Frontiers in Pharmacology
July 6, 2018
Elizabeth B. de Sousa Fernandes Perna, Eef L. Theunissen, Patrick C. Dolder et al.
18 citations
A single 100 mg dose of 4-fluoroamphetamine (4-FA), a phenethylamine novel psychoactive substance, produced strong elevation in blood pressure for 4-5 hours followed by sustained increased heart rate in healthy volunteers. Effects on mood and neurocognitive function peaked at 1 hour, including significant elevations of vigor, friendliness, elation, arousal, and positive mood, along with improvements in attention and motor performance. Negative affect also increased during the acute and subacute phases. The 150 mg dose was canceled after an interim safety review. The findings confirm clinical observations of acute toxicity and warrant warnings about health risks.
Frontiers in Pharmacology
June 28, 2022
Nataliya S. Vorobyeva, Alena A. Kozlova
16 citations
Classic psychedelics, which resemble serotonin and bind to serotonin receptors, are being studied as treatments for psychiatric conditions such as post-traumatic stress disorder, major depressive disorder, anxiety, and substance use disorders. Mental health disorders are common and pose a major public health challenge; existing treatments often face issues with treatment resistance and high relapse rates. This review examines three naturally occurring psychedelics—psilocybin, ibogaine, and N,N-dimethyltryptamine—focusing on their pharmacological properties and clinical potential. The article aims to summarize key research on these substances and consider their possible use as alternatives or additions to current pharmacological and psychological therapies.
Frontiers in Pharmacology
February 9, 2022
Karolina E. Kolaczynska, Dino Luethi, Dino Luethi et al.
16 citations
Mescaline, a psychedelic found in peyote, belongs to a class of compounds called scalines and 3C-scalines, which may serve as novel therapeutics for psychedelic-assisted therapy. This in vitro study examined several previously uninvestigated scalines and 3C-scalines at key monoamine targets. These compounds bound to the 5-HT2A receptor with weak to moderately high affinity (Ki = 150–12,000 nM). 3C-scalines showed a marginal preference for 5-HT2A over 5-HT2C and 5-HT1A receptors, while scalines showed no preference. Extending the 4-alkoxy substituent increased binding affinities and activation potency at 5-HT2A but not 5-HT2B receptors.
Frontiers in Pharmacology
September 16, 2021
Lukas A. Basedow, Thomas Riemer, Simon Reiche et al.
16 citations
Repeated use of serotonergic psychedelics such as LSD, ayahuasca, and peyote is associated with distinct neuropsychological profiles rather than a uniform pattern of impairment. A systematic review of 13 studies (539 participants) found that LSD users performed worse on executive-functioning tasks, ayahuasca users showed better performance on the Stroop incongruent task, and peyote users showed no differences across domains. However, methodological quality varied widely, and most studies failed to fully control for confounding factors like other substance use. The evidence suggests that different psychedelics may have different long-term cognitive consequences.
Frontiers in Pharmacology
July 22, 2022
Leor Roseman, Katrin H. Preller, Evgenia Fotiou et al.
15 citations
As psychedelic treatments become more mainstream and medicalized, there is a growing focus on their pharmacological and psychological effects on the individual, at the expense of their social and cultural dimensions. Alienation and related mental health problems are increasing, highlighting the need for therapies that also foster social cohesion and a more equitable society. Psychedelics have historically brought people together and revitalized cultures through shared experiences. This social aspect—psychedelic sociality—should be integrated into current research and practice to realize their potential for both individual therapy and broader societal change.
Frontiers in Pharmacology
April 18, 2024
Elad Lerer, Alexander Botvinnik, Orr Shahar et al.
14 citations
Psilocybin and a psilocybin-containing mushroom extract, but not the serotonin precursor 5-hydroxytryptophan, increased expression of immediate early genes cfos and egr1 in the somatosensory cortex of male mice. The head twitch response, a behavioral measure, did not correlate with gene expression changes. Blocking the 5-HT2C receptor enhanced psilocybin-induced egr2 expression, but other serotonergic modulators had no effect. These findings suggest that cfos and egr1 expression may be linked to psychedelic effects.
Frontiers in Pharmacology
December 3, 2020
Lauri Elsilä, Nuppu Korhonen, Petri Hyytiä et al.
13 citations
Acute doses of LSD at 0.025, 0.1, and 0.2 mg/kg did not alter reward-driven decision making in mice performing a touch-screen version of the Iowa Gambling Task, nor did the serotonin 2A receptor agonist 25CN-NBOH. The highest LSD dose (0.4 mg/kg) reduced premature responses and increased omission rates without affecting option selection. Amphetamine decreased correct responses and premature responding while increasing omission rates. Mice can perform previously learned decision-making tasks under LSD at commonly used doses.
Frontiers in Pharmacology
February 2, 2024
Joachim Neumann, Stefan Dhein, Uwe Kirchhefer et al.
12 citations
Hallucinogenic drugs like LSD, psilocybin, and DMT affect the brain by stimulating serotonin receptors, particularly 5-HT2A receptors, which likely causes their hallucinogenic effects. However, these drugs also act on the heart, potentially increasing the force of contraction and heart rate, and may lead to arrhythmias. This review examines the inotropic and chronotropic actions of bufotenin, psilocin, psilocybin, LSD, ergotamine, ergometrine, N,N-dimethyltryptamine, and 5-methoxy-N,N-dimethyltryptamine in the human heart.
Frontiers in Pharmacology
June 28, 2017
Patrick C. Dolder, Edna Grünblatt, Felix Müller et al.
12 citations
A single 100 μg dose of LSD did not change the expression of the serotonin 5-HT2A receptor gene (HTR2A) or the early growth response genes EGR1, EGR2, and EGR3 in the whole blood of 15 healthy subjects, measured 1.5 and 24 hours after administration. This null finding contrasts with rodent studies showing that LSD acutely increases EGR1 and EGR2 expression in the brain and that repeated use reduces 5-HT2A receptor binding. Whether chronic LSD administration alters gene expression in humans remains unknown.
Frontiers in Pharmacology
January 12, 2024
Ninon Freidel, Liliane Kreuder, Brenden Samuel Rabinovitch et al.
11 citations
Clinical trials of psychedelics for neurological and psychiatric disorders have systematically excluded people with past or current seizures, despite a lack of evidence that supervised psychedelic use causes or worsens seizures. No clinical trial or preclinical seizure model has shown that psychedelics induce seizures. This review presents cases where individuals experienced either seizures or seizure remission after psychedelic use, with the overall trend indicating safety in controlled clinical settings. The authors propose future research directions to include this population.
Frontiers in Pharmacology
January 1, 2013
Wendy K. Adams, Adam L. Halberstadt, Maarten van den Buuse
11 citations
Blocking NMDA receptors with phencyclidine (PCP) can produce schizophrenia-like symptoms in humans, but PCP also affects other systems. Rats with serotonin-depleting lesions in the dorsal hippocampus showed increased hyperactivity from PCP but not from the more selective NMDA blocker MK-801. Lesions in the ventral hippocampus had no effect. PCP and MK-801 both made the rats' movement paths smoother and less predictable, but the dorsal hippocampus lesions did not alter these qualitative effects for PCP, though they slightly reduced MK-801's effect on unpredictability. The results reveal a functional difference between PCP and MK-801 related to serotonin in the dorsal hippocampus, relevant to schizophrenia research.
Frontiers in Pharmacology
August 22, 2023
Mary G. Hornick, Ashley Stefanski
9 citations
The opioid epidemic in the United States persists, with opioid use disorder (OUD) at its core, involving physical addiction, psychological issues, and social-legal problems. Existing treatments have limited effectiveness due to access barriers, strict regimens, and failure to address non-pharmacological aspects. A growing body of research suggests hallucinogens, particularly psychoplastogens like ibogaine, ketamine, and classic psychedelics, may offer a unique, holistic alternative by combining pharmacological, neuroplasticity, and psychological mechanisms. However, legal, social, and safety concerns have hindered research. This review examines preclinical and clinical evidence for these compounds in treating OUD, while noting that further research is needed to establish long-term efficacy and proper safety and ethical guidelines.
Frontiers in Pharmacology
May 24, 2024
Norman Nyazema, Jonathan Tinotenda Chanyandura, B. Egan
7 citations
Traditional medical practitioners in southern Africa use several indigenous psychoactive plants for divination and treating mental illnesses. A review of socio-pharmacological studies identified commonly used or abused plants including Boophone disticha, Cannabis sativa, Datura stramonium, Leonotis leonurus, Psilocybe cubensis, and Sceletium tortuosum. Commercialization of Cannabis, L. leonurus, S. tortuosum, and Aspalathus is growing rapidly, while abuse liability of B. disticha, D. stramonium, and P. cubensis appears underappreciated. Five countries have traditional medical practitioner policies, and three have councils. The authors suggest working closely with practitioners to reduce harm and explore therapeutic development of these plants.
Frontiers in Pharmacology
March 16, 2023
Leandro Val Sayson, Darlene Mae Ortiz, Hyun Jun Lee et al.
4 citations
Mice lacking the Cryab gene show stronger addiction-like responses to the synthetic cannabinoid JWH-018, including greater self-administration and place preference, along with altered gamma brain waves, compared to normal mice. Repeated JWH-018 exposure did not change endocannabinoid or dopamine gene expression or dopamine levels in the brain's reward center between the two groups. However, the knockout mice displayed increased neuroinflammation, linked to upregulated NF-κB, and higher levels of synaptic plasticity markers. These findings suggest that heightened neuroinflammation via NF-κB may drive the enhanced cannabinoid addiction-related behaviors in Cryab knockout mice, making them a potential model for studying susceptibility to cannabinoid abuse.
Frontiers in Pharmacology
June 27, 2022
Snehal Bhatt, Maya Armstrong, Tassy Parker et al.
4 citations
Post-traumatic stress disorder (PTSD) and substance use disorders (SUDs) frequently co-occur, a link shaped by adverse childhood experiences, historical and multi-generational traumas, and social, cultural, and spiritual factors. Current treatments for PTSD are only modestly effective, and more research is needed on interventions for co-occurring PTSD and SUD, including whether to treat them together or sequentially. Interest in psychedelics as a treatment augmentation is reviving, though risks remain. This review covers the history of psychedelic research and practices, examining historical trauma, adverse childhood experiences, PTSD, and SUDs through the lens of New Mexico, a state with large Indigenous and Hispanic populations and high rates of trauma and substance use. Future directions include community-based participatory approaches respectful of Indigenous and minority communities.
Frontiers in Pharmacology
June 3, 2024
Gio Kim, Catherine K. Wang, Lily R. Aleksandrova et al.
3 citations
A systematic review of preclinical studies found that extracts from 19 mushroom species and 7 other fungus species nearly all produced antidepressant-like effects in animal models of depression. The review identified 50 relevant studies, mostly in male rodents, using oral administration in acute or chronic regimens. The most common animal model was unpredictable chronic mild stress, while the tail suspension test and forced swim test were frequently used as antidepressant screens. The review discusses each experiment in detail and evaluates the strengths and weaknesses of the studies, highlighting that the antidepressant potential of mushroom and fungus extracts extends beyond psilocybin-containing species to include both psychedelic and non-psychedelic varieties.
Frontiers in Pharmacology
July 7, 2025
Zhejun Xie, Ning Cao, Manlin Li et al.
2 citations
Harmine, an endogenous compound whose levels vary with physiological and disease states, may act as a neurotransmitter or neuromodulator. The protein APMAP-X1 catalyzes the formation of tetrahydroharmine, which is then oxidized by MPO to produce harmine. Harmine is metabolized, taken up, and released within the synaptic cleft, and it regulates neurotransmitter transporter expression. It binds to GPR85 and CLIC2 receptors in the central nervous system, inhibiting GPR85 and inducing cellular depolarization. These findings suggest harmine has neurotransmitter-like properties and may function as an endogenous neuromodulator, though direct evidence as a neurotransmitter remains limited.
Frontiers in Pharmacology
November 20, 2025
Karolina E. Kolaczynska, Daniel Trachsel, Marius C. Hoener et al.
1 citation
A class of psychedelic compounds called 4-substituted 2,6-dimethoxyphenethylamines and their amphetamine counterparts (Ψ derivatives) were tested for their interactions with monoamine receptors and transporters. These derivatives showed moderate to high affinity and activity at the human 5-HT2A receptor, the primary target for psychedelics, with binding affinities ranging from 8 to 1,600 nM and activation potencies from 32 to 3,400 nM. They acted as partial agonists at this receptor. The phenethylamine derivatives also bound to 5-HT1A and 5-HT2C receptors with moderate affinity, while amphetamine derivatives had weaker affinities. Some Ψ derivatives interacted with TAAR1 and adrenergic receptors. Compared to 2,4,5-trisubstituted derivatives, the 2,4,6-trisubstituted Ψ derivatives were generally less potent at the 5-HT2A receptor but more potent than 3,4,5-trisubstituted derivatives.
Frontiers in Pharmacology
September 17, 2025
Xiao Wang, Lijuan Yan, Jiaying Cai et al.
1 citation
A randomized controlled trial compares the risk of respiratory depression between esketamine-based and fentanyl-based analgesia during liver ablation guided by high-frequency harmonic scalpel. If esketamine shows superior respiratory safety, it could become a viable treatment option.
Frontiers in Pharmacology
June 3, 2026
Burton J. Tabaac, Robin L. Carhart-Harris, Teresa Yung
Three individuals with persistent symptoms after traumatic brain injury or hypoxic-ischemic brain injury completed a six-week protocol combining a participant-directed iboga-containing microdosing regimen (using whole root bark biomass with about 3.845% ibogaine content, yielding an estimated 3.8–38.5 mg/day ibogaine equivalent) with weekly Accelerated Experiential Dynamic Psychotherapy and supportive nutraceuticals. All three showed progressive neurological recovery; two reported complete symptom remission at long-term follow-up. Participants discontinued all prescription medications and reported resolution of headaches, brain fog, fatigue, irritability, and mood swings, with a return to regular activities and renewed enthusiasm. The authors note that the findings do not establish causality or iboga-specific efficacy due to the multimodal intervention and methodological limitations.
Frontiers in Pharmacology
May 26, 2026
Michal Ordak
The psychoactive mushroom Amanita muscaria is increasingly used recreationally and for self-therapy, promoted online for stress reduction, mood improvement, sleep, and pain relief despite limited clinical evidence and known toxicity. This narrative review synthesizes evidence showing rising intentional consumption, varied dosing, and outcomes from mild neurological symptoms to severe intoxication requiring hospitalization. Online narratives and informal harm reduction advice normalize use and may lead to underestimating risks. As a non-synthetic psychoactive substance sold in digital markets, A. muscaria poses regulatory and public health challenges, with no standardized management guidelines or systematic surveillance. Greater awareness of its toxicology, misuse patterns, and emergency care is needed.
Frontiers in Pharmacology
March 16, 2026
Alessandra Linardi, Ariadiny Lima Caetano, Rodrigo Portes Ureshino
Scientific interest in psychedelic substances has revived, offering new perspectives on treating neuropsychiatric and neurological disorders. Psychedelics induce neuroplasticity and alleviate symptoms of depression, anxiety, PTSD, and neurodegenerative diseases like Alzheimer's and Parkinson's. A review of six abused recreational drugs—methamphetamine, cocaine, synthetic cathinones, ketamine, nitrous oxide, and heroin—shows they share convergent neurotoxic mechanisms involving oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. Original research demonstrates that social hierarchy modulates methamphetamine reinforcement in rats and is associated with distinct phosphoproteomic signatures in the nucleus accumbens, with HDAC4 phosphorylation differing between dominant and subordinate rats. A mini-review discusses trace amine-associated receptors, particularly TAAR1, as potential therapeutic targets for anxiety and depression.
Frontiers in Pharmacology
March 11, 2026
Katrin Brache, Mauricio Diazgranados
Neuropsychiatric disorders affect nearly one billion people worldwide, and existing treatments are limited by side effects and variable efficacy. This review of 42 Colombian plant species used in Indigenous and local health systems for conditions overlapping with mental and neurological disorders found that ayahuasca (yagé) was the most frequently reported preparation, while Nicotiana tabacum, Erythroxylum coca, and Aloysia citrodora were the most commonly cited species. Leaves (38%), stems (14%), and roots (13%) were the most used plant parts, prepared as decoctions (21%) and infusions (17%).
Frontiers in Pharmacology
March 4, 2026
Mi Zhou, Y M Qi, Fan Zhou et al.
Adding a moderate dose of esketamine (0.03 mg/kg/h) to patient-controlled intravenous analgesia combined with a preoperative intercostal nerve block significantly reduced acute postoperative pain after thoracoscopic lobectomy, compared to a low dose of esketamine or sufentanil alone. Pain scores on the Numerical Rating Scale were lower at 2, 4, 24, 48, and 72 hours after surgery, and the need for rescue analgesia and opioid consumption decreased. The moderate esketamine group also had less postoperative nausea and vomiting than the sufentanil group. Low-dose esketamine did not improve pain control over sufentanil alone.
Frontiers in Pharmacology
December 4, 2025
Maya Nicolas
Ibogaine, a compound from the Tabernanthe iboga plant, may restore reward-system function across multiple disorders—including addiction, OCD, PTSD, and eating disorders—by upregulating GDNF, modulating glutamate and dopamine signaling, and reopening neuroplasticity. These conditions share disrupted dopaminergic and glutamatergic signaling in mesocorticolimbic circuitry, leading to maladaptive reinforcement and motivational dysregulation. Historical, preclinical, and observational evidence suggests ibogaine acts on underlying reward dysfunction rather than only symptoms. However, safety concerns include hERG channel inhibition, requiring strict medical protocols. This review proposes a unified mechanism but notes the framework requires empirical validation.