Archives of General Psychiatry
September 7, 2010
Gurpreet S Chopra, Marycie Hagerty, Charles S. Grob et al.
1,220 citations
In a double-blind, placebo-controlled study, twelve adults with advanced-stage cancer and anxiety received a moderate dose (0.2 mg/kg) of psilocybin. Safe physiological and psychological responses were documented, with no clinically significant adverse events. The State-Trait Anxiety Inventory trait anxiety subscale showed a significant reduction in anxiety at 1 and 3 months after treatment. The Beck Depression Inventory indicated improved mood that reached significance at 6 months; the Profile of Mood States showed mood improvement that approached but did not reach significance. The results support the need for more research into psilocybin for cancer-related anxiety.
Neuropharmacology
May 1, 2020
Adam L. Halberstadt, Muhammad Chatha, Adam K. Klein et al.
274 citations
Serotonergic hallucinogens like LSD cause head twitches in rodents through 5-HT2A receptor activation. This study tested whether the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm correlates with their potencies in rats and humans. Dose-response experiments with phenylalkylamine and tryptamine hallucinogens in C57BL/6J mice expanded HTR potency data to 41 compounds. For 36 agents with human data, a strong positive correlation (r = 0.9448) was found between mouse HTR potencies and human hallucinogenic potencies. HTR potencies also correlated with drug discrimination ED50 values in rats trained with LSD (r = 0.9484, n = 16) or 2,5-dimethoxy-4-methylamphetamine (r = 0.9564, n = 21). These three behavioral effects show consistent potencies linked to 5-HT2A receptor activation, supporting the HTR assay as a predictive preclinical model for hallucinogen potency in humans.
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.
Nat Commun
December 15, 2023
Jason Wallach, Andrew B. Cao, Maggie M. Calkins et al.
153 citations
Serotonergic psychedelics show therapeutic potential, but the specific roles of 5-HT2A receptor signaling pathways are unclear. Researchers developed selective ligands with varying Gq efficacies, including β-arrestin-biased ones. In male mice, 5-HT2A-Gq recruitment efficacy, not β-arrestin2 recruitment, predicted psychedelic potential measured by head-twitch response magnitude. Disrupting Gq-PLC signaling reduced this response, and a threshold Gq activation level was needed for psychedelic-like effects, explaining why partial agonists like lisuride are non-psychedelic. β-arrestin-biased agonists blocked psychedelic effects and caused receptor downregulation and tachyphylaxis. Fine-tuning 5-HT2A Gq-signaling enables development of non-psychedelic 5-HT2A agonists.
Cell Reports
March 28, 2023
Vern Lewis, Emma M. Bonniwell, Janelle K. Lanham et al.
129 citations
The non-hallucinogenic LSD analog 2-Br-LSD acts as a partial agonist at several aminergic G protein-coupled receptors, including 5-HT2A, but does not induce the head-twitch response in mice, indicating it lacks hallucinogenic effects. Unlike LSD, 2-Br-LSD does not activate 5-HT2B, avoiding a risk of cardiac valvulopathy. It produces weak 5-HT2A β-arrestin recruitment and internalization in vitro and does not cause tolerance after repeated dosing. In cultured rat cortical neurons, 2-Br-LSD promotes dendritogenesis and spinogenesis, and in mice it increases active coping behavior—an effect blocked by a 5-HT2A antagonist—and reverses behavioral effects of chronic stress. These findings suggest 2-Br-LSD has an improved pharmacological profile over LSD and potential therapeutic value for mood disorders.
Regional Anesthesia & Pain Medicine
May 4, 2020
Joel Castellanos, C. Leonard Woolley, Kelly Bruno et al.
118 citations
Chronic pain develops through complex mechanisms involving strengthened neural circuitry from repeated pain signals, leading to peripheral and central sensitization. Psychedelics, through serotonin 2A receptor agonism, may 'reset' brain functional connectivity involved in central neuropathic pain. They have a favorable safety profile compared to opioid analgesics. Clinical evidence for chronic pain is limited, but studies over 50 years show potential benefit for cancer pain, phantom limb pain, and cluster headache. The mechanisms are unclear but may involve similarities between psychedelic activation pathways and nociceptive modulation. Functional connectivity changes from psychedelics could help reverse neural changes in chronic pain. Further research is needed given the opioid epidemic and limited non-opioid options.
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.
ACS Pharmacology & Translational Science
December 14, 2020
Adam K. Klein, Muhammad Chatha, Lauren J. Laskowski et al.
103 citations
The 5-HT2A receptor is the primary target for psilocybin and other serotonergic hallucinogens. Seventeen tryptamines with 4-hydroxy or 4-acetoxy groups and various N,N-dialkyl substituents were tested. All acted as full or partial agonists at 5-HT2 subtypes, with similar potencies at 5-HT2A and 5-HT2B receptors, though bulkier N-alkyl groups reduced potency at 5-HT2C receptors and increased 5-HT2B efficacy. O-acetylation reduced in vitro 5-HT2A potency by 10- to 20-fold without altering efficacy. All compounds induced head twitches in mice, consistent with LSD-like effects. Acetylation had little effect on head-twitch potency, suggesting O-acetylated tryptamines may act as prodrugs deacetylated in vivo. These derivatives have psilocybin-like properties, supporting their classification as psychedelic drugs.
Current Topics in Behavioral Neurosciences
January 1, 2017
Adam L. Halberstadt
100 citations
NBOMe hallucinogens, such as 25I-NBOMe, are N-benzyl derivatives of 2C-X phenethylamines that bind with subnanomolar affinity to the 5-HT2A receptor and are highly potent in humans. Since 2010, online availability of these compounds has led to numerous toxicity cases and fatalities. A review of 51 reported cases indicates that rhabdomyolysis is a relatively common complication of severe NBOMe toxicity, potentially linked to seizures, hyperthermia, and vasoconstriction.
Schizophrenia Bulletin
August 5, 2020
Pantelis Leptourgos, Martin Fortier-Davy, Robin Carhart-Harris et al.
88 citations
A multidisciplinary working group reviewed evidence on the similarities and differences between hallucinations induced by psychedelics and those occurring in schizophrenia-spectrum disorders, examining data from pharmacology, brain imaging, phenomenology, and anthropology. The authors highlight both shared features and distinct characteristics across these scales, and attempt to integrate findings using computational approaches. They conclude with recommendations for future research, emphasizing the need for further study to clarify the relationship between these types of hallucinations.
ACS Chemical Neuroscience
July 15, 2015
David E Nichols, M Flori Sassano, Adam L. Halberstadt et al.
81 citations
A series of N-benzylated-5-methoxytryptamine analogues and a parallel series of N-benzylated 2C-I analogues were synthesized and tested. Most compounds showed highest affinity for 5-HT2 family receptors. Para substitution on the benzyl group reduced affinity, while ortho or meta substitution enhanced it. Large lipophilic groups improved affinity but often reduced functional activity. Functional testing at human and rat 5-HT2A, 5-HT2B, and 5-HT2C receptors revealed no general correlation between affinity and function. Several tryptamine congeners were potent functional agonists (EC50 values from 7.6 to 63 nM) but mostly partial agonists. In the mouse head twitch assay, many compounds induced head twitches, and this behavior correlated significantly with functional potency at the rat 5-HT2A receptor.
Journal of Natural Products
February 20, 2020
Alexander M. Sherwood, Adam L. Halberstadt, Adam K. Klein et al.
79 citations
A new synthetic method allows access to tryptamine natural products found in psilocybin-producing mushrooms. Laboratory and animal experiments tested whether these compounds are psychoactive. In mice, the natural product baeocystin did not produce a head twitch response, a behavioral marker of psychedelic activity, even though its predicted breakdown product, norpsilocin, strongly activates the 5-HT2A receptor, which is associated with psychedelic effects. This suggests that baeocystin itself may not be psychedelic, despite its metabolite's activity.
Drug Testing and Analysis
October 12, 2015
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
79 citations
1-Propionyl-d-lysergic acid diethylamide hemitartrate (1P-LSD), a non-controlled derivative of LSD, was characterized and tested for LSD-like effects. Using chromatographic, mass spectrometric, infrared, and nuclear magnetic resonance methods, the compound was compared to LSD. In male C57BL/6J mice, 1P-LSD produced a dose-dependent increase in head-twitch response (HTR) counts, a behavioral marker of 5-HT2A receptor activation. 1P-LSD had about 38% of the potency of LSD (ED50 = 349.6 nmol/kg vs. 132.8 nmol/kg for LSD). Pretreatment with the selective 5-HT2A receptor antagonist M100907 abolished the HTR, confirming that the response was mediated by 5-HT2A receptor activation. These results indicate 1P-LSD produces LSD-like effects in mice, consistent with classification as a serotonergic hallucinogen, though human psychoactive effects remain unknown.
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.
PLoS One
June 17, 2016
Jason Wallach, Heather Kang, Tristan Colestock et al.
73 citations
1,2-Diarylethylamines such as diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP) are sold as 'legal highs' and have been linked to fatal and non-fatal overdoses. Binding studies at 46 central nervous system receptors show these compounds are relatively selective N-methyl-D-aspartate receptor (NMDAR) antagonists with weak off-target inhibition of dopamine and norepinephrine reuptake. In rats, DPH and 2-MXP significantly reduced prepulse inhibition of startle (PPI), an effect seen with dissociative drugs like phencyclidine (PCP) and ketamine. DPH acted with a median effective dose (ED50) of 9.5 mg/kg, less potent than PCP and ketamine.
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.
ACS Chemical Neuroscience
October 28, 2019
Christian B M Poulie, Anders A. Jensen, Adam L. Halberstadt et al.
63 citations
N-Benzylphenethylamines (NBOMes) are synthetic psychedelics derived from phenethylamines like 2C-X compounds, which originate from the natural alkaloid mescaline. Like other classical psychedelics, they primarily activate serotonin 2A (5-HT2A) receptors. Since their emergence as New Psychoactive Substances in 2010, recreational use has caused acute toxicity and lethal outcomes, leading to their classification as Schedule I substances in 2013. Beyond recreational use, NBOMes have become valuable biochemical tools, such as [11C]Cimbi-36 for PET imaging of 5-HT2A and 5-HT2C receptors, and 25CN-NBOH, a highly selective 5-HT2A receptor agonist. This Review covers their history, chemistry, structure-activity relationships, ADME properties, and safety profiles.
Drug Testing and Analysis
June 5, 2017
Simon D. Brandt, Pierce V. Kavanagh, Brendan Twamley et al.
56 citations
Lysergic acid morpholide (LSM-775), a structural relative of LSD, appeared on the market for new psychoactive substances in 2013, but its potency and psychoactive effects in humans have been disputed. This investigation characterized a powdered sample using multiple analytical techniques and tested its receptor activity. LSM-775 acted as a nonselective agonist at 5-HT1A and 5-HT2A receptors. In head twitch studies with C57BL/6J mice, LSM-775 did not induce the head twitch response unless 5-HT1A receptors were blocked by the antagonist WAY-100,635 (1 mg/kg, subcutaneous). The findings suggest that activation of 5-HT1A receptors by LSM-775 masks its hallucinogen-like effects, consistent with reports that it produces only weak LSD-like effects in humans.
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.
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.
Scientific Reports
May 20, 2020
Adam L. Halberstadt
45 citations
A new automated method detects head-twitch responses (HTR) in mice, a behavior induced by hallucinogens, with 99.4% sensitivity. Traditional methods relying on amplitude-time features are unreliable due to variability in twitch characteristics and similarity to other behaviors like jumping. The approach transforms magnetometer recordings into time-frequency visual representations (scalograms), extracts deep features using a pretrained convolutional neural network (ResNet-50), and classifies them with a Support Vector Machine algorithm. Tested on recordings from 237 mice containing 11,312 HTR, the method correctly identified 11,244 twitches and was insensitive to other behaviors such as jumping and seizures. Deep learning on scalograms enables robust, reliable automated HTR detection.
Neuropharmacology
November 1, 2018
Landon M. Klein, Nicholas V. Cozzi, Paul F. Daley et al.
43 citations
Most DALT derivatives bind to several serotonin receptors, sigma sites, and other targets. In mice, several compounds triggered the head-twitch response, a behavioral proxy for hallucinogen effects, with 4-acetoxy-DALT being most potent, followed by 5-fluoro-DALT, 5-methoxy-DALT, 4-hydroxy-DALT, DALT, and 5-bromo-DALT; four derivatives did not induce the response. Head-twitch potency was not linked to binding affinity at either 5-HT1A or 5-HT2A receptors alone, but a regression analysis showed that 5-HT2A receptors contribute positively and 5-HT1A receptors contribute negatively to potency, explaining 87% of the variance. These results support the role of 5-HT2A receptors in the head-twitch response and suggest that 5-HT1A activation by tryptamine hallucinogens dampens this effect.
Drug Testing and Analysis
March 16, 2020
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
38 citations
1-Cylopropanoyl-LSD (1CP-LSD), a new lysergamide-based designer drug, was analyzed using multiple chemical and spectroscopic methods. Incubation with human serum converted 1CP-LSD into LSD, suggesting it may act as a prodrug for LSD in the body. In mice, 1CP-LSD induced a head-twitch response (HTR) with an ED50 of 430.0 nmol/kg, comparable to 1P-LSD (ED50 = 349.6 nmol/kg), indicating an LSD-like behavioral profile. The study includes analysis of blotters and pellets, and detected artificially induced degradation products during GC-MS analysis. Clinical studies are needed to determine its potency and effects in humans.
Neuropharmacology
November 19, 2019
Adam L. Halberstadt, Muhammad Chatha, Adam K. Klein et al.
37 citations
The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52) and other 1-acyl-substituted LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs assumed to act as prodrugs for LSD. Competitive binding studies and calcium mobilization assays showed 1-acyl-substitution reduced affinity for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude, and these derivatives had weak efficacy or acted as antagonists in Ca2+-mobilization assays. Despite this, they induced head twitches in mice with relatively high potency. High levels of LSD were detected in rat plasma after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating rapid and efficient deacylation in vivo, consistent with the prediction that these compounds serve as prodrugs for LSD.
Neuropharmacology
January 1, 2011
Maarten Van den Buuse, Emma Ruimschotel, Sally Martin et al.
37 citations
Mice lacking the serotonin-1A (5-HT(1A)) receptor showed enhanced hyperactivity in response to amphetamine, a model of the hyperdopaminergic state linked to psychosis. The response to MK-801, which models NMDA receptor hypoactivity, was unchanged. The effect of the hallucinogen 5-MeO-DMT was markedly reduced in the knockout mice. No changes were seen in sensory gating deficits induced by apomorphine, nor in the density of dopamine transporters or D1/D2 receptors. These results suggest that 5-HT(1A) receptors play a role in hallucinations and modulating dopamine activity, extending insight into their possible involvement in schizophrenia.