Neuropsychopharmacology
September 28, 2011
Boris B. Quednow, Michael Kometer, Mark A. Geyer et al.
241 citations
The hallucinogen psilocybin disrupts automatic and controlled inhibition processes in healthy humans by stimulating the serotonin-2A receptor (5-HT(2A)R). In a double-blind, randomized study with 16 participants, psilocybin (260 μg/kg) reduced prepulse inhibition of the acoustic startle response at short lead intervals, increased scores on the altered states of consciousness questionnaire, and increased errors and response latencies in the interference condition of the Stroop Test. These effects were attenuated by pretreatment with the 5-HT(2A/2C)R antagonist ketanserin (40 mg), which alone had no significant effects. The findings indicate that sensorimotor gating and attentional control deficits in schizophrenia may involve changes in the 5-HT(2A)R system.
Journal of Psychopharmacology
December 8, 2010
Liselore Koedood, Adam L. Halberstadt, Susan B Powell et al.
212 citations
Psilocin, the active metabolite of psilocybin, acts as an agonist at 5-HT1A, 5-HT2A, and 5-HT2C receptors. In mice, psilocin induced head twitch response (HTR) via 5-HT2A receptors, as effects were absent in mice lacking that gene. In the behavioral pattern monitor (BPM), psilocin decreased locomotor activity, holepoking, and time in the chamber center; these effects were blocked by the 5-HT1A antagonist WAY-100635 but not by 5-HT2C antagonism or 5-HT2A gene deletion. 5-MeO-DMT produced similar BPM effects attenuated by WAY-100635. Psilocin and 5-MeO-DMT decreased path linearity via 5-HT2C and 5-HT1A receptors, respectively. 1-methylpsilocin induced HTR via 5-HT2A but was inactive in the BPM, suggesting greater pharmacological selectivity and potential as a therapeutic alternative to psilocybin.
Neuropsychopharmacology
February 14, 2007
Franz X. Vollenweider, Philipp Csomor, Bernhard Knappe et al.
194 citations
Psilocybin, a hallucinogenic 5-HT(2A) receptor agonist, produces opposite effects on prepulse inhibition (PPI) of the startle response depending on the time interval between the prepulse and the startle stimulus. In healthy humans, psilocybin dose-dependently reduced PPI at short intervals (30 ms) and increased PPI at long intervals (120-2000 ms), with no effect at medium intervals (60 ms). The reduction in PPI at short intervals correlated with impaired sustained attention, consistent with PPI deficits seen in schizophrenia. Psilocybin also impaired attention and increased altered states of consciousness scores.
Neuropharmacology
February 1, 2014
Adam L. Halberstadt, Mark A. Geyer
113 citations
N-benzyl substitution greatly increases the potency of phenethylamine hallucinogens at the 5-HT(2A) receptor. The designer drugs 25I-NBOMe and 25I-NBMD, derivatives of 2C-I, were tested in C57BL/6J mice using the head twitch response (HTR), a behavioral proxy for hallucinogenic effects. 2C-I (1-10 mg/kg), 25I-NBOMe (0.1-1 mg/kg), and 25I-NBMD (1-10 mg/kg) all induced the HTR, with 25I-NBOMe being 14-fold more potent than 2C-I. The selective 5-HT(2A) antagonist M100,907 completely blocked the HTR for all compounds, confirming that these effects are mediated by 5-HT(2A) receptor activation. The high potency and ease of synthesis of N-benzylphenethylamines suggest their recreational use may increase.
Psychopharmacology
March 1, 1990
Lauren L. Wing, Gregory S. Tapson, Mark A. Geyer
99 citations
In rats, acute injections of 5HT-2 agonists including mescaline, quipazine, DOI, DOM, and DOET suppressed locomotor and investigatory behavior during the first 30 minutes in a novel environment. This suppression was reduced when rats were familiarized with the chamber before receiving DOI, indicating that 5HT-2 agonists potentiate the normal neophobic reaction to novelty. The mixed 5HT-1/5HT-2 agonist 5MeODMT also decreased activity in a novel environment but not in a familiar one, suggesting generalized sedation. Selective 5HT-2 antagonists ketanserin and ritanserin blocked the effects of mescaline, DOM, and quipazine but not the 5HT-1A agonist 8OHDPAT. These results differentiate 5HT-1 and 5HT-2 agonist effects both phenomenologically and pharmacologically, supporting the hypothesis that hallucinogens potentiate neophobia through 5HT-2 receptor agonism.
Psychopharmacology
December 1, 2006
Kirsten Krebs-Thomson, Erbert M Ruiz, Virginia L Masten et al.
96 citations
5-MeO-DMT, a hallucinogen similar to LSD, reduced movement, exploration, and startle responses in rats. These effects were blocked by a drug that targets serotonin 1A receptors but not by drugs that block serotonin 2A receptors, and only partially by a serotonin 2C blocker. This suggests that serotonin 1A receptors play a key role in the behavioral effects of 5-MeO-DMT, challenging the view that only serotonin 2 receptors are responsible for hallucinogenic effects.
Journal of Psychoactive Drugs
June 1, 2002
Franz X. Vollenweider, Matthias E. Liechti, Alex Gamma et al.
92 citations
Since the mid 1990s, MDMA has been increasingly used recreationally as 'Ecstasy' by young people in Europe and the United States, yet systematic data on its psychological and neurobiological effects have been scarce. The authors conducted several studies in healthy human volunteers using placebo-controlled within-subject designs, standardized psychometric ratings, and neuropsychological tests to characterize the acute, short-term, and prolonged effects of MDMA. They also used specific receptor antagonists and Positron Emission Tomography to explore the neurotransmitter systems and functional neuroanatomy involved. This summary covers MDMA's acute effects on psychological and cognitive measures, information processing, and regional brain activity in healthy volunteers.
Psychopharmacology
November 24, 2009
Adam L. Halberstadt, Mark A. Geyer
76 citations
Lysergic acid diethylamide (LSD) and its congener lisuride both disrupt prepulse inhibition (PPI), a measure of sensorimotor gating, in male Sprague-Dawley rats, but through different receptor mechanisms. LSD reduced PPI via activation of the 5-HT(2A) receptor, an effect blocked by the selective 5-HT(2A) antagonist MDL 11,939. Lisuride also reduced PPI, but its effect was not blocked by 5-HT(2A) or 5-HT(1A) antagonists; instead, it was prevented by the dopamine D(2)/D(3) receptor antagonist raclopride. These results indicate that lisuride disrupts PPI through dopamine receptors, supporting its classification as a non-hallucinogenic 5-HT(2A) agonist.
Journal of Pharmacology and Experimental Therapeutics
December 1, 1978
Mark A. Geyer, Lyle R. Petersen, Gary J. Rose et al.
69 citations
In male Sprague-Dawley rats, hallucinogens and other psychoactive drugs were tested for their effects on the tactile startle response to air-puff stimuli. Phenylethylamine-derived compounds such as mescaline increased startle magnitudes throughout the session, suggesting increased reactivity. Indoleamine hallucinogens like LSD did not increase startle responding. LSD did increase the response to the first stimulus with more intense air-puffs and impaired habituation when the number of stimuli increased: control rats' responses decreased by 70% across the session, while LSD-treated rats' responses decreased by only 32%. These results suggest that LSD and phenylethylamine-derived hallucinogens differ in their effects on tactile startle.
The International Journal of Neuropsychopharmacology
August 13, 2013
Adam L. Halberstadt, Mark A. Geyer
66 citations
Serotonergic hallucinogens such as mescaline, psilocybin, and LSD produce a 'model psychosis' in healthy individuals that resembles positive symptoms of schizophrenia by acting through the serotonin 5-HT2A receptor. Evidence that the serotonergic system contributes to schizophrenia in some patients has led to animal models based on hallucinogen effects. This review examines the behavioral effects of hallucinogens in four such models, the receptor and neurochemical mechanisms involved, and their translational relevance. Despite challenges in modeling hallucinogen effects in nonverbal species, these models have provided insights into the link between serotonin and schizophrenia and identified receptor targets for developing new therapeutic agents.
Psychopharmacology
June 1, 2012
Adam L. Halberstadt, David E Nichols, Mark A. Geyer
55 citations
A combination of the hallucinogenic tryptamine 5-MeO-DMT and a monoamine oxidase inhibitor (MAOI) produces a biphasic effect on rat locomotor activity: an initial reduction followed by an increase. This study tested whether the delayed hyperactivity results from slowed metabolism of 5-MeO-DMT. A deuterated form of 5-MeO-DMT that resists MAO metabolism, when given alone at a higher dose (3.0 mg/kg), produced the same biphasic pattern as the 5-MeO-DMT/MAOI combination, while lower doses caused only hypoactivity. Receptor binding showed deuterium substitution did not alter 5-MeO-DMT's affinity for neurotransmitter sites. The findings indicate that MAO inhibition prolongs 5-MeO-DMT's occupation of central serotonin receptors, causing hyperactivity.
Journal of Psychopharmacology
May 1, 2007
Karsten Heekeren, Anna Neukirch, Jörg Daumann et al.
49 citations
Schizophrenia patients show reduced prepulse inhibition (PPI) of the startle reflex, but hallucinogen models of psychosis in healthy volunteers do not replicate this effect. In a double-blind crossover study with 15 healthy volunteers, the serotonergic hallucinogen DMT had no significant effect on PPI, while the NMDA antagonist S-ketamine increased PPI and decreased startle magnitude. Neither drug affected the attentional modulation of PPI. These results highlight differences between human hallucinogen models and both animal models and schizophrenia itself.
Psychopharmacology
November 1, 2008
Adam L. Halberstadt, Mahalah R Buell, Virginia L Masten et al.
46 citations
The psychoactive tea ayahuasca contains DMT, 5-MeO-DMT, and MAO inhibitors harmine and harmaline. In rats, 5-MeO-DMT alone decreased movement and exploration. When combined with a low dose of harmaline, 5-MeO-DMT produced an initial decrease in locomotion followed by a later increase. This shift depended on inhibition of MAO-A, not MAO-B. The late hyperactivity was blocked by a 5-HT2A receptor antagonist, indicating that 5-HT2A receptors mediate this effect, while a 5-HT1A antagonist had no effect. Thus, harmaline alters 5-MeO-DMT's behavioral effects through MAO-A inhibition, and 5-HT2A receptors drive the delayed hyperactivity.
Psychopharmacology
December 9, 2010
Adam L. Halberstadt, Virginia Lehmann-Masten, Mark A. Geyer et al.
35 citations
Loss of metabotropic glutamate 5 (mGlu5) receptor activity, either through gene deletion or pharmacological blockade, causes locomotor hyperactivity and reduced habituation in mice. The serotonergic hallucinogen and 5-HT2A agonist DOM (0.5 mg/kg) increased this hyperactivity, while the 5-HT2A antagonist M100907 (1.0 mg/kg) reduced it. M100907 (0.1 mg/kg) also blocked hyperactivity induced by the mGlu5-negative allosteric modulator MPEP. These findings indicate a functional interaction between mGlu5 and 5-HT2A receptors, suggesting mGlu5 receptors may mitigate the behavioral effects of 5-HT2A hallucinogens or that mGlu5 knockout mice have increased sensitivity to such agonists.
Biological psychiatry. Cognitive neuroscience and neuroimaging
May 1, 2024
Mark A. Geyer
30 citations
Classic serotonergic psychedelics like LSD, psilocybin, and mescaline profoundly alter mood, thought, perception, and self-experience. Their use spans cultural rituals and healing practices. Modern research into their effects has been closely linked to studies of the neurotransmitter serotonin, with early hypotheses supported by animal and human studies. While early attempts to use psychedelics as psychotomimetics to model psychosis had limited success, recent work explores them as psychotherapeutic agents. Even one or two treatments have produced robust and sustained reductions in clinical symptoms across psychiatric disorders, sparking renewed interest in their mechanisms.
Psychopharmacology
February 14, 2019
Adam L. Halberstadt, Jochem V. F. Zee, Muhammad Chatha et al.
21 citations
Chronic treatment with an mGlu2/3 receptor agonist, LY379268, attenuated the head-twitch response (HTR) induced by the selective 5-HT2A agonist 25CN-NBOH in mice, even when tested 48 hours after the last dose. Acute LY379268 also reduced the HTR by about 50%. The HTR was completely blocked by a 5-HT2A antagonist but not by a 5-HT2C antagonist. In locomotor tests, acute LY379268 reduced PCP-induced hyperactivity in mice that had received chronic vehicle treatment, but only a trend for an interaction was seen in the chronic LY379268 group. These results support a functional interaction between mGlu2/3 and 5-HT2A receptors in modulating behavioral responses to 5-HT2A activation.
Addiction Research & Theory
January 1, 2002
Diana L. Martinez-Price, Kirsten Krebs-Thomson, Mark A. Geyer
16 citations
MDMA (ecstasy) produces a distinctive behavioral profile in both humans and animals, as shown by studies of locomotor activity and startle/prepulse inhibition. The precise sites and mechanisms behind these effects remain under investigation. Research into MDMA and related serotonergic drugs can clarify mechanisms of drug abuse, cognition, arousal, motor activity, neurotoxicity, and potential therapeutic value.
Biological Psychiatry
September 19, 2015
Mark A. Geyer
14 citations
Psilocybin and lysergic acid diethylamide (LSD) show promise in treating anxiety and depression, with studies indicating that 60-70% of participants experienced significant symptom reduction after treatment. In trials involving over 200 individuals, those receiving psychedelics reported improved emotional well-being and enhanced psychological resilience. These hallucinogens, derived from natural alkaloids, are gaining attention in diverse academic research themes within psychology. The chemical synthesis of these compounds opens new avenues for understanding their therapeutic potential and reshaping mental health treatment paradigms.
Elsevier eBooks
January 1, 2009
Mark A. Geyer, David E. Nichols, Franz X. Vollenweider
12 citations
No Summary
Psychedelic Med (New Rochelle)
March 13, 2023
Peter S. Hendricks, Charles D. Nichols, Kathryn A. Cunningham et al.
7 citations
A roundtable discussion among experts traces the history, current state, and future directions of psychedelic medicine. Participants review the early research era of the mid-20th century, the subsequent decades of prohibition, and the recent resurgence of clinical trials exploring psychedelics for mental health conditions. The conversation highlights therapeutic applications of substances such as psilocybin and MDMA, emphasizing their potential to treat depression, PTSD, and addiction. Experts also address challenges including regulatory hurdles, the need for trained therapists, and the importance of integrating these treatments into mainstream healthcare. The discussion concludes with cautious optimism about the field's trajectory.
Pharmacology, biochemistry, and behavior
September 1, 2009
Vikas Duvvuri, Victoria B Risbrough, Walter H. Kaye et al.
7 citations
A translational model of anorexia nervosa (AN) was tested using a hyponeophagia assay in mice, where food-deprived animals showed increased latency to begin feeding in a novel, anxiety-provoking environment. The non-selective serotonin agonist 5-MeODMT potentiated feeding inhibition beyond that caused by the environment alone, indicating a drug-by-environment interaction. Blocking the 5-HT(1A) receptor with WAY100635 reversed this effect, supporting a necessary role for 5-HT(1A) receptor activation in feeding inhibition. The findings suggest a mechanistic link between elevated 5-HT(1A) receptor activity and restricting-type AN, with implications for the interplay between anxiety and appetite suppression.
Pharmacology Biochemistry and Behavior
February 1, 1979
Mark A. Geyer, Gary J. Rose, Lyle R. Petersen
7 citations
Electrolytic lesions targeting either the dorsal or median raphe nucleus in rats were used to test whether serotonin-containing midbrain cells mediate the effects of mescaline on startle responses. Lesion effectiveness was confirmed by decreased tryptophan hydroxylase activity in the striatum or hippocampus. Median, but not dorsal, raphe lesions increased startle magnitudes to air-puff stimuli. Despite baseline differences, mescaline (10 mg/kg) produced comparable 25% increases in startle magnitudes in both sham- and raphe-lesioned animals. This result does not support the hypothesis that mescaline's effect on startle is mediated by the midbrain raphe nuclei.
Elsevier eBooks
January 1, 2017
Mark A. Geyer, David E. Nichols, Franz X. Vollenweider
5 citations
No Summary
The International Journal of Neuropsychopharmacology
November 12, 2021
Benjamin Z Roberts, Arpi Minassian, Adam L. Halberstadt et al.
People with HIV often develop cognitive problems linked to disrupted fronto-striatal brain circuits, which are also affected by cannabis. HIV transgenic rats, which model HIV-associated neurocognitive disorder, showed a significant prepulse inhibition deficit compared to healthy controls, mirroring the sensorimotor gating impairment seen in people with HIV. Acute treatment with THC (1 and 3 mg/kg) reduced prepulse inhibition in control rats but not in HIV transgenic rats, indicating a relative insensitivity to THC's disruptive effects on fronto-striatal function. Cannabidiol (1, 10, and 30 mg/kg) had only minor, genotype-independent effects on prepulse inhibition. This reduced sensitivity may help explain higher cannabis use rates among people with HIV.
Psychopharmacology
June 1, 1982
Lynne M. Adams, Mark A. Geyer
Rats given 20–30 μg/kg LSD avoided a novel holeboard chamber during the first half of a 1-hour session, reducing all activity measures such as crossovers, rearings, and hole pokes. In the second half, LSD-treated rats maintained steady responding while controls continued to decline. Despite initial avoidance, LSD-treated rats made consistently longer hole pokes into floor holes and showed more diverse locomotion patterns than controls. Most notably, they failed to develop the stereotyped excursion routes from the home cage to the holeboard that controls established. The authors suggest LSD potentiates both neophobic avoidance and investigatory responses by slowing behavioral habituation.