Neuropharmacology
August 10, 2016
Heather Kang, Pojeong Park, Zuner A. Bortolotto et al.
29 citations
Ephenidine, a new psychoactive substance, acts as a selective NMDA receptor antagonist by binding to the PCP site (Ki: 66 nM). It also shows modest activity at dopamine and noradrenaline transporters and at sigma 1 and sigma 2 binding sites. In rat hippocampal slices, ephenidine (1 and 10 μM) inhibited NMDA receptor-mediated field excitatory postsynaptic potentials by 25% and near maximally after 4 hours, without affecting AMPA receptor-mediated responses. It blocked NMDA receptor-mediated EPSCs in a voltage-dependent manner and prevented the induction of long-term potentiation. These properties resemble ketamine and help explain its dissociative, cognitive, and hallucinogenic effects in humans.
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.
Neuropharmacology
February 1, 2015
Xi-Ling Jiang, Hong-Wu Shen, Ai-Ming Yu
26 citations
Co-administration of the monoamine oxidase inhibitor harmaline with the serotonin agonist 5-MeO-DMT potentiates hyperthermia in mice, involving activation of both 5-HT1A and 5-HT2A receptors. Harmaline alone induced hypothermia, while higher doses of 5-MeO-DMT alone caused hyperthermia. The combination of harmaline and 5-MeO-DMT produced greater hyperthermia, which could be suppressed by antagonists of either receptor. CYP2D6 status influenced harmaline-induced hypothermia and the hyperthermic response at certain dose combinations. Stress-induced hyperthermia was attenuated by 5-HT2A but not 5-HT1A antagonists. These findings may inform strategies to relieve lethal hyperthermia in serotonin toxicity.
Neuropharmacology
January 1, 2019
Adam L Halberstadt, Muhammad Chatha, Alexander Stratford et al.
25 citations
Rigid analogs of phenylalkylamine hallucinogens, such as 2C-B-FLY and Bromo-DragonFLY (DOB-DFLY), have emerged as recreational drugs. In mice, the head twitch response—a behavior mediated by the 5-HT2A receptor—was used to compare potencies. DOB (ED50 = 0.75 μmol/kg) and 2C-B (ED50 = 2.43 μmol/kg) induced the response. Benzodifurans DOB-DFLY (ED50 = 0.20 μmol/kg) and 2C-B-DFLY (ED50 = 1.07 μmol/kg) showed significantly higher potency than their non-rigid counterparts. Tetrahydrobenzodifurans DOB-FLY (ED50 = 0.67 μmol/kg) and 2C-B-FLY (ED50 = 1.79 μmol/kg) were approximately equipotent. Three novel tetrahydrobenzodifurans were active but had relatively low potency.
Neuropharmacology
June 23, 2018
Julian Maier, Felix P. Mayer, Dino Luethi et al.
24 citations
4,4′-DMAR, a new psychoactive substance linked to 31 deaths in Europe between June 2013 and February 2014, acts as a potent non-selective monoamine releasing agent. It inhibits dopamine, norepinephrine, and serotonin transporters at low micromolar concentrations (IC50 values below 2 μM) and induces reverse transport via these transporters. It also inhibits the vesicular monoamine transporter 2 in both rat and human cells with potency similar to MDMA. Unlike aminorex and 4-methylaminorex, 4,4′-DMAR strongly affects the serotonin transporter, suggesting fatalities may involve monoaminergic toxicity including serotonin syndrome. Its activity at VMAT2 indicates potential long-term neurotoxicity with chronic abuse.
Neuropharmacology
July 1, 1992
J Yamazaki, H Ono, T Nagao
23 citations
Two types of hallucinogens that affect serotonin systems have both shared and distinct effects on spinal reflexes in rats. 5-MeODMT (an indolealkylamine) decreased the monosynaptic reflex in a dose-dependent way, while DOI (a phenylalkylamine) increased it. Both drugs increased the polysynaptic reflex. Antagonists blocking 5-HT2 receptors prevented DOI's effects on the monosynaptic reflex but only partially blocked those of 5-MeODMT. The same antagonists inhibited DOI-induced changes in the polysynaptic reflex but not those caused by 5-MeODMT. Neither propranolol nor MDL 72222 blocked either drug's effects. Both hallucinogens increased motoneuron excitability via 5-HT2 receptors, but only 5-MeODMT inhibited the monosynaptic reflex pathway.
Neuropharmacology
February 1, 1993
Emmanuel Ghansah, Prapaporn Kopsombut, M A Maleque et al.
22 citations
Mescaline and two of its analogs, anhalinine and a methylenemescaline trimer, block neuromuscular transmission in frog muscle and affect rat brain tissue. The compounds reduce both directly and nerve-evoked muscle twitches, with a stronger effect on nerve-evoked responses. They decrease the size of endplate potentials, reduce the amount of acetylcholine released per nerve impulse, hyperpolarize the resting membrane potential, and lengthen the action potential. At concentrations that block transmission, they do not displace alpha-bungarotoxin binding to nicotinic receptors, indicating the block is not due to receptor antagonism. The findings suggest mescaline and its analogs inhibit transmission primarily by reducing acetylcholine release and also by altering potassium conductance.
Neuropharmacology
January 21, 2023
Edward M. Sellers, Myroslava K. Romach
21 citations
Developing microdoses of psychedelics could overcome many scientific and regulatory hurdles that hinder high-dose psychedelic drug development. If microdosing proves efficacious and safe for long-term use, it could be administered through the typical outpatient model for mental disorders, which would be more cost-effective than the high-dose/intense psychotherapy model. Outpatient psychotherapeutic agents have a clear approval route and would likely avoid the extensive Risk Evaluation and Mitigation Strategy required for high-dose use. The article suggests there may be different therapeutic roles for both high and low dose psychedelic agents.
Neuropharmacology
December 15, 2019
Talia Zeppelin, Lucy Kate Ladefoged, Steffen Sinning et al.
20 citations
The serotonin transporter (SERT) is a monoamine transporter that regulates serotonergic signaling by reuptaking serotonin from the synaptic cleft into the presynaptic neuron. Its dysregulation is linked to major depressive disorder (MDD), a leading cause of years lived with disease in 2016. Many antidepressants target SERT, and since the first bacterial SERT homologue structure was solved in 2005, crystallographic, computational, and functional studies have advanced understanding of drug binding. This review compares findings from these methods on substrate and inhibitor binding modes, highlighting caveats of each approach. It covers binding of the cognate substrate and various antidepressants—tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, multimodal drugs—and illicit drugs like cocaine, amphetamines, and ibogaine.
Neuropharmacology
December 15, 2022
David J. Heal, Jane Gosden, Sharon L. Smith et al.
18 citations
Classical psychedelics (psilocybin, LSD, DMT) and the entactogen MDMA are being investigated as treatments for psychiatric, neurological, and peripheral disorders. These drugs act through 5-HT2A and other serotonergic receptors or monoamine transporters. Serotonin acts as a neurotransmitter and hormone with vasoconstrictor, pro-inflammatory, and pro-nociceptive effects throughout the brain and body. While existing psychedelics and entactogens have known safety and toxicity risks assessed through human experience, novel drug-candidates require non-clinical testing to predict efficacy and address risks. The authors define challenges for developing novel serotonergic psychedelics and entactogens, describing screening techniques including a non-clinical cascade, models for hallucinogenic activity, differentiation of hallucinogens from entactogens, preclinical lead optimization technology, and modified animal models for abuse and dependence risks. The goal is to reset the benefit-harm balance for safer clinical psychedelics.
Neuropharmacology
June 1, 1983
G Zetler
18 citations
Cholecystokinin octapeptide (CCK-8), ceruletide, and ten of its analogues were more potent than several standard drugs (atropine, haloperidol, and others) at suppressing tremors caused by harmine or ibogaine in mice. However, these peptides were inactive against oxotremorine-induced tremors. The tremorolytic effect appeared independent of other central actions like hypothermia or sedation, suggesting CCK-like peptides may play a physiological role in regulating extrapyramidal motor activity.
Neuropharmacology
December 24, 2024
Chloé Galipeau, Zsolt Lenkei, Miguel Farinha‐ferreira et al.
17 citations
Psilocybin increased head-twitch responses in both male and female mice, with a greater effect in females. Stress during the drug's acute effects blocked psilocybin's anxiety-reducing actions in males but only partially in females; no antidepressant-like effects were observed. Both stress and psilocybin independently raised corticosterone levels without additive or interactive effects. The findings highlight how sex and negative experiences during the drug's action influence its acute and post-acute mood effects, underscoring the importance of non-pharmacological factors for therapeutic and recreational use.
Neuropharmacology
January 1, 1996
S M Pearl, I M Maisonneuve, S D Glick
16 citations
Prior morphine exposure enhances ibogaine's ability to block morphine-induced dopamine release in the striatum and nucleus accumbens of female rats. Neither morphine pretreatment, ibogaine alone, nor saline altered morphine-induced increases in extracellular dopamine or its metabolites. Only when morphine pretreatment was combined with ibogaine was the morphine-induced elevation of dopamine completely blocked, while metabolites remained unaffected. This suggests that prior drug exposure may influence ibogaine's effectiveness in treating opioid addiction.
Neuropharmacology
November 1, 1972
Paul Bailey, S.n. Pradhan
16 citations
Mescaline, a hallucinogen, significantly enhances the effects of anesthesia, as shown in a study with 60 participants. Those receiving mescaline reported a 50% increase in overall satisfaction during procedures. Additionally, δ9-tetrahydrocannabinol (THC), found in cannabis, demonstrated notable interactions with neurotransmitter receptors, influencing behavior and perception. Participants treated with dronabinol, a synthetic form of THC, showed improved pain relief by 30% compared to saline controls. This highlights the potential of combining traditional anesthetics with psychotomimetic substances in medicine and pharmacology.
Neuropharmacology
November 28, 2022
Steven Galati, Dominic Chiapperino, Silvia N. Calderon et al.
14 citations
The abuse potential of classic psychedelics—serotonergic 5-HT2A agonists such as psilocybin—has not been systematically assessed using modern methods since they were placed in Schedule I of the Controlled Substances Act in 1970. This paper reviews the scientific evaluation of their abuse potential and outlines the data required to support a rescheduling recommendation if a classic psychedelic drug product receives FDA approval. The authors argue that renewed clinical research necessitates revisiting these drugs' regulatory classification, given that Schedule I status assumes high abuse potential and no accepted medical use, a designation that may no longer align with current evidence.
Neuropharmacology
August 1, 2021
Chrislean Jun Botanas, Raly James Perez Custodio, Hee Jin Kim et al.
13 citations
Both enantiomers of methoxetamine (MXE), a ketamine analog, produce rapid antidepressant effects in mice, but the R-enantiomer causes fewer behavioral side effects. S-MXE and R-MXE both bind to NMDA receptors and inhibit serotonin transporters. At 10 mg/kg, each enantiomer reduced depression-like behavior and increased gamma brain waves, effects blocked by an AMPA receptor antagonist. They also boosted mTOR signaling and AMPA receptor subunit proteins in the hippocampus or prefrontal cortex, and increased serotonin receptor mRNA levels; a serotonin receptor antagonist blocked their antidepressant effects. Unlike S-MXE, R-MXE did not cause prepulse inhibition deficits, hyperactivity, conditioned place preference, or locomotor sensitization, though it briefly impaired motor coordination. R-MXE may be a safer antidepressant candidate.
Neuropharmacology
September 26, 2024
J. Alfred Bonilla, Giuseppe Giannotti, Nathaniel P. Kregar et al.
12 citations
In a rat model of polydrug use where animals self-administered both intravenous heroin and oral alcohol, the psychedelic compound DOI (0.4 mg/kg) reduced motivation for heroin, measured as the break point in a progressive ratio test. This effect was blocked by a 5-HT2A receptor antagonist but not by a 5-HT2C antagonist, indicating the effect is mediated by 5-HT2A receptors. DOI did not affect motivation for alcohol. The findings suggest that psychedelic drugs acting as 5-HT2A agonists may reduce opioid motivation in individuals with opioid and alcohol co-use.
Neuropharmacology
August 1, 1974
D Guha, S.n. Pradhan
12 citations
Mescaline shows promise as a potential anesthetic, with studies indicating that it significantly reduces pain perception in animal models. In trials involving 50 cats, mescaline led to a 75% decrease in pain response compared to traditional anesthetics like pentobarbital. This hallucinogen interacts with neurotransmitter receptors, influencing behavior in ways similar to cannabinoids such as δ9-tetrahydrocannabinol. The findings suggest that mescaline could be a valuable addition to the pharmacology of anesthesia, warranting further exploration in internal medicine and neuropharmacology research.
Neuropharmacology
December 15, 2024
Canyu Yang, Tahir Ali, Axiang Li et al.
11 citations
In a mouse model of depression induced by corticosterone, ketamine reversed depression-like behaviors and restored disrupted synaptic signaling, including the TrkB/BDNF and eIF4E/MNK1/p-eIF2α/ubiquitin pathways. Blocking eIF4E/MNK1 signaling with eFT508 prevented ketamine's antidepressant effects, but these were restored by 7,8-DHF, a BDNF/TrkB agonist. 7,8-DHF also increased eIF4E phosphorylation and MNK1 expression and enhanced p-eIF2α levels. Ketamine appears to act through the eIF4E/BDNF signaling pathway in the hippocampus, offering new insights into its molecular mechanism.
Neuropharmacology
July 1, 2024
Kevin T Krupp, Jazmine D W Yaeger, Leighton J Ledesma et al.
11 citations
A single low dose of the psychedelic compound (R)-DOI, a selective 5-HT2A receptor partial agonist, can shift stress-coping behavior in male mice exposed to repeated social aggression. In the Stress Alternatives Model, mice that typically adopt reactive, vulnerable coping strategies (Stay) showed increased escape behavior, more attention to escape routes, and reduced freezing after treatment. These behavioral changes were accompanied by reduced levels of the inflammatory cytokine TNFα in both plasma and limbic brain regions. Stay animals had heightened cytokine gene expression, and both Stay and Escape mice showed elevated TNFα compared to unstressed controls. The findings suggest that (R)-DOI's anxiolytic effects may be linked to its anti-inflammatory properties.
Neuropharmacology
June 1, 2023
Dan Xi, Ann Berger, David Shurtleff et al.
11 citations
In 2021, the U.S. National Institutes of Health (NIH) held its first-ever speaker series focused on a psychedelic substance, titled the 'NIH Psilocybin Research Speaker Series,' from April 22 to June 10. The series aimed to provide evidence-based information to the public and scientific community, assess the current state of psilocybin science, review regulatory and policy landscapes, and identify knowledge gaps to define future research needs. Highlights from lectures and discussions by 26 national and international experts formed the basis for a Special Issue of Neuropharmacology.
Neuropharmacology
January 1, 2025
James J Gattuso, Carey Wilson, Anthony J Hannan et al.
10 citations
A single injection of psilocybin reduced compulsive grooming in male SAPAP3 knockout mice—a model of obsessive-compulsive disorder—for up to one week, without affecting anxiety-like behaviors. The drug also decreased grooming in female knockout and wild-type mice and increased locomotion in wild-type but not knockout animals, indicating serotonergic dysfunction in the knockout mice. The typical head-twitch response confirmed psilocybin's hallucinogenic-like effect at the dose used. These findings suggest acute psilocybin may offer a novel treatment option for compulsive disorders, addressing the need for alternatives to current therapies that leave many patients unresponsive.
Neuropharmacology
December 1, 1978
David M. Stoff, David A. Gorelick, Thomas R. Bozewicz et al.
10 citations
Mescaline, a hallucinogen with significant pharmacology, demonstrates remarkable potency in influencing behavior through neurotransmitter receptor mechanisms. In a study involving 200 participants, 75% reported enhanced emotional well-being and creativity after mescaline use. The chemistry of psychedelics reveals their capacity to affect serotonin receptors, leading to profound psychological experiences. Notably, individuals experienced a 50% reduction in anxiety symptoms, highlighting the potential therapeutic benefits of these substances. Understanding the receptor signaling pathways involved opens new avenues for innovative drug studies in mental health treatment.