Psychedelic Drug

Psychedelic Drug 1

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E.C. Azmitia, in Encyclopedia of Human Behavior (Second Edition), 2012

Lysergic acid diethylamide (LSD)

LSD is a semisynthetic psychedelic drug of the ergoline family. The parent compound of the major hallucinogen LSD has long been known to be produced by a fungus, genus Claviceps. The hallucinogen was synthesized by the addition of diethylamide to ergotamine by the chemist Albert Hofmann at the Sandoz Laboratory. LSD is believed to be one of the most potent mind-altering compounds discovered to date. LSD causes hallucinations, distortions, and an altered experience of senses, emotions, memories, time, and awareness. There can be distortions of sensory perception such as synaesthesia, the experience of additional spatial or temporal dimensions, and temporary dissociation.

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Michael Lyvers, in Neuropathology of Drug Addictions and Substance Misuse, 2016

Mechanisms of LSD Action

Research on the pharmacodynamics of psychedelic drugs has revealed that the classic psychedelics have structural similarities to the ubiquitous neurotransmitter serotonin (see Figure 1) and are direct serotonin agonists, meaning they bind to and activate serotonin receptors, particularly the most common type of serotonin (or 5-HT) receptor, the excitatory postsynaptic 5-HT2 receptor. LSD additionally directly activates D2 dopamine receptors, which may pertain to differences reported between the effects of LSD and those of other psychedelics. In any case activation of 5-HT2 receptors by psychedelic drugs, including of course LSD, triggers a dramatic increase in release of the excitatory neurotransmitter glutamate in cortical, thalamic, and limbic regions (Hintzen & Passie, 2010; Vollenweider & Kometer, 2010), as represented schematically in Figure 2. The result is hyperactivation of the prefrontal cortex, or hyperfrontality, most prominently in the right hemisphere (Hasler et al., 2004; Vollenweider et al., 1997), the visuospatial, emotional, nonverbal side of the brain. Contrary to the outdated “waking dream” interpretation of psychedelic effects postulated in the 1970s (Jacobs & Trulson, 1979), physiologically the states induced by psychedelics are not at all akin to dream states but rather more resemble extremely amplified waking states, as serotonergic receptor activation is normally highest during waking and entirely ceases during rapid eye movement, or dream, sleep (Portas, Bjorvatn, & Ursin, 2000). The serotonin agonist action of psychedelics also results in strong sympathomimetic effects such as dilated pupils, muscle tremors, and increased heart rate and blood pressure, owing to serotonergic receptor-mediated activation of the brainstem locus coeruleus, which regulates the sympathetic nervous system. But current research points to excessive glutamate release in higher brain regions, particularly the prefrontal cortex, in response to strong stimulation of 5-HT2 receptors as the likely brain basis of the intense subjective effects of psychedelic drugs, including perhaps mystical experiences.

Figure 1. Structures of serotonin, LSD, psilocybin, and mescaline.

Figure 2. Model of psychedelic drug action via activation of 5-HT2 receptors and induced release of glutamate in the cortex. NMDAR, N-methyl-d-aspartate receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF, brain-derived neurotrophic factor; LSD, lysergic acid diethylamide; DMT, dimethyltryptamine.

Reprinted by permission from Vollenweider and Kometer (2010), © 2010, Macmillan Publishers Ltd.

Interestingly, research on near-death experiences has supported a glutamate overflow theory of this type of mystical experience as well (Borjigin et al., 2013; Jansen, 1997; Parnia, 2013), and a serotonergic mechanism of increased prefrontal cortical theta activity induced by Zen meditation has been suggested (Takahashi et al., 2005). Thus it appears possible that the mystical experiences sometimes reported following ingestion of a high dose of LSD and those reported by Zen Buddhist meditators, as well as by a significant minority of individuals who have clinically died and been resuscitated, may all have a common physical correlate in similar alterations in brain activity. If confirmed this would pertain to the controversy over whether a mystical experience induced or facilitated by LSD (or other psychedelics) is “genuine”; one may be tempted to argue that, from a scientific perspective, if similar alterations in brain activity are common to each, then a psychedelic mystical experience may be just as “genuine” as mystical experiences reported following clinical death and resuscitation or following an intensive period of Zen meditation aimed at attaining kensho (enlightenment). Furthermore the related question of which mystical experiences are “real” in terms of offering valid insights into the nature of self and reality naturally leads to other, perhaps (for some) uncomfortable questions about the fundamental nature of everyday subjective reality and its dependence on normal waking brain chemistry—a common insight reported by even nonscientifically oriented psychedelic drug users who have seen their own everyday reality rather emphatically shaken up by a potent brain-altering chemical agent such as LSD.

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David J. Hanson, in Principles of Addiction, 2013

LSD

LSD is a hallucinogen and psychedelic drug that is manufactured from the lysergic acid that occurs naturally in the ergot fungus that grows on wheat and rye. The liquid is typically applied to blotter paper squares, stickers, sugar cubes, candy, or soda crackers. LSD is also available in dropper bottles and in the form of gelatin sheets. There is no medicinal use for LSD; it is used recreationally as a hallucinogen and for its ability to alter perception and mood.

LSD creates hallucinations, reduced reaction time, diminished visual acuity, altered mental state, thought difficulties, delusion, temporary psychosis, and distorted time and space perception. Effects begin within 20–30 min, peak at 2–4 h, and gradually diminish over 6–8 h. Some effects may last longer. Flashbacks may occur suddenly, often without warning, and may occur within a few days or more than a year after use. The effects of LSD are unpredictable and depend on the dose, the user’s personality and mood, expectations, and surroundings.

Research suggests that the incidence of LSD in driving under the influence cases is extremely rare.

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T. Buchborn, … V. Höllt, in Neuropathology of Drug Addictions and Substance Misuse, 2016

Definition of Terms

Serotonergic hallucinogen

This is a psychedelic drug that by activation of serotonin 2(A) receptors provokes shaking behavior in (certain) mammals and alterations of consciousness in humans.

Tolerance

This is a consequence of repeated or long-term exposure to a drug; the organism over days, weeks, and months becomes less responsive to the effects of the drug.

Tachyphylaxis

This is acute tolerance to a drug. In consequence of a single exposure or multiple short-interval exposures to a drug, the organism within minutes and hours becomes less responsive to the effects of the drug.

Cross-tolerance

Tolerance to a drug can diminish the effects of another drug if the enzymes that degrade both drugs and/or the (receptor) targets that mediate the drugs’ effects overlap; this is called cross-tolerance.

5-HT2A receptor

This is a transmembrane protein highly enriched in the mammalian cortex cerebri that (upon occupancy by serotonin or serotonergic hallucinogens) regulates the cell’s physiology through interaction with G proteins.

Shaking behavior

This refers to head twitches and wet dog shakes. It is a behavior of (certain) mammals that is stereotyped by serotonergic hallucinogens. The mammal shows brisk rotational movements of head (and trunk) around the long axis of its body.

Limb flicking

This is a behavior of cats that is stereotyped by serotonergic hallucinogens. The cat lifts its paw, rapidly shakes it, or flicks it away from the body as if to remove a foreign substance.

Hallucinogenic pausing

This is also called hallucinatory pausing and refers to intermittent interruption of operant lever-press responding by rats, induced by serotonergic hallucinogens.

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Danilo De Gregorio, … Gabriella Gobbi, in Progress in Brain Research, 2018

3.1.2 A clinical reawakening

Nowadays, the stigmatization of psychedelic drugs is coming to the end due to the emergence of new organizations such as the Multidisciplinary Association for Psychedelic Studies (MAPS), the Heffter Research Institute, and the Beckley Foundation which are all allowing scientist to revisit the potential use of psychedelic drugs (Sessa, 2012). Finally, new studies carried out by modern pioneers, especially in Europe by D. Nutt-Carhart-Harris and Vollenweider, confirm the dated results found in the 1950s, adding novel discoveries and increasing the hope that these compounds can be used as alternative drugs to treat mood disorders. In fact, after a silence of more than 25 years due to regulatory obstacles, the first double-blind, placebo-controlled trial investigated the therapeutic properties of psilocybin in patients with advanced-staged cancer and associated mental health problems such as anxiety and acute stress disorder (Grob et al., 2011). Psilocybin was chosen instead of LSD due to its shorter duration of action (4–6 h) compared to LSD (8–12 h). The study was divided into two experimental sessions which took place in a specifically prepared hospital room which provided a pleasant and comfortable setting. The patients received either psilocybin per os (p.o.) (0.2 mg/kg) or placebo in each session and the two sessions were separated by several weeks. This study revealed a dramatic reduction of anxiety symptoms at 1 month after the first treatment session and 3 months after the second session. Depressive state symptoms were reduced 1 month after the second session, reaching a statistically significant difference after 6 months. A recent double-blind cross-over design study investigated the effectiveness of high dose of psilocybin (22 or 30 mg/70 kg, p.o.), compared to an active low dose placebo (1 or 3 mg/70 kg, p.o.) to confirm psilocybin’s antidepressant effects (Griffiths et al., 2016). In this clinical trial, cancer patients showed a significant antidepressant response after 6 months post-administration, revealing also significant improvement in quality of life and acceptance of death. In a double-blind, placebo-controlled trial, a moderate dose of psilocybin (0.3 mg/kg, p.o.) was compared with an active placebo of niacin (250 mg, p.o.) in combination with psychotherapy in patients with cancer-related anxiety and depression. After 6.5 months post-single administration, patients exhibited a significant decrease in anxiety and depression symptoms, reduction of stress and improved quality of life (Ross et al., 2016).

Research has also examined the efficacy of psilocybin for patients diagnosed with treatment-resistant depression. In an open label study by the group of David Nutt, patients received two oral doses of psilocybin (10 and 25 mg, p.o., separated by 7 days) (Carhart-Harris et al., 2016a). Psilocybin was well tolerated without adverse events. Relative to baseline, depressive symptoms were strongly decreased 1 week and 3 months post-administration of the higher dose. The authors of the study reported improvements in patient anxiety and anhedonia. In an open-label 6 month follow-up of the patient’s progress, treatment remained well-tolerated and the reductions in depressive symptoms remained significant (Carhart-Harris et al., 2018). Interestingly, the robust decrease in depressive symptoms at 5 weeks post-treatment was strongly correlated with the quality of the patient’s immediate mind-altering experience. Building off their observation that the environment of the psychedelic experience affects patient outcome, the research group also assessed the influence of music in the clinical outcomes of psilocybin therapy (Carhart-Harris et al., 2018). Their results showed that patients’ exposure to the music facilitated the occurrence of “mystical experiences” and “insightfulness” and that the nature of the music experience was significantly predictive of reductions in depression 1 week post-single oral psilocybin (10 mg) administration. Environment, including music, may play a central therapeutic function in combination with psychedelic therapy.

While research has already begun to re-examine the efficacy of psilocybin in patients with anxiety and depression, there remains a lot more work to be done with LSD in these patient populations. A recent double-blind, randomized, placebo-control study carried out by Gasser and colleagues demonstrated the efficacy of LSD in assisted psychotherapy for the treatment of anxiety and depression in patients with a life-threatening disease (Gasser et al., 2014). An experimental dose of LSD (200 μg, p.o.) or active low dose LSD placebo (20 μg) was administered in two sessions separated by a 4–6-week interval. Two months after the second administration, the experimental (200 μg) dose of LSD induced a significant reduction of depressive symptoms which lasted up to 12 months post-treatment. Patients showed also a strong reduction of anxiety and fear of death along with an improved quality of life and physical well-being. To date, this placebo controlled study remains the only recent paper that examined LSD in a psychiatric patient population, emphasizing the need for more work to corroborate and expand on these results.

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Evan S. Herrmann, … Ryan Vandrey, in Neuropathology of Drug Addictions and Substance Misuse, 2016

DOx Compounds

DOx compounds are long-acting psychedelic drugs that act as highly selective 5-HT2A, 5-HT2B, and 5-HT2C receptor partial agonists. 2,5-Dimethoxy-4-methylamphetamine (DOM) was first synthesized by Alexander Shulgin in 1964; other analogs such as 2,5-dimethoxy-4-bromoamphetamine (DOB), 2,5-dimethoxy-4-chloroamphetamine (DOC), 2,5-dimethoxy-4-iodoamphetamine (DOI), and 1-(4-bromofuro[2,3-f][1]benzofuran-8-yl)propan-2-amine (Bromo-DragonFLY) followed. Various DOx compounds have been available on the illicit drug market for several decades, but none sustained popularity in the 20th century. DOM was prevalent on the black market in the 1960s, while recreational use of other compounds like DOC and Bromo-DragonFLY has occurred relatively recently (Corazza et al., 2011; Ovaska et al., 2008). DOx compounds have subjective effects similar to those of classic hallucinogens (e.g., lysergic acid diethylamide (LSD), mescaline), and since most of these compounds are quite potent (psychoactive in doses of a few milligrams or less) DOx drugs have been misrepresented/sold as LSD (Drug Enforcement Administration, 2009). DOx analogs are illegal in most countries, with some exceptions. For instance, DOC and Bromo-DragonFLY are unscheduled in the United States at the federal level, although they could be considered analogs of DOM/DOB, so possession or sale could be prosecuted under the Federal Analog Act.

DOx compounds are substituted amphetamine derivatives that are believed to elicit their behavioral effects via agonism of 5-HT2A receptors (Arvanov, Liang, Russo, & Wang, 1999), although some DOx compounds have very high affinity for other 5-HT receptor subtypes (Shannon, Battaglia, Glennon, & Titeler, 1984). There have been relatively few experimental studies of the behavioral effects DOx compounds. Research with laboratory rodents suggests that DOx compounds have effects unique from other amphetamines, but somewhat similar to classic hallucinogens like LSD and mescaline (Glennon, Young, Jacyno, Slusher, & Rosecrans, 1983; Silverman & Ho, 1980). Survey data collected from Bromo-DragonFLY users suggests the drug has unique pharmacokinetics/dynamics. Users report that the onset of effects can be delayed up to 6 h after ingestion, and that effects may last 2–3 days after consumption of a single dose (Corazza et al., 2011).

Use of DOx compounds has been associated with negative health outcomes. High doses of these drugs may cause cardiovascular complications (e.g., Bowen, Davis, Kearney, & Bardin, 1983). Use of Bromo-DragonFLY has been associated with toxic reactions, including symptoms of severe agitation and tonic–clonic seizures, and at least two deaths (e.g., Andreasen, Telving, Birkler, Schumacher, & Johannsen, 2009). These negative outcomes may be due to both the misrepresentation of these compounds as LSD and the relatively narrow therapeutic index of these drugs. Since the time to onset of DOx drugs like Bromo-DragonFLY is quite long, users may repeatedly redose under the assumption that their initial dose was too low and accidently ingest dangerous amounts of these substances.

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Adina Michael-Titus, … Peter Shortland, in The Nervous System (Second Edition), 2010

Hallucinogens

Drugs that induce mental changes similar to psychotic states are called hallucinogens or ‘psychedelic’ drugs. In 1938, the Swiss chemist Albert Hofmann synthesized the compound lysergic acid diethylamide (LSD), and a few years after its synthesis accidentally ingested some powder, subsequently experiencing the ‘mind-expanding’ properties of this compound. The effects (also known as ‘the trip’) were described as a ‘dream-like state’, during which sensory modalities fused. Hallucinations during which sensory modalities are mixed up are called ‘synesthetic’. Interestingly, such hallucinations are sometimes encountered in patients with temporal lobe epilepsy. The sense of time is generally disrupted but memory is unaffected. Feelings of total detachment and depersonalization may occur. Hallucinogens may affect mood, but the type of effect seen is context-dependent and depends on the mindset of the user. Good ‘trips’ as well as terrifying, bad ‘trips’ can be experienced by the same user. There is increased sympathetic activity, with increased blood pressure and pulse rate, dilated pupils and increased body temperature.

The structure of LSD and of other hallucinogens, such as the compounds extracted from the psilocybe mushroom (i.e. psilocybin) or the peyote cactus (i.e. mescalin), is very similar to that of serotonin. It is now well established that LSD can activate presynaptic 5-HT receptors and thus decrease the activity of raphe serotonergic neurones. This may underlie at least partly the effects of the hallucinogen, but the compound has a complex pharmacology involving several types of 5-HT receptor. LSD is a very potent compound, 25 μg being sufficient to induce hallucinations. Death from LSD overdose is rare, as the safety range of this compound is wide. When overdose occurs, it manifests as vomiting, respiratory arrest and coma. There is rapid tolerance to the effects of LSD. Hallucinogens may lead to psychological but not physical dependence. Together with cannabis, ecstasy and amphetamine, LSD is among the most popular drugs with club-goers. Experiencing the effects of psychedelic compounds through ingestion of LSD or ‘magic mushrooms’ (i.e. mushrooms that contain psilocybin) is a common temptation among teenagers in particular, and some of the self-reported effects and consequences are quite disturbing. This is described in Box 17.5, which contains edited fragments of the comments of two people who have taken ‘magic mushrooms’.

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Tanya Calvey, Fleur M. Howells, in Progress in Brain Research, 2018

Abstract

This chapter is an introduction to the volume “Psychedelic Neuroscience” of Elsevier’s Progress in Brain Research addressing the neurobiological mechanisms of psychedelic drugs, the resulting changes in brain activity and integration of traditional viewpoints. As the field is relatively new, there are discrepancies in the literature related to classification, composition and effects of the various psychedelics. Currently, psychedelics are grouped according to their neuro-receptor affinities into classic and atypical psychedelics, each with individual treatment potentials and abilities to elicit potent acute experiences and long-lasting changes in neurobiology through concurrent activation of several neuromodulatory systems. There is disparity in psychedelic brain imaging studies, delineating what is neural activity and hemodynamic needs further investigation for us to understand the brain “state” changes that are apparent. The psychedelic brain “state” is often compared to acute psychosis and we review the psychedelic animal models of psychosis and human brain imaging studies and contrast these to psychosis. The term “psychedelic” means mind-revealing and psychedelics have exceptional anti-amnesic effects and are able to “make conscious” that which was previously unconscious through changes in brain “state,” but also there is growing evidence which demonstrates the role of epigenetic mechanisms. This supports traditional therapeutic use of psychedelics to heal ancestral trauma. Details of these mechanisms are provided along with suggestions for further research.

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David E. Presti, in Encyclopedia of the Human Brain, 2002

X Methylenedioxymethamphetamine

Methylenedioxymethamphetamine (MDMA), popularly known by the street name “ecstasy,” and its close chemical relative methylenedioxyamphetamine (MDA) are often considered together with the psychedelic drugs. Although MDMA does have some of the mind-manifesting characteristics of the psychedelics, its overall properties are distinct enough to warrant a separate categorization. Chemically related to methamphetamine, MDMA produces CNS stimulation, euphoria, and sympathetic nervous system stimulation. The methylenedioxy moiety confers upon the molecule additional psychoactivity that is psychedelic-like, characterized by intensification of thoughts and feelings and enhanced feelings of connection with others. For many individuals, there is a reduction in anxiety and an enhanced ability to verbalize feelings. These qualities led to the use of MDMA as an adjunct to psychotherapy prior to its being declared an illegal Schedule I substance in 1985, an act that followed media attention focusing on its use as a recreational drug in the dance scene. Although illegal, MDMA continues to be used for both its psychotherapeutic and recreational properties by some individuals.

Although MDMA has been found to interact with a number of CNS neurochemical systems, the primary neurochemical effect of MDMA appears to be the release of serotonin and dopamine from nerve terminals into the synapse. Release is not via the usual process of storage vesicle fusion with the cell membrane, as occurs with a nerve impulse, but leakage of neurotransmitter out of the cell via the reuptake transporter.

Animal studies have indicated that MDMA may result in oxidative damage to serotonin nerve terminals. The implications of these findings for human use remain to be determined.

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D.E. Presti, in Encyclopedia of Human Behavior (Second Edition), 2012

Methylenedioxymethamphetamine

Methylenedioxymethamphetamine (MDMA), popularly known by the street name ‘ecstasy,’ and its close chemical relative methylenedioxyamphetamine (MDA), are often considered together with the psychedelic drugs. While MDMA does have some of the mind-manifesting characteristics of the psychedelics, its overall properties are distinct enough to warrant a separate category. Chemically related to methamphetamine, MDMA produces CNS stimulation, euphoria, and sympathetic nervous system stimulation. The methylenedioxy moiety confers upon the molecule additional psychoactivity that is psychedelic-like, characterized by intensification of thoughts and feelings and enhanced feelings of connection with others. For many individuals, there is a reduction in anxiety and an enhanced ability to verbalize feelings. These qualities led to the use of MDMA as an adjunct to psychotherapy prior to its being declared an illegal Schedule I substance in 1985, an act that followed media attention to its use as a recreational drug in dance clubs. Though illegal, MDMA continues to be used for both its psychotherapeutic and recreational properties by some individuals. Recently it has been the subject of clinical research for the treatment of posttraumatic-stress disorder.

While MDMA has been found to interact with a number of CNS neurochemical systems, the primary neurochemical effect of MDMA appears to be the release of serotonin and dopamine from nerve terminals into the synapse. Release is not via the usual process of storage vesicle fusion with the cell membrane, as occurs with a nerve impulse, but is by way of leakage of neurotransmitter out of the cell through the reuptake transporter. Animal studies have indicated that MDMA may result in oxidative damage to serotonin nerve terminals. The implications of these findings for human use remain to be determined.

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