Frontiers in Pharmacology
January 1, 2024
Xinxia Yang, Dongdong Chen
10 citations
Adverse drug events from ketamine and esketamine differ between men and women. Analyzing reports from the FAERS database between 2004 and 2023, 2907 female and 1634 male esketamine reports showed that completed suicide, decreased therapeutic product effects, urinary retention, and hypertension were more common in men. For ketamine, 552 female and 653 male reports indicated that toxicity to various agents, bradycardia, cystitis, and agitation were more likely in men, while women were more likely to develop suicidal ideation, increased transaminase levels, sclerosing cholangitis, and sterile pyuria. These gender differences should guide individualized clinical treatment.
Frontiers in Pharmacology
January 1, 2021
Gabrielle M Henriques, Alexia Anjos-Santos, Isa R S Rodrigues et al.
10 citations
Ibogaine, a psychedelic from the African plant Tabernanthe iboga, blocked the reinstatement of a conditioned place preference for ethanol in male mice, suggesting it may disrupt learned alcohol-seeking behaviors. Ethanol (1.8 g/kg) induced a conditioned place preference, but ibogaine (10 or 30 mg/kg) did not produce rewarding effects on its own. Repeated ibogaine treatment after ethanol conditioning prevented reinstatement of the preference both when mice received a priming ethanol injection and when they were re-exposed to the ethanol-paired compartment without the drug. These results indicate ibogaine could have therapeutic potential for alcohol use disorder at doses that lack rewarding effects.
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
January 1, 2022
Margarida L F Martins, Paniz Heydari, Wenlong Li et al.
9 citations
Ibogaine, a psychedelic alkaloid used orally for substance use disorders despite being unlicensed, is rapidly converted to noribogaine and noribogaine glucuronide in mice. The drug efflux transporters ABCB1 and ABCG2 modestly restrict ibogaine's oral availability, possibly through hepatobiliary or intestinal excretion, and ABCB1 limits its brain penetration. In wild-type mice, the brain-to-plasma ratio was 3.4, increasing 1.5-fold in mice lacking both transporters. Human OATP transporters and CYP3A4 had no major impact on ibogaine pharmacokinetics, suggesting low risk of drug interactions or interindividual variation from these pathways.
Frontiers in Pharmacology
January 1, 2024
Yunfeng Yu, Juan Deng, Keke Tong et al.
8 citations
Adding esketamine to anesthesia for children undergoing gastrointestinal endoscopy shortens recovery time by about 2.3 minutes, reduces propofol needed by 0.7 mg/kg, and lowers the risk of involuntary movements by 59% and choking by 51%, while increasing heart rate and blood pressure. However, general doses raise dizziness risk by 98%. Low doses (≤0.3 mg/kg) provide the same benefits without increasing dizziness. Trial sequential analysis confirmed these findings are conclusive.
Frontiers in Pharmacology
January 1, 2025
Georgina de la Rosa, Esther Papaseit, Olga Hladun et al.
7 citations
Alpha-pyrrolidinopentiophenone (α-PVP), a synthetic cathinone similar to MDPV and cocaine, produces rapid-onset psychostimulant and empathogenic effects after a single intranasal dose. In nine participants with prior psychostimulant use, 10 mg or 20 mg of α-PVP caused an acute increase in blood pressure and heart rate that peaked 40 minutes after administration. Subjective effects appeared quickly and resolved within 3 to 5 hours. The drug's psychostimulant properties resembled those of cocaine, and its empathogenic effects were similar to those of MDMA and other cathinones like methylone.
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
January 1, 2024
Xulin Chen, Xian Wang, Caijuan Li et al.
7 citations
Over the past 20 years, research on NMDA receptors as targets for depression treatment has grown steadily, with 5,092 publications identified. The United States leads in collaborations, publications, and citations. Co-cited reference analysis revealed 15 main clusters. Recent hotspots include ketamine (an NMDA receptor antagonist) for treatment-resistant depression, oxidative stress, synaptic plasticity, and neuroplasticity-related factors such as brain-derived neurotrophic factor. While ketamine's application and mechanisms in major depressive disorder remain a hot topic, its side effects have spurred investigation into new rapid-acting antidepressants.
Frontiers in Pharmacology
January 1, 2025
Jinming Chen, Ying Mai, Xiaolei Cheng et al.
5 citations
In children aged 3 to 6 undergoing endotracheal intubation without muscle relaxants, the combination of remimazolam and esketamine with a fixed dose of remifentanil (2.5 μg/kg) provided safe and effective intubation conditions while maintaining hemodynamic stability. Using Dixon's up-and-down method, the 50% effective dose (ED50) for esketamine was 0.74 mg/kg and the 95% effective dose (ED95) was 0.97 mg/kg. For remimazolam, the ED50 was 0.39 mg/kg and the ED95 was 0.56 mg/kg. No significant adverse events were observed, and heart rate and blood pressure remained stable during induction. These doses serve as initial references for pediatric intubation without muscle relaxants.
Frontiers in Pharmacology
January 1, 2025
Haoning Guo, Liling Tang, Miaoquan He et al.
5 citations
A systematic review and meta-analysis of 47 studies found that both ketamine and esketamine are associated with a higher rate of adverse events than placebo in treating major depressive disorder, but serious adverse events were not significantly increased. Common side effects include dizziness, dissociation, nausea, vertigo, and blurred vision, which are dose-dependent and transient. Esketamine showed a potential tolerability advantage over ketamine, with higher number needed to harm values, meaning fewer people experience side effects per dose. No significant long-term issues were found for cognitive function, bladder symptoms, or addiction-related measures. Direct head-to-head trials are needed to confirm these findings.
Frontiers in Pharmacology
January 1, 2024
Ruixue Liu, Chunxiao Liu, Dianwei Feng et al.
5 citations
An analysis of adverse event reports from the FDA adverse event reporting system between 2019 and 2023 identified 14,606 reports in which esketamine nasal spray was the primary suspected drug. Psychiatric disorders accounted for 33.20% of the 518 distinct adverse event signals, followed by nervous system disorders (16.67%) and general disorders (14.21%). Dissociation was the most frequent and intense signal, reported 1,093 times. Uncommon but strong signals included hand-eye coordination impaired, feeling guilty, and feelings of worthlessness. Dissociative disorder, not listed in the product's summary of product characteristics, also showed a strong signal. Close clinical attention to psychiatric and nervous system adverse events is warranted.
Frontiers in Pharmacology
January 1, 2025
Elizabeth G Neureiter, M Quincy Erickson-Oberg, Aparna Nigam et al.
4 citations
N-methyl-D-aspartate receptors (NMDARs) are ion channels in brain synapses crucial for learning and memory, but their overactivity contributes to nervous system disorders. Clinically, these disorders are treated with channel-blocking drugs that inhibit NMDARs via two mechanisms: traditional block, where charged drugs enter the channel directly from extracellular fluid after activation, and membrane-to-channel inhibition (MCI), where uncharged drugs first enter the hydrophobic cell membrane, then move into the channel through a fenestration upon receptor activation. MCI is poorly understood despite its clinical relevance. This review examines how membrane-associated drugs inhibit NMDARs and other ion channels, and how the path of drug access may influence therapeutic potential.
Frontiers in Pharmacology
January 1, 2024
Brock Bakewell, Michael P. Johnson, Madison Lee et al.
4 citations
Drug-induced musical hallucinations—hearing music without external sound—are rare but can be triggered by medications such as antidepressants, opioids, anti-Parkinson drugs, ketamine, and voriconazole. A review of 27 cases (average age 58.3 years, 67.9% female) found that common underlying conditions included hearing impairments, psychiatric disorders, cancers, and neurodegenerative diseases. Six patients also experienced visual hallucinations. Onset varied from 75 minutes to 240 days. In 24 of 27 patients (88.9%), hallucinations completely resolved after stopping or adjusting the trigger drug, changing its route or formula, or adding sedatives or antipsychotics. The mechanism likely involves altered neurotransmitter balance and interactions between the drug and the patient's condition.
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
January 1, 2023
Kateřina Syrová, Klára Šíchová, Hynek Danda et al.
4 citations
2C-B-Fly-NBOMe, a new psychoactive substance related to the psychedelic entactogen 2C-B, was studied in adult male Wistar rats. After injection, peak drug levels in blood serum occurred at 30 minutes (28 ng/ml) and in brain tissue at 60 minutes (171 ng/g), with the compound still detectable in the brain after 8 hours. The drug dose-dependently reduced locomotor activity and strongly disrupted the acoustic startle response, with a weaker effect on prepulse inhibition. It did not cause significant changes in body temperature. The overall profile resembles that of 2C-B and other NBOMe substances, suggesting slow brain penetration and inhibitory effects on motor performance and sensorimotor gating.
Frontiers in Pharmacology
January 1, 2023
Prithvi Hemanth, Pallavi Nistala, Vy T Nguyen et al.
4 citations
For a series of 13 compounds related to the psychedelic agent 2,5-DMA, rat brain 5-HT2 receptor affinities correlate strongly with human 5-HT2A (r = 0.942) and 5-HT2B (r = 0.916) affinities. Human 5-HT2A affinity also correlates with the lipophilicity of the 4-position substituent (r = 0.798). In functional assays, eight of ten compounds acted as agonists at the human 5-HT2B receptor, while two acted as antagonists. Human 5-HT2B affinity, but not agonist action, correlates with substituent lipophilicity (r = 0.750). Rat and human 5-HT2A affinity may approximate human 5-HT2B affinity but cannot predict agonist action. Some 2,5-DMA analogs on the clandestine market may pose cardiac valvulopathy risk with chronic use via h5-HT2B activation.
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
January 1, 2025
Sarah Delcourte, Amel Bouloufa, Renaud Rovera et al.
3 citations
Bright light stimulation (BLS) alone was ineffective against anxiety- and depressive-like behaviors in a novel mouse model of refractory depression, induced by social isolation and chronic despair during the active dark phase. However, BLS potentiated the effects of antidepressant treatments, including ketamine, through a circuit involving rod retinal photoreceptors, lateral habenula (LHb) astroglia, and serotonin (5-HT). Chemogenetic activation of LHb astroglia or serotonin depletion blocked this potentiating effect. The findings suggest BLS enhances antidepressant efficacy via a previously unknown neural pathway.
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
January 1, 2024
Carles Colom-Rocha, Cristian Bis-Humbert, M Julia García-Fuster
3 citations
Adolescent exposure to ethanol, alone or combined with cocaine, increases voluntary ethanol consumption in adult male and female rats, but does not cause lasting negative affect. Cocaine alone has no effect on later ethanol intake. In rats exposed to adolescent ethanol, adult treatment with cannabidiol reduces ethanol consumption in both sexes, while ketamine reduces it only in females. These findings identify two potential therapeutic interventions to mitigate the long-term impact of early drug initiation.
Frontiers in Pharmacology
January 1, 2015
Eduardo R Butelman, Mary Jeanne Kreek
3 citations
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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
January 1, 2025
Itzchak Angel, Rita Perelroizen, Wendy Deffains et al.
2 citations
Ketamir-2, a new ketamine analog designed for improved oral bioavailability and safety, is a low-affinity NMDA receptor antagonist that selectively binds to the PCP site with an IC50 of about 100 µM. Unlike ketamine, which induces hyperlocomotion in mice—a behavior linked to schizophrenia-like psychomotor agitation—Ketamir-2 does not cause hyperlocomotion. In behavioral tests for anti-depressive and anxiolytic effects (Open Field, Elevated Plus Maze, Forced Swimming Test), Ketamir-2 showed significant effects at variable doses, while ketamine often did not differ from vehicle or showed opposite responses. The findings suggest Ketamir-2 may offer a safer profile without ketamine's dissociative side effects.
Frontiers in Pharmacology
January 1, 2025
Paula Aarseth Tunstad, Tor-Morten Kvam, Malin V. Uthaug et al.
2 citations
An anonymous internet survey of Norwegian-speaking adults who had a memorable experience with a classic psychedelic substance found that 85% reported a small to large positive change in subjective wellbeing after the experience. Integration, ego dissolution, and emotional breakthrough had a clear positive predictive effect on self-reported wellbeing. Variables with smaller but significant effects included challenging experiences, nature or ceremony settings, and a therapeutic or seeking intention. The authors view these findings as hypothesis-generating rather than confirmatory due to study limitations.
Frontiers in Pharmacology
January 1, 2025
Denise Elfriede Liesa Lockhofen, Nils Hübner, Ranjan Debnath et al.
2 citations
Ketamine, which blocks the NMDA receptor and temporarily mimics schizophrenia-like symptoms, primarily disrupts how the brain processes distracting stimuli rather than targets or rewards. In a visual attention task with reward-related distractors, healthy volunteers given a subclinical dose of ketamine showed increased gamma band power compared to placebo, especially during salient distractor trials. These effects were linked to the occurrence of negative symptoms. The findings highlight the glutamate system's role in dysfunctional gamma oscillations, early salience processing alterations, and negative symptoms in schizophrenia.