Hallucinogens Round Table PDF

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Round table discussion on all aspects of hallucinogens....

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Hallucinogens, PCP, and Ketamine – Chapter 15 - Powerful effects on perceptual and conscious processes Hallucinogenic Drugs - LSD (lysergic acid diethylamide), mescaline, psilocybin, bufotenine, dimethyltryptamine (DMT), 5-methoxy-dimethyltryptamine (5-MeO-DMT), and salvinorin A - Psychotomimetic (psychosis-mimicking), psychedelic (mind-opening), and hallucinogenic (hallucination-producing) - Mescaline o Many hallucinogens are synthesized by plants or are based on plant-derived compounds o Mescaline found in several species of cacti ( peyote cactus) - Psilocybin o Numerous species of mushrooms manufacture alkaloids with hallucinogenic properties o Major ingredients of these mushrooms are psilocybin and the related compound is psilocin o After ingestion, psilocybin is enzymatically converted to psilocin (psychoactive agent) - Dimethyltryptamine and Related Tryptamines o Found in number of plants indigenous to south America o DMT lacks bioactivity when ingested orally, because of liver metabolism (i.e., first pass metabolism) by monoamine oxidase (MAO); however, when smoked or taken by insufflation (snorting), it can produce a brief but intense hallucinatory experience o Ayahuasca (vine of the soul) is a strong reddish-brown drink created by peoples of the Amazonian rain forest. One plant provides DMT while the vine contributes several alkaloids called beta-carbolines, which inhibit MAO activity by blocking DMT breakdown by liver MAO, thereby permitting the substance to reach the brain and exert its hallucinogenic effects - LSD o LSD is a synthetic compound; structure based on a family of fungal alkaloids o Discovery of LSD:  First synthesized in 1938  Was interested in alkaloids taken from ergot  Began to combine lysergic acid (core structure in all ergot alkaloids) with other compounds  D-lysergic acid diethylamide (LSD-25)  Purpose was to generate a new circulatory and respiratory stimulant (analeptic)  Accidentally ingested small amount of newly synthesized LSD  hallucinations  Sandoz first marketed LSD in 1947 as Delysid for the purpose of helping patients with neuroses to uncover repressed thoughts and feelings o When LSD was reported to alter serotonergic activity, the finding generated excitement about the possibility of understanding human mental activity and behavior at a chemical and physiological level o One way of using LSD was in psycholytic therapy based on the concept of drug-induced “psycholysis” (psychic loosening or opening)  involves administering LSD in low but gradually increasing doses to promote the release of repressed memories and to enhance communication with the analyst o Psychedelic therapy – patient was given a single high dose of LSD with the hope of gaining insight into problems through a drug-induced spiritual experience o LSD active orally - NBOMes o N-benzylphenethylamines – 2010; new class of synthetic hallucinogens o First class 25I-NBOMe – I = presence of iodine atom on the phenyl ring

Subject to first-pass metabolism when consumed orally, so are usually taken by the sublingual or buccal routes of administration o Very potent  likely to overdose - Salvinorin A o DEA hasn’t listed the herb in its schedule of controlled substances o 31 states enacted legislation prohibiting human consumption o Salvinorin A is the principal psychoactive ingredient in Salvia o Few, if any, psychoactive effects are produced by swallowing Salvia, because the Salvinorin A is inactivated in the GI tract o Quickly and effectively absorbed through lungs when smoked  most rapid and intense hallucinogenic experience o Effects when smoking (like DMT) dissipates rapidly (within 15 minutes) o Most commonly reported by users:  Becoming objects, visions of various 2D surfaces/films/membranes, revisiting places from the past/childhood, loss of body/identity, various sensations of motion/being pulled or twisted by forces of some kind, incontrollable hysterical laughter, overlapping realities o Unique psychoactive profile Pharmacology of Hallucinogenic Drugs - Different Hallucinogenic Drugs Vary in Potency and in their Time Course of Action o LSD as most potent  Salvinorin A  25I-NBOMe  Psilocybin  DMT  Mescaline o Ones taken orally generally have same time course but also dependent upon dose o Smoking DMT and Salvia release effects within seconds, reach a peak in a few minutes, and are over within an hour or less - Hallucinogens Produce a Complex Set of Psychological and Physiological Responses o LSD trip can be divided into 4 phases: (1) onset, (2) plateau, (3) peak, (4) comedown o LSD trips occur about 30 mins to 1 hour after administration  visual effects with intensification of colors and patterns or strange objects seen when eyes closed  next two hours are plateau phase where subjective sense of time slows and heightened visual effects  peak phase begins after 3 hours and lasts for another 2-3 hours; user feels as if in another world (time has been suspended, may experience synesthesia)  comedown may last 2 hours or longer o Good or bad trip dependent on: the dose, the individual’s personality, expectations, previous drug experiences, and the physical/social setting o Altered states of consciousness (ASC) rating scale has 5 primary dimensions: oceanic boundlessness, ego-disintegration anxiety, visionary restructuralization, reduced vigilance, and auditory alterations  Oceanic boundlessness: derealization and loss of ego boundaries (feeling one with the world) which corresponds to the positive mystical experiences often reported by users  Ego-disintegration anxiety: drug-induced thought disorder as well as negative emotional responses to the loss of ego boundaries  Visionary restructuralization: distortion of visual perception o Physiological responses, in the case of LSD, reflect activation of sympathetic nervous system and include pupil dilatation, small increases in heart rate, blood pressure, and body temperature - Most hallucinogenic drugs share a common indoleamine or phenethylamine structure o Most have either a serotonin-like or a catecholamine-like structure o

Serotonin-like (indoleamine) hallucinogens include LSD, psilocybin, psilocin, DMT, 5MeO-DMT, and synthetic tryptamines o Only mescaline and NBOMes have a catecholamine-like structure and are structurally related to NE and amphetamine o Mescaline, NBOMes, DOM, and TMA are known as phenethylamine hallucinogens o The most unusual structurally is Salvinorin A Indoleamine and phenethylamine hallucinogens are 5-HT2A receptor agonists o LSD binds with high affinity to at least 8 different serotonergic receptor subtypes  Other classical indoleamine hallucinogens such as psilocybin and DMT possess similarly nonselective serotonergic receptor binding profile o Phenethylamine hallucinogens (mescaline, DOM, NBOMes) only bind with high affinity to the class of 5-HT2 receptors o Both classes are 5-HT2A receptor agonists, and the hallucinogenic properties of these compounds require activation of this receptor subtype o When LSD binds to target, a kind of “lid” formed by part of the receptor protein closes over the binding pocket, temporarily trapping the drug in place o Drug-induced head twitch response and drug discrimination tests screen for hallucinogenlike effects Salvinorin A is a K-opioid receptor agonist o Has little effect on 5-HT2A or any other 5-HT receptors o Potent agonist at the k-opioid receptor o Proposed involvement of thalamus, temporal cortex, parietal cortex, and claustrum The neural mechanisms underlying hallucinogens are not yet fully understood o EEG and fMRI o EEG studies show that hallucinogens disrupt the normal rhythmic oscillations measured in cerebral cortex, probably because of excitation of 5-HT 2A receptor-expressing pyramidal neurons in layer 5 of prefrontal cortex and other cortical areas o Oscillatory activity depends on a glutamatergic network and its disruption helps account for some of the consciousness-altering aspects of a trip o fMRI study with ayahuasca suggests an association of visual perceptual changes with neural activation in the primary visual cortex Hallucinogenic drug use leads to adverse effects in some users o Don’t produce physical withdrawal symptoms after chronic use o Hallucinogen dependence syndrome has been identified in small percentage of users o DSM-5 contains category called other hallucinogen use disorder o Most hallucinogenic drugs produce rapid tolerance with repeated use o Hallucinogen tolerance has been linked to 5-HT 2A receptor down-regulation o Mescaline hasn’t been found to produce 5-HT2A down-regulation despite the fact that it can produce behavioral tolerance similar to that seen with indoleamine hallucinogens o Bad trip – experiencing an acute anxiety or panic reaction in response to the drugs effects; rare when users are prescreened for emotional stability and the environmental conditions are carefully controlled o Flashbacks and a more serious problem called hallucinogen persisting perception disorder (HPPD) o In HPPD, severe perceptual symptoms persist for a long period of time following drug use and are experiences sufficiently frequently to cause significant distress or impairment to the individual o Most severe reactions are toxic reactions that may involve psychiatric and/or somatic symptoms depending on the drug and the dose o

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Numerous reports of NBOMe users suffering from delusions, severe agitation and aggressive behavior, seizures, tachycardia, hypertension, extreme hyperthermia, rhabdomyolysis (muscle breakdown), and kidney damage - Can hallucinogenic drugs be used therapeutically? o Therapeutic use of hallucinogens was quickly abandoned when LSD and other hallucinogens were given a Schedule I designation in the 1970 schedule of controlled substances o Peak experience is the desired subjective state during the period of drug action. There are 6 elements: (1) sense of unity or oneness (2) transcendence of time and space (3) deeply felt positive mood (4) sense of awesomeness, reverence, and wonder (5) meaningfulness of psychological or philosophical insight or both, and (6) ineffability (sense of difficulty in communicating the experiences by verbal descriptions) o Afterglow is the second therapeutic component where mood is elevated and energetic; there is a relative freedom from concerns of the past and from guilt and anxiety, and the disposition and capacity to enter into close relationships is enhanced o Being studied for treatment of drug addiction, major depression, and ODC, and for helping the terminally ill patients cope with fear and anxiety associated with impending death PCP and Ketamine - Phencyclidine (PCP) and ketamine - Tried to use PCP as anesthetic  trancelike or catatonic-like state characterized by a vacant facial expression, fixed and staring eyes, and maintenance of muscle tone - Ketamine came into being as a safer alternative to PCP (less potent and shorter acting) Pharmacology of PCP and Ketamine - Methoxetamine is a ketamine analog - PCP and ketamine produce a state of dissociation o PCP reported feelings: detached from body, sensation of vertigo or of floating, numbness, dream-like state o PCP affective reactions: drowsiness, apathy, loneliness, negativism or hostility toward the experimenters, or alternatively feelings of euphoria and inebriation o PCP  marked cognitive disorganization manifested by difficulty in maintaining concentration or focus, deficiencies in abstract thinking, and halting speech o Low doses of ketamine yielded reactions similar to those mentioned for low-dose PCP o When participants received anesthetic doses of ketamine they seemed to lose all mental contact with their environment for 10 mins or longer (but eyes open and retained muscle tone)  dissociative anesthesia o Dissociative anesthesia applies to both PCP and ketamine o The state of being (“k-hole”) can be described as spiritually uplifting or terrifying o When administered at anesthetic dose, drug disrupts cortical information transfer, especially between frontal and posterior cortical regions (dissociative role) - PCP and ketamine are noncompetitive antagonists of NMDA receptors o NMDA receptor is an important ionotropic receptor for the excitatory amino acid neurotransmitter glutamate o They both block the receptor at a site different from where the site at which glutamate or NMDA binds o Cerebral cortex and hippocampus contain significant numbers of NMDA receptors, and blockade of the receptors in these areas  cognitive deficits from PCP and ketamine o Another potential mechanism of PCP and ketamine is increased presynaptic glutamate release (therefore overactive glutamate transmission via non-NMDA receptors) within the cortex, which is a secondary consequence of NMDA receptor antagonism o

PCP/Ketamine Models of Schizophrenia  Researchers argued that LSD symptoms were similar to those observed in patients with schizophrenia  LSD and other hallucinogens produce mainly visual distortions whereas hallucinations in patients with schizophrenia are usually auditory  Hallucinogens fail to produce negative symptoms of schizophrenia, which include reduced speech, flat affect, and social withdrawal  LSD model of schizophrenia was replaced by model involving subjective and behavioral effects of PCP or ketamine  High dose of ketamine/PCP  disordered thought, delusions, motor disturbances, maybe some negative symptoms  Studies demonstrated an exacerbation of symptoms in patients with schizophrenia following ketamine and PCP administration  glutamate hypothesis of schizophrenia = hypoactivity of the glutamatergic system is a key factor in the pathogenesis of the disorder  Reduced NMDA receptor subunit expression in postmortem brain tissues from patients with schizophrenia PCP and Ketamine have significant abuse potential o Both highly reinforcing in animal species o Both subject to use and dependence o Prevalence of ketamine use and abuse is currently much greater than PCP o Reinforcing Effects  Monkeys self-administered PCP at high doses to be intoxicated continuously  They couldn’t support themselves on 4 legs  awkward sitting position  PCP and ketamine activate midbrain dopamine (DA) cell firing and stimulate DA release (PFC)  enhancement of dopaminergic neurotransmission could contribute to reinforcing effects o Use and Abuse  Individuals using PCP have found drug combinations in which tobacco or marijuana cigarettes are dipped in a liquid containing PCP  Accounts of dose escalation and compulsive use (ketamine)  Several other noncompetitive NMDA receptor antagonists are also used recreationally for their psychoactive properties (dextromethorphan – over-thecounter cough and cold meds) Use of PCP, ketamine, or related drugs can cause a variety of adverse consequences o Chronic use  negative effects o Ketamine users: distressing urological symptoms including cystitis (bladder inflammation), painful urination, and incontinence (severe  kidney damage); some develop GI disturbances, deficits in memory and other cognitive functions, greater delusional thinking o Brain imaging studies found evidence for both gray and white matter abnormalities in chronic ketamine users o Reports of increased D1 dopamine receptor binding in the PFC of ketamine users  may be a result of decreased presynaptic dopaminergic transmission in this area o Repeated treatment with high doses of ketamine provokes apoptotic cell death in developing brain of both rats and monkeys o Evidence for ketamine-induced disruption of neurogenesis (formation of new nerve cells) during early brain development o Some preliminary findings suggest that exposure to general anesthesia in infancy or early childhood may be associated with later cognitive deficits o

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Novel therapeutic applications have been proposed for ketamine o Recent research suggests ketamine may have additional therapeutic applications in the treatment of major depression and in pain relief o SSRIs take several weeks of administration before significant therapeutic benefits o A single IV dose of ketamine has been demonstrated to produce rapid, although temporary, symptom improvement in clinically depressed patients o Clinical trials under way to determine whether ketamine or similar NMDA receptor antagonist could be developed as an approved treatment for major depression o Since tolerance to repeated opiate drug treatment is partially mediated by the NMDA receptor, an additional benefit of ketamine administration is the ability to reverse opioid tolerance

Pre-Quiz Please, respond the quiz by highlighting your answers Once completed, please send it to [email protected] 1. Select two true statement: a) Many hallucinogenic drugs either are synthesized by plants or are based on plantderived compounds b) Both DMT and LSD are a synthetic compounds c) Ayahuasca lacks bioactivity when ingested orally because of liver metabolism d) Plant-derived NBOMes are very potent which makes it easy for the user to overdose e) Salvinorin A is inactivated in the gastrointestinal tract 2. Select two FALSE statements: a) Both LSD and DMT have a serotonin-like structure b) Both NBOMes and DMT have a catecholamine-like structure c) Mescaline is structurally related to the neurotransmitter norepinephrine (NE) as well as to the psychostimulant amphetamine d) Both serotonin-like and catecholamine-like hallucinogens are 5-HT2A receptor antagonists e) LSD binds with high affinity to at least eight different serotonergic receptor subtypes 3. Select two FALSE statements: a) Hallucinogens lack the high degree of abuse potential b) Hallucinogens do not produce physical withdrawal symptoms after chronic use c) Hallucinogen dependence has not been identified in users of hallucinogenic drugs d) Most hallucinogenic drugs do not produce rapid tolerance with repeated use e) Flashbacks are potential complications of hallucinogen use 4. Select one FALSE statement: a) Both PCP and ketamine are anesthetic agents b) PCP and ketamine produce a state of dissociation c) PCP and ketamine are both noncompetitive antagonists at the NMDA receptors d) One of the potential mechanisms of PCP and ketamine action is decreased presynaptic glutamate release

e) High doses of PCP produces schizophrenia-like symptoms 5. Select two FALSE statements: a) Both PCP and ketamine are reinforcing drugs b) PCP is a widely used street drug c) PCP and ketamine activate midbrain dopamine cell firing and stimulate dopamine release in the prefrontal cortex d) Impaired (doesn’t impair but excites) dopaminergic neurotransmission in the mesolimbic pathway could contribute to PCP’s and ketamine’s positive reinforcing effects e) Chronic use of ketamine or PCP can produce many different negative effects...