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Chapter 12

PSYC62H3 Chapter 12: Psychedelic Drugs

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University of Toronto Scarborough
Zachariah Campbell

Chapter 12: Psychedelics  induce a reality-altering experience consisting of hallucinations, sensory distortions, or delusions  further classified into hallucinogens, mixed stimulant-psychedelics, and dissociative anesthetics Hallucinogens  Represent a large class of psychedelic drugs that produce hallucinations at their main pharmacological effects  LSD (lysergic acid diethylamide) = most representative hallucinogen psychedelic drug o LSG and its precursor, lysergic acid, are schedule I controlled substances  Other hallucinogens include: o Psilocybin: main psychoactive constituent in hallucinogenic mushrooms “shrooms” o Mescaline: found in peyote cactus native to southern North America  users chew disk-shaped buttons within the cactus crown o Dimethyltryptamine (DMT): found in hallucinogenic South American plants  the body produces small amounts of endogenous DMT LSD Ingestion and Effects  LSD and most other hallucinogens are normally orally administered  LSD is highly potent, with effective amounts beginning at 0.025 mg  A common preparation method involves applying drugs of a LSD solution on squares of blotter paper or postage stamps and users lick the paper  LSD through oral administration route reaches peak absorption after 60 minutes and is metabolized by cells in the liver  LSD’s elimination half-life is approximately 3 hours, with pharmacological effects lasting as long as 8 hours LSD and the Serotonin Neurotransmitter System  Chemical structure of LSD resembles serotonin’s chemical structure, allowing LSD to act as a receptor agonist with a high binding affinity for 5-HT1A, 5-HT2A, 5-HT6, and 5- HT7 receptors  LSD activates serotonin receptors postsynaptically on other neurotransmitter neurons such as glutamate and GABA neurons  In the visual cortex, LSD activates both 5-HT1A and 5-HT2A receptors o Hallucinogenic activation of serotonin receptors can interfere with modal object completion o N170 waveform through EEG recordings is strongly associated with modal object completion  LSD-like hallucinogens inhibit both modal object completion and weaken the N170 waveform amplitudes in the visual cortex o Reduced N170 waveform amplitudes correlated with overall decreased activity in the occipital lobe  Hallucinogens alter functioning in the locus coeruleus o LSD’s activation of post synaptic 5-HT2A receptors increases the activity of both glutamate and GABA neurons  causes normally suppressed sensory information from locus coeruleus to cerebral cortex becomes more refined and salient  In the PFC, LSD activation of 5-HT2A receptors causes increased glutamate release o Increased glutamate release then increases activity in the PFC, a central integration area for processed sensory information o Enhanced activity levels in the PFC and temporomedial cortex occur while individuals experience visual hallucinations LSD’s Mild Physiological Effects and Profound Hallucinogenic Effects  Few, if any, physiological effects occur with normally used amounts  at normally used doses, a person may exhibit only modest changes in heart rate, slight dizziness, increased pupil diameter, or mild nausea  LSD and other serotonin-like hallucinogens exhibit pronounced subjective experiences  True hallucination: perception of images or sounds that are not real  experience is rare  Pseudo-hallucinations are more common = altered perception of things that are real  Trip= overall hallucinogenic experience o Good trip= characterized by having highly desirable sensory distortions and pseudo-hallucinations  enhanced perception or insightfulness  User may also experience synesthesia: experiencing sensory stimuli in an incorrect sensory modality  e.g. experiencing sounds when seeing colours o Bad trip= disturbing true hallucinations, psychotic episodes, negative emotional states, altered perceptions of time, and out-of-body sensations Hallucinogens and Flashbacks  Flashback: random, short, and nondistressing memory of a previous hallucinogenic experience  Hallucinogenic persisting disorder: recurring, length, and unpleasant memory from a previous hallucinogenic experience Mixed Stimulant-Psychedelic Drugs  Substances that exhibit both psychostimulant and hallucinatory effects as their primary pharmacological effects  MDMA or Ecstasy  one such drug o Known for psychedelic and psychostimulant effects o Is an entactogen = “touching within” o Also known as an empathogen = enhanced empathy o Users become friendlier, exhibit closeness with others, and perceive greater insight into their thoughts and emotions  MDMA shares a similar chemical structure with amphetamine and possess many of amphetamine’s psychostimulant effects  MDMA also produces LSD-like hallucinations MDMA Metabolism and the Length of Psychedelic Drug Effects  MDMA is administered orally, usually through swallowing an MDMA-containing tablet  MDMA readily absorbs through the gastrointestinal tract, reaching peak blood plasma levels after approximately 2 hours  MDMA’s elimination half-life is approximately 9 hours  Recreational doses remain in the blood for at least 24 hours  MDMA is metabolized in the liber primarily by CYP2D6 enzymes and to a lesser extent by CYP1A2  CYP1A2 converts MDMA to MDA that also exhibits psychedelic drug effects  Deficiencies in CYP2D6 enzymes (found in 10% of Caucasians) lead to accumulation of MDMA in the body  leads to prolonged drug effects and an increased probability of adverse effects at low to moderate doses o Selective serotonin reuptake inhibitors (SSRIs) inhibit CYP2D6 activity, inhibiting MDMA metabolism o De la Torre et al (2000)  MDMA’s elimination rate = not constant, MDMA metabolism slows down over time  taking further MDMA doses contributes to stronger and longer-lasting pharmacological effects than may otherwise be expected MDMA and Serotonin and Dopamine Neurotransmission  Acute administration of MDMA alters serotonin neurotransmission at axon terminals through: o Prevents serotonin storage into vesicles and permitting escape to synaptic cleft o Reversing serotonin membrane transporters and expelling unstored serotonin out into the synaptic cleft  These two actions produce an increase in extracellular brain serotonin levels and an increased activation of serotonin receptors  MDMA produces similar actions at dopamine axon terminals, leading to enhanced extracellular levels of dopamine in the brain  But, MDMA’s effects on dopamine axonal terminals are weaker than its effects on serotonin axonal terminals  MDMA’s effects on serotonin and dopamine are dose-dependent o At lower doses, MDMA effectively inhibits serotonin entry into vesicles and reverses the direction of serotonin reuptake transporter o Few effects occur at dopamine axon terminals, producing minimal changes in dopamine release o At higher doses, MDMA remains effective at enhancing serotonin levels but now also inhibits dopamine entry into vesicles and reverses the dopamine membrane transporter direction  Chronic administration of MDMA can produce severe damage to serotonin neurons  loss of brain serotonin, serotonin metabolite 5-HIAA, tryptophan hydroxylase, and serotonin reuptake transporter o Hatzidimitriou et al, 1999  four days of administration led to significant reduction in serotonin neurons 2 weeks after treatment and 7 years after treatment o In humans, heavy MDMA users have less 5-HIAA in CSF, suggesting less serotonin production in the nervous system o PET imaging techniques in humans reveal lower levels of serotonin membrane transporters in routine MDMA users o In humans, MDMA-induced reduction in serotonin reuptake transporter levels may not be permanent MDMA’s Psychedelic and Psychostimulant Effects  MDMA’s physiological effects resemble those of psychostimulant drugs such as amphetamine at higher doses (activating the sympathetic nervous system)  Low MDMA doses elicit few physiological  both low and high MDMA doses elicit significant subjective effects  Kolbrich et al (2009)  low MDMA doses = feelings or sensations of heightened senses, racing thoughts, and euphoria  High MDMA dose = included these effects as well as perceptions of increased energy and feelings of closeness to others  The subjective effects of MDMA relate to both psychostimulants and hallucinogenic drugs  MDMA produces increases in a scale for drug “likeing” = indication of reinforcing effects  Based on animal models, MDMA exhibits reinforcing effects  MDMA is a representative drug for empathogens = enhanced empathy  Women appear more sensitive than men to
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