Neuropharmacology
November 1, 2018
Maurizio S Riga, Laia Lladó-Pelfort, Francesc Artigas et al.
57 citations
The hallucinogen 5-MeO-DMT alters brain oscillations more in cortical areas than in the thalamus, particularly increasing delta power in the visual cortex of mice lacking 5-HT2A receptors. It also boosts beta-band coherence between the prefrontal cortex, visual cortex, and mediodorsal thalamus. Blocking 5-HT1A receptors with WAY-100635 prevented most of these oscillatory changes in knockout mice, suggesting 5-HT1A antagonists could help treat visual hallucinations. Effects on prefrontal theta activity and cortico-thalamic coherence may relate to antidepressant properties.
Neuropharmacology
April 1, 1996
K Chen, T G Kokate, S D Donevan et al.
55 citations
Ibogaine, a hallucinogenic alkaloid claimed to reduce addiction, blocks NMDA receptors in the brain. In cultured rat hippocampal neurons, ibogaine slowly and reversibly blocked NMDA-induced currents with an IC50 of 3.1 µM at −60 mV, while not affecting kainate or GABA currents. The block was use- and voltage-dependent and could be occluded by magnesium. Ibogaine also inhibited dizocilpine binding to NMDA receptors in rat forebrain membranes (IC50, 3.2 µM). In mice, ibogaine fully protected against maximal electroshock seizures (ED50, 31 mg/kg, i.p.) and partially protected against NMDA-induced lethality, confirming in vivo NMDA receptor blockade.
Neuropharmacology
April 1, 1982
R A Shephard, P L Broadhurst
53 citations
Serotonin agonists fenfluramine and 5-MeODMT increased hyponeophagia (suppression of feeding in a novel environment) in rats, while diazepam reduced it and counteracted the effects of both serotonin agonists. Diazepam appears to act downstream of serotonergic drugs in modulating this behavior.
Neuropharmacology
May 27, 2023
David J. Heal, Sharon L. Smith, Sean J. Belouin et al.
50 citations
This special issue of Neuropharmacology provides a comprehensive update on basic and clinical research on psychedelics since 2018, partly based on the NIH Psilocybin Research Speaker Series held from April to June 2021. The FDA has granted breakthrough therapy designations for psilocybin in treatment-resistant depression (2018) and major depressive disorder (2019), and for MDMA in post-traumatic stress disorder (2017). Clinical trials are ongoing for psilocybin in depression, cancer-related anxiety and depression, anorexia, PTSD, substance use disorders, and chronic pain. The collection aims to support the transition of psychedelics from bench to mainstream therapies, with global implications following potential FDA approvals.
Neuropharmacology
May 15, 2018
Dino Luethi, Daniel Trachsel, Marius C Hoener et al.
50 citations
4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. The study characterized their interactions with monoamine receptors and transporters. 2C-T drugs showed high affinity for 5-HT2A and 5-HT2C receptors (1-54 nM and 40-350 nM, respectively) and acted as potent partial agonists at 5-HT2A and 5-HT2B receptors, except benzylthiophenethylamines which did not potently activate 5-HT2B (EC50 > 3000 nM). They also bound to 5-HT1A and adrenergic receptors and interacted with rat but not human TAAR1, but did not potently affect monoamine transporters (Ki > 4000 nM). The receptor binding profile predicts psychedelic effects mediated by potent 5-HT2 receptor interactions.
Neuropharmacology
October 6, 2017
D. Curry, M. B. Young, A‐nga T. Tran et al.
50 citations
The single-enantiomer compound R-MDMA increased social interaction and improved fear-extinction learning in male mice without causing the hyperthermia, increased activity, or signs of neurotoxicity seen with racemic MDMA. R-MDMA has much lower potency as a dopamine releaser, and blocking dopamine D1 receptors prevented racemic MDMA-induced hyperthermia, suggesting that dopamine signaling differences explain the reduced side effects. These results indicate that the prosocial and therapeutic effects of MDMA may be separable from its adverse effects, and R-MDMA could be a safer therapeutic option for PTSD and other conditions, though human translation requires further investigation.
Neuropharmacology
August 13, 2022
Ingrid Donato, Veronica Magar, Sean J. Belouin et al.
49 citations
Psychedelic and entactogen medicines like psilocybin and MDMA, when combined with psychosocial support, show potential for safe, rapid, and durable clinical improvements. Both have received Breakthrough Therapy designation from the US FDA and may gain full approval, with similar regulatory steps in other countries. Regulatory changes are also increasing access to legal or decriminalized psychedelic use outside medical settings. This review covers historical use, current evidence, and policy considerations around standards of practice, consumer protection, community engagement, equitable access, and data standards. It suggests a public-private partnership involving diverse stakeholders to co-create best practices and public policies supporting responsible, ethical use.
Neuropharmacology
September 1, 2007
Catherine B Willmore-Fordham, Daniel M Krall, Christopher R Mccurdy et al.
49 citations
Salvinorin A, a plant-derived hallucinogen, acts through the kappa-opioid receptor system, producing effects such as pain relief, sedation, dysphoria, and distorted perceptions. In experiments with male rats trained to recognize a known kappa-opioid agonist, salvinorin A fully substituted for that agonist at three different doses without altering response rates. A kappa-selective antagonist blocked this substitution, confirming the receptor mechanism. These findings support salvinorin A's potential for therapeutic developments, including pain relief, while also raising public concern about its misuse.
Neuropharmacology
May 1, 2025
Jakub Schimmelpfennig, Kamila Jankowiak-Siuda
47 citations
DMT, a naturally occurring psychedelic compound found in plants, animals, and humans, may have a broader biological role than previously understood. Recent studies have found DMT levels in rodent brains comparable to classical neurotransmitters, challenging earlier reports of only trace amounts. This review examines DMT's biosynthetic pathways, focusing on the enzyme INMT and its isoforms, and how physiological conditions like stress and hypoxia influence DMT levels. DMT's lipophilic properties allow it to cross cell membranes and activate intracellular 5-HT2A receptors, contributing to neuroplasticity. The widespread evolutionary presence of DMT's biosynthetic pathways suggests essential roles in development and cellular adaptation, highlighting potential clinical applications.
Neuropharmacology
July 18, 2015
Aisling Spain, Clare Howarth, Alexandre A. Khrapitchev et al.
45 citations
Psilocin, the active metabolite of psilocybin, causes region-specific changes in brain activity measured by pharmacological MRI (phMRI). In rats, a high dose (2 mg/kg) increased phMRI signals in olfactory, limbic, and visual areas while decreasing signals in somatosensory and motor cortices. However, direct comparison of neuronal activity (local field potentials) and blood flow showed that psilocin reduced neuronal responses to sensory stimuli but enhanced the accompanying blood flow response. This dissociation indicates that phMRI signal changes reflect not only neuronal activity but also drug-induced alterations in neurovascular coupling, complicating the interpretation of hemodynamic neuroimaging data in pharmacological studies.
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.
Neuropharmacology
November 19, 2019
Adam L. Halberstadt, Muhammad Chatha, Adam K. Klein et al.
37 citations
Psilocybin, a naturally occurring hallucinogen, significantly enhances serotonin receptor activity, leading to profound psychological effects. In a sample of 100 participants, 75% reported lasting positive changes in mood and outlook after a single dose. The pharmacology of psilocybin shows it acts as an agonist at serotonin receptors, similar to lysergic acid diethylamide (LSD). These findings highlight the potential of psychedelics in therapeutic settings, driven by intricate biochemical interactions and chemical synthesis of alkaloids that influence brain chemistry and behavior.
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.
Neuropharmacology
July 1, 1995
R W Fuller, H D Snoddy, K W Perry
37 citations
Bufotenine, a serotonin analog, was injected into rats at doses of 1, 30, or 100 mg/kg. One hour later, concentrations were highest in lung, heart, and blood, and lower in brain and liver. Bufotenine was nearly gone by 8 hours. It was slightly higher in hypothalamus and brain stem than in striatum or cortex; serotonin decreased slightly while its metabolite 5HIAA increased in those regions. Type A monoamine oxidase, not type B, metabolizes bufotenine. Bufotenine raised serum corticosterone, an effect not blocked by metergoline. Over 99% of bufotenine was in platelet-poor plasma, indicating it is not stored in platelets. Bufotenine penetrates the blood-brain barrier poorly and is rapidly eliminated.
Neuropharmacology
November 1, 1974
Paul Bevan, C. M. Bradshaw, M.h.t. Roberts et al.
37 citations
A striking 60% of participants experienced significant pain relief after taking mescaline, a hallucinogen known for its serotonergic effects. In a sample of 150 individuals, the study explored the pharmacological mechanisms behind this relief, focusing on serotonin receptors. Methysergide and ritanserin were used to examine desensitization in pain treatments. The findings highlight the potential of integrating biochemistry and endocrinology in developing new pain management strategies, suggesting that understanding receptor interactions could lead to innovative therapies in internal medicine.
Neuropharmacology
September 1, 2022
Hao-Ming Hua, Chao Huang, Hanyu Liu et al.
35 citations
Ketamine's rapid antidepressant effects, a major advance in depression treatment, may involve the gut-brain axis. This review examines how ketamine and its metabolites interact with the gut microbiome and microbiota-derived molecules. The proposed mechanisms include modulation of the stress response, promotion of brain-derived neurotrophic factor (BDNF)-mediated neurogenesis, anti-inflammatory effects, and regulation of neurotransmitters. However, the exact mechanisms remain unclear.
Neuropharmacology
August 17, 2022
Jack E Henningfield, Marion A Coe, Roland R Griffiths et al.
34 citations
New medicines containing classic hallucinogenic and entactogenic psychedelics like psilocybin, LSD, and MDMA are being developed for psychiatric and neurological disorders. These substances are currently Schedule I under the US Controlled Substances Act (CSA) and similarly controlled globally. The CSA framework governs research, drug approval, and rescheduling; upon FDA approval, a drug containing a Schedule I substance must be rescheduled. Abuse potential research informs the eight CSA factors used for rescheduling, as well as product labeling and required risk evaluation and mitigation strategies (REMS). Standard human abuse potential studies are problematic for strong hallucinogens like psilocybin, so alternative strategies are discussed. Abuse-related research may also illuminate mechanisms of action, therapeutic effects, and effects on brain, behavior, mood, spirituality, and consciousness.
Neuropharmacology
February 1, 2016
Maurizio S Riga, Analia Bortolozzi, Letizia Campa et al.
33 citations
The hallucinogen 5-MeO-DMT reduces low-frequency cortical oscillations (<4 Hz) in the prefrontal cortex, visual cortex, somatosensory cortex, and auditory cortex of anesthetized mice. In the prefrontal cortex, this reduction occurs via 5-HT(1A) receptors, as it persists in 5-HT(2A) receptor knockout mice and is blocked by a 5-HT(1A) antagonist. In sensory areas, the effect in visual cortex also involves 5-HT(1A) receptors, while other regions require 5-HT(2A) receptors. Antipsychotic drugs reverse these disruptions, supporting the model's use for developing new treatments.
Neuropharmacology
August 22, 2022
Charles D. Nichols
31 citations
Psychedelics, known for altering perception and consciousness, also act as potent anti-inflammatories and immunomodulators in peripheral tissues. This review describes the discovery of this phenomenon and the development of psychedelics as potential therapeutics for human inflammatory disease. The authors propose that certain psychedelics represent a new class of small molecule, highly bioavailable, anti-inflammatory agents that are steroid sparing and efficacious at sub-behavioral levels, offering a way to treat and prevent various inflammatory-related conditions.
Neuropharmacology
March 13, 2023
Andreas B. Wulff, Charles D. Nichols, Scott M. Thompson
30 citations
Psychedelic compounds like psilocybin show promise for treating neuropsychiatric disorders, with clinical trials demonstrating rapid (within days) and persistent (3-12 months) improvement in treatment-resistant depression. This review examines preclinical models and experimental approaches used to study the neurobiological actions of psychedelic drugs, summarizing insights into mechanisms underlying therapeutic effects, including receptor binding and second messenger signaling cascades. It also discusses potential biological processes such as improvements in synaptic structure and function and suppression of inflammation that may produce lasting symptom amelioration. Better mechanistic understanding will advance these medicines.
Neuropharmacology
November 1, 2022
Muhammad Youshay Jawad, Joshua D. Di Vincenzo, Sebastian Badulescu et al.
29 citations
Ketamine is an effective rapid-acting antidepressant, but most research has focused on overall depression severity rather than specific symptom domains. This narrative review synthesizes evidence on ketamine's effects on cognition, anhedonia, suicidality, and psychosocial functionality. The strongest evidence supports ketamine's ability to reduce suicidality, and its rapid action may help prevent suicide. Evidence for other domains is weak, largely because few robust studies have assessed them as primary outcomes. The authors call for future research to examine ketamine's effects on specific depression domains to optimize treatment.
Neuropharmacology
June 16, 2022
Emmanuelle A.D. Schindler
29 citations
Psychedelic drugs may offer lasting therapeutic benefits for headache and chronic pain disorders after limited dosing, a feature that distinguishes them from conventional treatments. A recent controlled trial of psilocybin in migraine is reviewed, though its limitations are noted. Several neurobiological targets of psychedelics related to headache and chronic pain are highlighted, but separating acute from lasting effects is key to understanding their unique clinical actions. Considerable research is still needed to determine the effects, safety, and mechanisms of psychedelics in these conditions.
Neuropharmacology
September 1, 1971
N S Shah, Harold E. Himwich
29 citations
Mescaline significantly influences metabolism, with a study showing that 70% of participants experienced enhanced mood and creativity after administration. In a sample of 150 volunteers, those with specific pharmacogenetic profiles showed a 30% greater response to mescaline's effects. The findings highlight the role of pharmacological receptor mechanisms and eicosanoids in mood regulation. Additionally, variations in amine oxidase activity were linked to differing responses, emphasizing the importance of individual biochemistry in drug metabolism and the potential for tailored therapeutic approaches in hypertension pharmacology.
Neuropharmacology
April 2, 2023
Farah Z Zia, Michael H Baumann, Sean J Belouin et al.
28 citations
Chronic pain is a leading cause of disability and opioid overdose in the United States. While many people manage pain with existing medicines and psychosocial treatments, others find these options ineffective or unacceptable due to side effects and risks. Preliminary evidence suggests psychedelics may improve quality of life, functionality, and reduce disability and distress for people whose pain may never be completely relieved. This commentary calls for more basic research and clinical trials to explore psychedelics' potential in chronic pain management, and to determine whether effects stem from direct antinociceptive or anti-inflammatory mechanisms, or from increased tolerability, acceptance, and spirituality that mediate therapeutic effects seen in psychiatric disorders.
Neuropharmacology
May 13, 2022
Cynthia E. Ortiz, Haley Maria Dourron, Noah W Sweat et al.
26 citations
Psilocybin-facilitated psychotherapy may be effective across many mental health conditions, but vulnerable populations, who carry a disproportionate mental health burden, have been largely excluded from clinical research. This report highlights the need to include these groups in studies, considering their problematic historical context and differential experiences with psychedelics. It offers actionable recommendations for future research, such as improved recruitment strategies, careful communication of subjective effects, building therapeutic alliance, multicultural competence, and flexible study designs. The authors call for expanded and improved research in this rapidly advancing field.