PSYC 383 Lecture 9 PDF

PSYC 383 Psychopharmacology: Lecture 9 – Hallucinogens: Psychedelics & Dissociatives The Liminality Crisis How do we tell the difference between what is real and what is illusory? Liminal states of mind are subjective crisis points: the apex of uncertainty in perception and/or belief Fro...

PSYC 383 Psychopharmacology: Lecture 9 – Hallucinogens: Psychedelics & Dissociatives The Liminality Crisis How do we tell the difference between what is real and what is illusory? Liminal states of mind are subjective crisis points: the apex of uncertainty in perception and/or belief From liminal states, our assumptions about the nature of reality are challenged Is my mind perceiving or creating reality? Where do I end? Where does environment begin? Am I who I’ve been thinking I am? What is “I”? Intense liminal crises can lead to one of several possible outcomes, including: Panic, paranoia, denial Surrender (Pan-)agnosticism Courage and wisdom  Psychedelics “…the feature that distinguishes psychedelic agents from other classes of drugs is their capacity reliably to induce or compel states of altered perception, thought, and feeling that are not (or cannot be) experienced otherwise except in dreams or at times of religious exaltation” Jerome Jaffe (1990) Drugs and Dream Similarity (Sanz et al., 2018) Drugs and Dream Similarity (Sanz et al., 2018) Brief History of Psychedelics Psychedelics History of Psychedelics Psychedelics have been used by indigenous peoples of nearly every continent for millennia Ceremonially, ritualistically/mystically, medicinally, as performance enhancers, etc. The term psychedelic comes from Greek words that mean “mind manifesting”, coined by Humphrey Osmond (with Aldous Huxley) First isolated psychedelic was mescaline by German chemist Arthur Heffter in 1897 MDMA first synthesized in 1912, but resynthesized and popularized by Sasha and Ann Shulgin in 1965 and used in therapy during the 70’s & 80’s LSD first synthesized in 1938 by Albert Hofmann, and psychedelic properties accidentally discovered in 1943 - “bicycle day” All psychedelics placed on Schedule I of the Controlled Substances Act, MDMA added in 1985 by DEA, counteracting federal judge ruling Clinical History of Psychedelics Termed “psychotomimetics” by early researchers and were thought to induce schizophrenic-like symptoms Later renamed due to lack of experiential overlap Early clinical uses included treatment for alcoholism & other addiction (smoking), autism Psilocybin and LSD psychotherapy improves alcoholism, OCD signs MDMA (entactogen rather than a psychedelic) used in the late 70s, early 80s primarily by psychiatrists for couples counselling Classes of Psychedelic Drugs Two primary structural classes that correspond to a minor functional difference: the phenethylamines and the tryptamines Phenethylamines: Mescaline Mescaline is the prototypical psychedelic phenethylamine, found in several species of cactus including peyote and san pedro However, it is one of the weaker phenethylamines Used and legally protected in traditional Native American religions, often made in tea First artificially synthesized in 1919 and later popularized to western audiences by Aldous Huxley in his book “The Doors of Perception”, describing visual fractals, synaesthesia, time distortions, etc. Half-life of about 6 hours Phenethylamines: MDMA, MDA, etc. Often referred to as “entactogens” (from “touch” - empathy inducing) rather than psychedelics, but with some similar pharmacology Potent releaser of all monoamines (5-HT, DA, NE) resulting from binding at transporter sites (SERT, DAT, NET), but also has affinity as an agonist at M1, M2, α1, α2, β, 5-HT1, 5-HT2, D1, and D2 receptors Unlike most psychedelics, MDMA is neurotoxic on serotonergic neurons at high doses and can induce serotonin syndrome Psychological effects include euphoria, increased emotional empathy (emotional contagion, suggestibility), decreased cognitive empathy Substituted Phenethylamines 2,5-Dimethoxy-4-[x]-amphetamine DOM (methyl), DOI (iodine), DOB (bromine), DON (nitrogen), DOC (chlorine) 2C-x family of research compounds are similar, differing in the placement of the NH2 group 2C-B, 2C-I, 2C-E, 2C-P, etc… NBOMe (addition of a benzyl ring on the N) otherwise virtually identical to the 2C-X family, but can have radically different affinities Variably potent psychedelics, lethal at high doses Tryptamines: Psilocybin Classical and naturally derived psychedelic from the Psilocybe genus of mushrooms - used ritualistically and medicinally in many religious/cultural practices Psilocybin is converted rapidly into psilocin with similar pharmacological effects, binding affinities Can also contain psychoactive (nor)baeocystin Consistently ranked as one of the least harmful illegal drugs, and considerably less harmful than alcohol and tobacco Approximately 12% of the adult population of North America have consumed psilocybin at least once Tryptamines: Bufotenin From bufo alvarius - Sonoran desert toad that produces bufotenine The toad produces the psychedelic bufotenin as an excretion through its semi-permeable skin Not as commonly used as other psychedelics due to the difficulty of acquiring these toads Similar pharmacology to other tryptamines Extremely high LD50 - also found in some Caribbean and South American plants Tryptamines – DMT, 5-MeO-DMT Ayahuasca: One of several ritualistic brews made from vines and other Amazonian plants by several indigenous South American peoples contains the psychedelic dimethyltryptamine (DMT), and other psychoactive compounds such as harmine and harmaline (MAO inhibitors) Ayahuasca has been used for millennia and is now being tested for its use in treatment-resistant depression and addictions 5-MeO-DMT also found in many plants and one toad species, usually smoked in purified form with brief, intense psychedelic effects Lysergic Acid Diethylamide (LSD-25) Bicycle Day – April 19, 1943 "... Little by little I could begin to enjoy the unprecedented colors and plays of shapes that persisted behind my closed eyes. Kaleidoscopic, fantastic images surged in on me, alternating, variegated, opening and then closing themselves in circles and spirals, exploding in colored fountains, rearranging and hybridizing themselves in constant flux …" Albert Hoffmann LSD Ultimately derived from ergotamine found in ergot, a fungus that grows on rye or sorghum hosts Can be crystallized and stored in a variety of ways; the most common administration route is oral (blotter paper) Much more diverse or rich receptor affinities than other psychedelics, accounting for some of its unique psychological effects Was used widely in psychiatric contexts before scheduling, for treatment of alcoholism and other disorders MKUltra - declassified CIA use of LSD for mind control Canadian connection: Dr. D. Ewan Cameron at McGill University Psychological Effects of Psychedelics The half-lives of psychedelics vary considerably, but experiences follow a similar qualitative pattern of expression based on dose Short-length experiences can last 1 hour or less (DMT), medium-length can last 4-6 hours (psilocybin), and long ones >12 hours (LSD) Psychological Effects of Psychedelics Recall that all drug experiences are a result of dose, set, and setting Many subjective effects involve altered and/or mystical states of consciousness; frequently associated with ecstatic states, can devolve into states of anxiety/despair The Marsh Chapel “Good Friday” Experiment (1962): Divinity degree graduate students given high doses of psilocybin or niacin Houston Smith among the students (comparative religion scholar) “The most powerful cosmic homecoming I have ever experienced” At 8–16 months after psilocybin sessions, more than 60% of subjects rated the experience as “very enriching,” and more than 90% described it as enriching to at least a medium degree (Studerus, 2011) Not directly linked to mental health problems, suicide (Johansen and Krebs, 2015; Jones & Nock, 2022)  Psychological Effects of Psychedelics Enhanced suggestibility, emotional responses to music and other perceptual stimuli (food, sex, etc.) Enhanced interpersonal closeness, gratitude, life meaning/purpose, forgiveness, death transcendence, satisfaction with life, mindfulness Increased implicit emotional empathy, but no effect on cognitive empathy Reduced psychological distress, general psychopathological symptoms (on average) Psychological Effects of Psychedelics  Psychological Effects: Perception Visual Perception: Binocular rivalry - two images presented in either eye, perception of each image typically alternates in relatively rapid succession Reduced binocular rivalry switching and increased image blending duration after psilocybin (Carter et al., 2007) Psilocybin reduces global, but enhances local motion sense (Carter et al., 2004) Decreased coherence sensitivity in random dot patterns Reduced tracking performance (at high doses) Reduced object completion (Kanizsa figures) is correlated with reduction in N170 ERP component in EEG (Kometer et al., 2011) Colour enhancement is very common Psychological Effects: Perception Psychological Effects: Perception Effects on Auditory Perception: Enhanced emotional responses to music facilitates trance states Effects on Time Perception: Time distortion is common in both directions, but short intervals are more frequently perceived to last longer (e.g., minutes feel like hours or vice versa) Reduced ability to reproduce interval durations longer than 2.5s (typical is ~4s) High dose psilocybin slows down the preferred tapping rate from ~700ms to ~950ms, Time distortion may reflect effects on short term memory (Wittmann et al., 2007) Effects on Sleep: General increase in wakefulness, reduction of both REM and slow-wave sleep DOI decreases the number but not the duration of REM episodes blocked by 5-HT2A antagonist ketanserin  Psychological Effects: Personality Psilocybin is the only known pharmacological agent (so far) to produce a (presumably) permanent change in a personality dimension: Openness to experience significantly increases after psilocybin use, contingent on the induction of a “mystical” experience on the SOCQ (States of Consciousness Questionnaire) Psychological Effects: Personality A follow-up study revealed other dimensions affected by acute psilocybin experiences Increases in openness, extraversion, and conscientiousness Decreases in neuroticism Psychedelics and Nature-Relatedness Lyons & Carhart-Harris (2018) Pilot study of psilocybin effects on patients with treatment-resistant depression (n=14) Authoritarianism - contrasted with libertarianism, emphasizes limitations to individual freedoms (PPQ-5 scale) decreases after psilocybin use Nature relatedness - defined as “the subjective sense of connection with the natural environment” (NR-6 scale) increases after the use of psilocybin Psychedelics and Nature-Relatedness  Psychedelics and Nature-Relatedness Lifetime experience with psychedelics predicts pro-environmental behaviour and knowledge about climate change Correlational studies (Forstmann et al., 2017; Longo et al., 2022; Sagioglou et al., 2022) Perhaps only psilocybin (Forstmann et al., 2023) Nature-relatedness is enhanced: NR-6 questionnaire administered online to 654 participants before and after psychedelic Baseline NR-6 score correlated with previous use, and increases in scores at 2-, 4-weeks and 2- years post predicted improvements in mental well-being Kettner et al., 2019 Psychological Effects: “Mystical” There is a wide variety of possible psychedelic experience, but a consistent sequence seems to emerge as a function of dose, and to a lesser extent set and setting (Masters & Houston, 1967): The Sensory Realm: Visual, auditory, synesthetic, etc., a “perceptual feast” (synaesthesia) The Recollective-Analytic Level: Personal problems, relationships, and life-goals examined The Symbolic Level: Profound self-understanding and self-transformation The Integral Level: Confrontation with “the Ground of Reality”, God, Mysterium, Noumenon, Essence, or “Fundamental Reality” Almost always considered to be a “religious” experience Psychological Effects: “Mystical” Griffiths et al. (2019) study comparing non-user mystical experiences with psychedelic mystical experiences – the biggest difference is the label “God” Non-drug (N = 809) Psilocybin (N = 1184) LSD (N = 1251) Ayahuasca (N = 435) DMT (N = 606) Common experience: communication with (a) benevolent, intelligent, sacred, eternal, all-knowing being(s) 2/3 of atheist subjects no longer identified as such after psychedelic use Psychological Effects: “Mystical” 10 Minute Break Mechanisms of Action All psychedelic drugs act as agonists for the 5-HT2A receptor, which is necessary but not sufficient for the psychedelic experience The major pharmacological differences between psychedelic classes: Phenethylamines: 5-HT2A, 5-HT2C Tryptamines: 5-HT2A, 5-HT2C, 5-HT1A Lysergic Acid (LSD): 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A, 5-HT6, 5-HT7, D1, D2, D3, D4, α1 Importantly, the mGlu2 receptor must be coactivated with 5-HT2A in order to generate the psychedelic response 5-HT2A and mGlu2 form a functional heterodimer in the cortex Mechanisms of Action Mechanisms of Action Neurophysiology Unexpected decreases found in thalamus, ACC, PCC, and medial prefrontal cortex Reduced “hub” area activity and areas of the DMN correspond to “ego-dissolution” Novel Functional Dynamics Novel Functional Dynamics Not only are there novel brain states that are only achievable through the use of psychedelics, the probabilistic transition dynamics between functional states is changed Red arrow = increased likelihood; Blue arrow = decreased likelihood Unified, Default Doral- Somato- Ventral Limbic Visual Non-specific mode Attention motor Attention Novel Functional Dynamics REBUS - Relaxed Beliefs Under Psychdelics A recently proposed model for how psychedelics work involves a synthesis of several previous brain models: 1. The Free-Energy Principle (Friston, 2005; 2010) 2. Hierarchical Predictive Coding (Huang & Rao, 2011; Wacongne et al., 2011) 3. Bayesian Brain Hypothesis (Knill & Pouget, 2004) 4. The Entropic Brain Hypothesis (Carhart-Harris et al., 2014; Carhart-Harris, 2018) Free-Energy Principle & Hierarchical Predictice Coding: The mind combines bottom-up and top-down information at multiple stages in a set of neural network hierarchies to optimize expected reward (or utility), and minimize prediction error (cost) Bayesian Brain Hypothesis: The primary mechanism by which “optimization” is negotiated is via Bayes theorem (ongoing statistical sampling) at each level of the hierarchy Hierarchical Predictive Coding The Entropic Brain Hypothesis Entropy is a measure of order vs. disorder in an information structure, all other things being equal All conscious states can be placed on an entropy spectrum from low (rigid) to high (flexible) The increase in functional connectivity throughout the brain resulting from use of psychedelic drugs can be described as entropy gain Clinical Applications: Anxiety & Depression State-Trait Anxiety Inventory scores show significant reductions in trait anxiety at both 2 and again at 12 months after LSD session compared to baseline (Gasser et al., 2014; 2015) Significant reduction in end-of-life anxiety and depression in patients diagnosed with terminal cancer after treatment with psilocybin (Griffiths et al., 2016; Ross et al., 2016) Treatment-resistant patients were treated with psilocybin and placed in an fMRI scanner - all patients showed decreased scores of depression after 1 week, half of patients at 5 weeks (Carhart-Harris et al., 2017) Decreased amygdala activity (cerebral blood flow) predicted outcome MDMA treatment reduced severe social anxiety in autistic adults (Danforth et al., 2018) High doses of MDMA produce fear amnesia and antidepressant effects (Pantoni et al., 2022)  Clinical Applications: Depression In a study of 26 treatment-resistant patients with depression, two psychotherapy-assisted sessions with 10mg and 25mg of psilocybin, respectively, yielded significant decreases in depressive signs (Carhart-Harris et al., 2018) “Two main change processes were identified in relation to the treatment. The first concerned change from disconnection (from self, others, and world) to connection, and the second concerned change from avoidance (of emotion) to acceptance.” (Watts et al., 2017) Clinical Applications: PTSD MDMA is being explored as a treatment for treatment- resistant PTSD: Phase 3 clinical trials: 67% of subjects did not meet diagnostic criteria for PTSD on an 18-month follow-up to three MDMA sessions as measured on the CAPS-V (clinician administered PTSD scale) Compared to 32% for placebo Functional impairment decrease compared to placebo on the Sheehan Disability Scale Significant decrease compared to placebo on the Beck Depression Inventory-II Cause may be fear extinction & memory reconsolidation Decreased amygdala and insula activation, increased connectivity between the amygdala and hippocampus Eating disorder symptoms reduced by MDMA assisted therapy (Brewerton et al., 2022) Clinical Applications: PTSD Biopsychosocial Healing Lifetime classic psychedelic use is associated with a reduced odds of past year larceny/theft, assault, arrest for property crime/violent crime Lifetime use of most other drugs is associated with increases Psilocybin use has “protective effect for antisocial criminal behavior” “Among women who did not use psychedelics, prescription opioid use increased the hazard of suicide… whereas prescription opioid use was not associated with suicidal ideation or attempt among those who used psychedelics” (Argento et al., 2018) Historical use in couples counselling, autism, body dysmorphia Prolonged pro-environmental and anti-authoritarian attitude increases after single instance of psychedelic use (but perhaps only psilocybin) 10 Minute Break Dissociatives Dissociatives get their name from some of their most common effects: depersonalization, derealization, and dissociation Detachment from self, surroundings, and/or a sense of reality Most dissociatives act primarily through antagonism of NMDA, with variable affinity and differences in receptor binding profiles depending on the specific drug Dissociative is a term that refers to the characteristic subjective effect of depersonalization that occurs at high doses, where one has the feeling of observing oneself from the outside rather than as being a causal agent of one’s behaviour Many other subjective effects such as perceptual distortions and cognitive enhancements or impairments can also be elicited Dissociatives Salvia Divinorum Plant in the mint family - native to Oaxaca, Mexico The primary psychoactive molecule is salvinorin A Opioid κ-receptor agonist Unusual pharmacology, smoked salvia seeds generate dissociative effects for as short as five minutes, with residual effects lasting ~30 minutes Potential anxiolytic/antidepressant effects involve both κ-receptor and endocannabinoid action (CB1 receptor) Salvia Divinorum Subjective effects: Effects can range from euphoric to dysphoric Intense vestibular and interoceptive sensations changes in spatial orientation and body pressure Descriptions of revisiting childhood memories Cartoon-like imagery, contact with agential “entities” Pharmacological action: First known naturally occurring non-nitrogenous κ-receptor agonist Effects are blocked by quadazocine, a κ-receptor antagonist Tolerance does not generalize to ketamine (NMDA antagonists) No significant neurotoxic effects Effects depend on administration route (smoked vs. oral) Ibogaine Derived from Central African shrub Tabernanthe iboga, used for centuries by “shamans”, currently used by the syncretic bwiti religion Rapidly converted by the body into noribogaine Modern clinical use in treating addictions, especially alcoholism and opioid additions: non-competitive NMDA antagonist, reduces opioid withdrawal symptoms in mice Fatal at high doses from cardiovascular effects, induces whole body tremors at moderate doses Ibogaine Neuropharmacological effects: Receptors with high affinity for ibogaine: κ and δ opioid receptors, NMDA, mACh1/2, 5-HT3, σ1/2, NA channel Some affinity also for 5-HT2A, SERT, DAT Increases expression of GDNF (glial derived neurotrophic factor) Subjective effects: Distortions in the perception of time and space Cognitive distortions including thought loops and delusions Visual enhancement of colour and acuity, but also distortions Classical dissociation - feelings of observing oneself from outside Can be considered to simultaneously exhibit both psychedelic and dissociative subjective effects Dextromethorphan (DXM) Opioid-like compound found in many over-the-counter cough medication since the mid-20th century, taken orally & reduces pain Similar pharmacology to ketamine and PCP: non-competitive NMDA antagonist, Ca2+ channel antagonist other affinities include σ1, μ, β and α1 NE receptors, 5-HT1b/d There are proposed antidepressant effects of DXM at high doses Can be used to effectively treat the inappropriate laughing and/or crying (“pseudobulbar affect”) that is common in ALS Decreases motor cortex excitability, can treat excitotoxic symptoms Dextromethorphan (DXM) High doses of DXM can produce subjective effects that are similar to classical psychedelics, but with a dissociative component Dose-dependent positive correlation with hallucination and mysticism Phencyclidine (PCP) Potent dissociative with high abuse potential, similar pharmacology to other dissociatives: non-competitive NMDA, σ1, and nAChR antagonist also acts as an agonist at D2 and 5-HT2 receptors Model for schizophrenia: Induces prepulse inhibition deficits in both rodents and primates NMDA dysfunction can lead to secondary mesolimbic dysfunctions Perinatal administration of PCP seems to induce schizophrenia-like symptoms as rodents mature, deficits treated by clozapine Neurodegenerative effects also follow from perinatal PCP exposure Other receptors (D1, 5-HT1, 5-HT7, mGlu2/3) involved in the treatment of PCP induced deficits, including psychotomimetic effects Phencyclidine (PCP) Subjective Effects: Similar to the effects of ketamine but with stronger potency Psychomotor agitation, disorientation, can lead to aggression Slurred speech, unsteady gait, analgesia Delusions, hallucinations, loss of memory, erratic behaviour Ego dissolution (depersonalization), paranoia PCP is either smoked, taken orally, or injected Medial prefrontal cortex is activated after consumption of PCP via the hippocampus-mPFC pathway No impairments in attentional shifting in rats sensitized to PCP Social deficits resulting from chronic PCP use can be treated with oxytocin Ketamine Somewhat weaker in effect than PCP but more popular recreationally Again, typical dissociative pharmacology - principally antagonism at the NMDA receptor, but with affinities at several other receptors: potentiates GABAA μ, δ, κ, but not for analgesia Na+, K+, and Ca2+ channels adenosine receptors induces catecholamine release Originally used for sedation (and still is by veterinarians), but more recently being tested for likely anti-depressive effects Ketamine Like many other dissociatives (with the exception of salvia), there is a relatively high potential for abuse with ketamine use (e.g., John Lilly) Neurotoxic at high doses - functional brain differences in ketamine treated monkeys, reduced tyrosine hydroxylase, and apoptotic effects during brain development - reinforcement partially non-DAergic Ketamine stimulates DA release, especially in the mesocortical pathway Long term ketamine users show reduced D1 receptor binding in the PFC Ketamine Ketamine Ketamine & Depression "Twenty-four hours after a single infusion, [Montgomery-Asberg Depression Rating Scale] scores were reduced on average by 2.08 points on a 0 to 6 scale, and 81% of patients received a rating of 0 or 1 post-infusion.” (Price et al., 2009) Attenuation of burst firing in the lateral habenula is sufficient to produce antidepressant effect (Yang et al., 2018) “Among responders, median time to relapse after the last ketamine infusion was 18 days.” (Murrough et al., 2013) Ketamine & Depression