Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

“…that psilocybin reduces activity and connectivity in core nodes of the default-mode network, brain regions that are active during the resting state and potentially involved in introspective processes (for more information, see: Raichle et al., 2001; Mason et al., 2007; Buckner et al., 2008).”

“…that psilocybin reduces activity and connectivity in core nodes of the default-mode network, brain regions that are active during the resting state and potentially involved in introspective processes (for more information, see: Raichle et al., 2001; Mason et al., 2007; Buckner et al., 2008).”

“CSTC loops are parallel, anatomically segregated circuits relaying information between the basal ganglia, thalamus, and cortex (Alexander et al., 1986, 1990).”

“Since cortical oscillations play a fundamental role in a diverse set of mental processes and are required for the coordination of neural processing (Gray et al., 1989; Singer, 1999; Buzsaki and Draguhn, 2004; Sejnowski and Paulsen, 2006; Fries, 2009; Klimesch, 2012), it is tempting to speculate that the reduction of n…”

“One potential explanation is that the hemodynamic responses measured by fMRI are actually better correlated with cortical oscillatory activity than with neuronal firing (Mathiesen et al., 1998; Logothetis et al., 2001; Behav Brain Res.”

“Since cortical oscillations play a fundamental role in a diverse set of mental processes and are required for the coordination of neural processing (Gray et al., 1989; Singer, 1999; Buzsaki and Draguhn, 2004; Sejnowski and Paulsen, 2006; Fries, 2009; Klimesch, 2012), it is tempting to speculate that the reduction of n…”

“Under anesthesia or during slow-wave sleep, cortical networks display slow (0.5–1 Hz) and delta (1–4 Hz) oscillations (Steriade et al., 1993a,b; Steriade, 1997) that reflect alternations between periods of silence (DOWN states) and periods of depolarization with repetitive spiking (UP states).”

“Since cortical oscillations play a fundamental role in a diverse set of mental processes and are required for the coordination of neural processing (Gray et al., 1989; Singer, 1999; Buzsaki and Draguhn, 2004; Sejnowski and Paulsen, 2006; Fries, 2009; Klimesch, 2012), it is tempting to speculate that the reduction of n…”

“The 5-HT2 receptor class was later reorganized to include three subtypes: 5-HT2A (equivalent to the site known historically as the 5-HT2 receptor or the D receptor), 5-HT2B (formerly known as the 5HT2F receptor), and 5-HT2C (formerly known as the 5-HT1C receptor) (Hoyer et al., 1994).”

“The classic hallucinogens, which include psilocybin (psilocin) and (+)-lysergic acid diethylamide (LSD), are a structurally diverse group of compounds that are 5-HT2A receptor agonists and produce a unique profile of changes in thoughts, perceptions, and emotions (Halberstadt, 2015; Nichols, 2016).”

“In the study byHalberstadt et al. (2011a), the response to psilocin was not affected by deletion of the 5-HT2A receptor gene.”

“LSD has a high affinity for a range of different neurotransmitter receptors, but its characteristic psychological effects are thought to be mediated by serotonin 2A receptor (5-HT2AR) agonism (7).”

“…this limitation, we also wish to emphasise that the evidence is compelling that 5-HT2AR agonism is key to psychedelics’ most characteristic effects (Halberstadt, 2015), 5-HT1AR agonism attenuates rather than augments these effects (Pokorny et al., 2016; Strassman, 1996) and more selective 5-HT2AR…”

“Classic psychedelics, also known as classic hallucinogens, are a family of psychoactive substances that exert their subjective effects primarily by agonism (or partial agonism) of serotonin 2A (5-HT2A) receptors (Halberstadt, 2015; Nichols, 2016).”

“The pharmacological profiles of psilocin and LSD are particularly interesting because both substances currently receive high interest as research tools and potential therapeutic substances in psychiatry (Geyer, 2015; Halberstadt, 2015; Kupferschmidt, 2014).”

“…acid diethylamide (LSD), mescaline, and dimethyltryptamine (DMT; contained in the sacramental beverage ayahuasca) share a primary pharmacological site of action at the serotonin 2a (5HT2a) receptor, and display striking similarities in their subjective effects (Halberstadt, 2015; Nichols, 2016).”

“Today, research has repeatedly shown that psychedelics do not cause dependence or compulsive use (Halberstadt, 2015; Johnson et al., 2018; Morgenstern et al., 1994; Nichols, 2016).”

“LSD, psilocybin and mescaline are all classical serotonergic psychedelics with main mechanism of action at the 5-HT2A receptor (Halberstadt, 2015).”

“Recent findings have elucidated additional neuronal signaling pathways downstream from the 5-HT2A receptor that is potentially involved in the unique behavioral effects induced by hallucinogens (Halberstadt 2015; Hanks and Gonzalez-Maeso 2013).”

“All three of the behavioral effects included in the present investigation (HTR in mice, hallucinogen discriminative stimulus effects in rats, and psyche-delic effects in humans) have been linked to 5-HT 2A activation (Halberstadt, 2015; Nichols, 2016).”

“Stimulation of phospholipase A2 does not seem to directly related to the subjective effects of psychedelic compounds (Halberstadt, 2015; Kurrasch-Orbaugh et al., 2003).”

“Behavioral Pattern Monitor (BPM) studies in rats have shown that psychedelics exhibit a distinguishable profile of behavioral effects analogous to the enhanced sensitivity and reactivity to environmental stimuli that occurs in humans [55].”

“It has been proposed that the PET study findings of hyperfrontality reflect the increased neuronal firing activity while fMRI BOLD measures correlate with cortical oscillatory activity (Halberstadt, 2015).”

“…they are thought to exert their primary effects primarily through agonist or partial agonist activity at serotonin 2A (5HT2A) receptors, and that they substitute for the prototypical classic hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) in drug discrimination experiments (Halberstadt, 2015).”

“, 1997), suggesting that additional ligandereceptor interactions contribute to receptor activation (Halberstadt, 2015; Nichols, 2004).”

“It has been suggested that the 5-HT1A receptor also contributes to the effects of LSD [22, 32], and indeed, this is confirmed by the improved performance of the 5-HT1A receptor-binding map compared to the 5-HT1B, 5-HT4, and 5-HTT maps [22].”

“LSD acts primarily as a serotonergic agonist, but also shows action at dopaminergic and adrenergic receptor sites (Halberstadt, 2015; Nichols, 2004).”

“A molecule’s propensity for 5-HT2A affinity and agonist activity predicts its potential for (and potency of) subjective psychedelic effects (Glennon et al., 1984; McKenna et al., 1990; Halberstadt, 2015; Nichols, 2016; Rickli et al., 2016).”

“Insofar as there is substantial evidence that LSD alters psychological functions by targeting 5-HT2A receptors (Halberstadt 2015; López-Giménez and González-Maeso 2018; Nichols 2016; Preller et al. 2017), one possible outcome was that microdoses of LSD would produce temporal underreproduction, as…”

“While their immediate effects on perception and mood are well-documented (Halberstadt, 2015), some of their complex effects at higher doses have received less attention until more recently.”

“Of particular interest in this regard are findings from animal studies showing that 5- HT2A agonist activity (Halberstadt 2015) correlates with an increase in associative learning (Harvey et al. 2003) and improvements in the ability to adapt behavior more flexibly (Boulougouris et al. 2008).”

“There has been a flurry of research in recent years using both neuroimaging and experimental methods to investigate the neural correlates of experiences induced by psychoactive drugs, including ego dissolution (for indepth reviews of this body of research, see dos Santos, Osório, Crippa, & Hallak, 2016; Halberstadt, 2…”

“In addition, psilocybin has a short acute window of 2–6 h, which contributes to more manageable and inexpensive clinical trials, differing greatly from mescaline and LSD with acute windows of 6–8 h and 8–20 h, respectively [27, 28].”

“Moreover, psychedelics share a common mechanism of action at different 5-HT receptors, primarily the 5-HT2A receptor (Geyer and Vollenweider, 2008), which appears to be crucial for the specific psycho-vegetative effects, probably by activating a complex signal cascade (Halberstadt, 2015; Vollenweider and Kometer, 2010…”

“Indeed, these drugs have an action on the serotoninergic system by a 5-HT1A/2A/2C agonism (Halberstadt, 2015).”

“LSD and other ergolines also act upon dopaminergic (D1, D2) and adrenergic receptors [4], while mescaline and DOI are selective agonists at 5-HT2A, 5-HT2B, and 5-HT2C sites [81].”

“Most importantly, as we have reviewed elsewhere (Halberstadt 2015), manipulations that suppress recurrent glutamatergic network activity also block the HTR.”

“The primary molecular target of all classic hallucinogens is thought to be the serotonin 2A (5HT2A) receptor (Halberstadt, 2015; Nichols, 2004), which is rapidly down-regulated following hallucinogen administration.”

“…action of these compounds (Vollenweider et al., 1998; Hintzen and Passie, 2010; Vollenweider and Kometer, 2010; Kometer et al., 2012, 2013; Hanks and González-Maeso, 2013; Baumeister et al., 2014; Tylš et al., 2014; Halberstadt, 2015; Nichols, 2016; Valle et al., 2016; Tagliazucchi et al., 2016).”

“3The psychoactive effects of classical, or serotonergic psychedelics are commonly mediated via activation of central serotonin 2A (5HT2A) receptors [7]; classical psychedelics include the indoleamines such as dimethyltryptamine (DMT), psilocybin (4-phosphoryloxy-DMT), and lysergic acid diethylamide (LSD); and the phen…”

“Psilocybin intraperitoneal treatment restored Grm2 expression (F[1,16] = 8.”

“Although many psychedelics exhibit complex receptor pharmacology (Halberstadt and Geyer, 2011; Nichols, 2016), all are believed to exhibit their primary effects through activation of the brain serotonin 5-HT2A receptor (Glennon et al., 1984; Halberstadt, 2015) in both humans (Vollenweider et al.”

“This agonism, particularly the 5-HT2A agonism, could provoke a glutamate release leading to an activation of the fronto-cortical glutamate receptor (Halberstadt, 2015).”

“…that share 5-HT2A receptor agonist properties, and which, at higher doses, induce profound alterations in thought, perception, and emotion (Halberstadt, 2015; Nichols, 2016; Rickli et al., 2016), along with experiences of ego dissolution (Letheby and Gerrans, 2017; Milliere, 2017), and/or…”

“It can also produce mild visual hallucinatory phenomena, which have been linked to the 5-HT2A receptor, the same receptor targeted by the classic psychedelics (Gouzoulis-Mayfrank et al., 1996; Harris et al., 2002; Liechti and Vollenweider, 2001).”

“Here, we tested ±DOI at 1, 3, and 5mg/kg i.p.”

“Classic hallucinogens (CH) are powerful psychoactive substances that are categorized into two broad chemotype classes: indoleamines (including tryptamines and ergotamines) and phenylalkylamines (including phenethylamines and phenylisopropylamines; Halberstadt, 2015).”

“However, in recent years the remarkable effects mediated by LSD and psilocybin in rodent models of cognitive and psychiatric disorders and in human treatment trials of depression, posttraumatic stress, obsessive-compulsive disorder, autism, and various forms of addiction have substantiated this potential and rekindled…”

“Indeed, 5-HT2C and 5-HT1A receptors may also play a role (see reviews by Nichols 2004, 2016; Halberstadt 2015; Carbonaro and Gatch 2016) as well as other known and, perhaps, unknown receptors or compounds yet to be identified in what may be a far more complex system than we know.”

“…is excitatory and appears to mediate depolarizing effects (Davie et al., 1988; Eison and Mullins, 1996; Hasuo et al., 2002), but it may also have inhibitory activity or even interact with a number of other inhibitory interneurons (Avesar and Gulledge, 2012; Halberstadt, 2015; Wang et al., 2016).”

“Created with BioRender.com. psychedelic state in rodents, is completely blocked by 5HT2A-R antagonists (Halberstadt, 2015).”

“It is assumed that LSD’s principal “psychedelic” effects are mediated by activation of serotonin 2A receptor (5-HT2AR) [Halberstadt, 2014].”

“These substances elicit an extremely varied array of effects, spanning the entire brain functional hierarchy, from low-level sensory, to mood, and high-level cognitive alterations (Halberstadt, 2015; Nichols, 2016; Preller and Vollenweider, 2016; Kyzar et al., 2017; Vollenweider and Preller, 2020; Inserra et al., 2021…”

“Several receptor-level and molecular studies have shown that 5-HT1A/2C receptors play a role in the effects of psychedelics (Halberstadt, 2015; Marek, 2018; Nichols, 2004, 2016).”

“One class of serotonergic hallucinogens is the phenylalkylamines, which can be further divided into phenylisopropylamines like 1-(4-iodo-2,5-dimethoxyphenyl) propan-2-amine (DOI) and phenethylamines like 2-(4-iodo-2,5dimethoxyphenyl)ethanamine (2C-I) (Halberstadt, 2015) (see Fig.”

“Their main mechanism of action is based on an agonist (or partial agonist) action at serotonin (5-HT)2A receptors (Rickli et al. 2016), which explains the unique and powerful ability of hallucinogens to affect the human psyche (Halberstadt 2015; Preller et al. 2017).”

“Although the psychedelic drugs LSD, psilocybin, and mescaline are derived from structurally distinct chemical entities, their hallucinogenic effect is similar [80, 81] and primarily mediated through 5-HT2A receptors [82].”

“5HT2A receptor activation is coupled with several intracellular signaling pathways [Halberstadt, 2015].”

“Over the past decade there has been a renewed focus on the pharmacology and effects of serotonergic hallucinogens (Halberstadt, 2015; Nichols, 2016).”

“5-HT2A receptors are highly expressed on glutamatergic pyramidal neurons and GABAergic basket and chandelier cells in layer Vof the prefrontal cortex (Halberstadt 2015).”

“Hallucinogens induce their characteristic effects by activating 5-HT2A receptors (Nichols 2004; Halberstadt, 2015), but it remains to be determined whether their effects on temporal perception are mediated by 5-HT2A.”

“Despite the structural difference, they produce very similar effects, which are mediated mainly via their agonistic action on 5-HT2A receptors [5, 6].”

““Classical” serotonergic psychedelics, including psilocybin and LSD, act as agonists on the serotonin system, with relative selectivity for the 5HT2A receptor (24), whilst dissociative psychedelics, such as ketamine, hijack the glutamatergic system, acting as NMDAR antagonists (25).”

“gic acid diethylamide, and dimethyltryptamine [DMT]) are altered perception and cognition,(3) mystical or spiritual experiences,(4,5) and occasional anxiety and physiological distress,(6) and the molecular mechanism of action of hallucinogens is understood to be 5HT2A receptor agonism.(7,8) A set of pharmacologically…”

“It is a 5-HT2a receptor agonist that causes distortions in perception, thoughts, and emotions, as well as self-boundary dissolution [1].”

“…hallucinogens” (Nichols, 2004), “serotonergic hallucinogens” Frontiers in Pharmacology | www.frontiersin.org 1 August 2018 | Volume 9 | Article 994 (Halberstadt, 2015), or “psychedelics” (Nichols, 2016), are reported to be effective in some clinical studies of AUD (Krebs and Johansen, 2012;…”

“Given the difficulties associated with hallucinogen studies in humans, animal behavioral models have been widely used to investigate the pharmacology of serotoninergic hallucinogens (Halberstadt 2015; Halberstadt and Geyer 2018).”

“Serotonergic psychedelics or classic hallucinogens are described as substances capable of altering thought, perception, and mood, without memory impairment, delirium, or addiction, with activation of the serotonin (5- HT) 2A receptor (5- HT2AR) as a main pharmacological mechanism (Glennon et al., 1984; Halberstadt, 20…”