic THC in Sesame Oil •Appetite stimulant in AIDS patients. •Treatment for nausea and vomiting associated with chemotherapy. •Reduce muscle spasms and pain in MS. •Reduce intraocular pressure in glaucoma. •Antidepressant and analgesic actions are claimed. •Neuroprotective effects against effect of head trauma, stroke or ischemic insult. Therapeutic Uses of Marijuana 2830/7.23

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