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
January 1, 2024
Ying Xiao, Xuefeng Hu, Wei Xing et al.
1 citation
A novel formulation combining deuterated dextromethorphan (SAL0114) with bupropion showed twice the metabolic stability of standard dextromethorphan in both laboratory and mouse tests, and bupropion further increased its exposure by 2.4 times. The combination demonstrated superior antidepressant and synergistic effects in mouse and rat models compared with the non-deuterated dextromethorphan-bupropion combination, while maintaining the same in vitro activity. Deuteration did not alter the compound's activity but improved its stability, potentially reducing neurologic side effects from metabolites and allowing lower bupropion doses. Clinical studies are needed to confirm these preclinical findings.
Frontiers in Pharmacology
January 1, 2023
Nataliya S. Vorobyeva, Alena A. Kozlova
1 citation
correction
No Summary
Frontiers in Pharmacology
June 3, 2026
Burton J. Tabaac, Robin 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
January 1, 2026
Michael B. Gatch, Shuping Jia, Ritu A. Shetty et al.
Two synthetic cathinones found on the street, N-cyclohexyl butylone and N-cyclohexyl methylone, were tested for their psychostimulant effects in mice and rats. Both compounds stimulated locomotor activity in mice, but were less potent and less effective than methamphetamine. In rats trained to discriminate methamphetamine or cocaine from saline, N-cyclohexyl butylone fully substituted for those drugs, suggesting it could produce similar psychoactive effects and motivate illicit use. N-cyclohexyl methylone failed to fully substitute for methamphetamine or cocaine and caused convulsions at higher doses, indicating greater danger but possibly lower abuse liability. Neither compound substituted for MDMA. The large N-cyclohexyl chemical group likely reduced the drugs' effectiveness, but a longer side chain in N-cyclohexyl butylone may have counteracted this.
Frontiers in Pharmacology
January 1, 2026
Patricio Sáez-briones, Amanda Silva-Rodríguez, Michelle Morales-Vidal et al.
MDMA (Ecstasy) suppressed helping behavior in adult male rats at doses of 5 mg/kg and 10 mg/kg, fully eliminating the behavior, while lower doses (1 mg/kg and 0.5 mg/kg) caused partial inhibition only after the rats switched roles. The lowest dose (0.25 mg/kg) had no effect. Electrophysiological recordings showed that MDMA reinforced long-term depression in the nucleus accumbens core and increased long-term potentiation in the anterior cingulate cortex, with the latter depending on serotonin and oxytocin. These neuroplastic effects align with mechanisms thought to promote prosocial behavior, yet the drug disrupted helping behavior, suggesting MDMA may impair neural processes essential for executing helping actions without reducing the willingness to help.
Frontiers in Pharmacology
January 1, 2026
Joseph Geraci, Erik Viirre, Bessi Qorri et al.
Classic psychedelics like LSD, psilocybin, and DMT affect perception and brain plasticity mainly by activating the 5-HT2A receptor and triggering calcium-dependent signaling. A speculative but testable hypothesis suggests these biochemical cascades might connect with quantum processes in the brain, specifically through nuclear spin dynamics in phosphate-based 'Posner molecules' (Ca9(PO4)6). Intense 5-HT2A-driven neural activity and calcium flux during psychedelic use could allow phosphorus nuclear spins in these molecules to become entangled and shielded from decoherence, later influencing neuronal signaling when the clusters release calcium. This framework, building on Fisher's quantum cognition model, proposes testable predictions and outlines short-, medium-, and long-term experiments to confirm or refute quantum involvement, which could transform understanding of mind-brain relationships and psychiatric treatment.
Frontiers in Pharmacology
January 1, 2026
Yang Qu, Shujin Li, Li Tian et al.
A meta-analysis of nine randomized controlled trials involving 1,449 patients found that esketamine improves symptoms in treatment-resistant depression but significantly increases dose-dependent adverse events. Compared with controls, esketamine raised the risk of nine adverse events including nausea, dissociation, dizziness, vertigo, elevated blood pressure, and somnolence. Risks were strongly dose-dependent: the high-dose group (≥56 mg or 0.40 mg/kg) had a greater risk than the low-dose group (≤28 mg or 0.20 mg/kg), with relative risk for nausea of 3.72 versus 1.69 and for dissociation of 10.65 versus 3.27. Although esketamine improved clinical response rate (relative risk = 1.94), it increased treatment discontinuation due to adverse events by 2.22-fold. Clinical use should adopt personalized dosing strategies balancing efficacy and tolerability.
Frontiers in Pharmacology
January 1, 2026
Michaela Krivosova, Matteo Marcatili, Gessica Guerrera et al.
In a real-world group of 32 patients with treatment-resistant depression receiving intranasal esketamine over two months, no single demographic, clinical, or genetic variable—including BDNF (rs6265), OPRM1 (rs1799971) polymorphisms, or CYP2B6, CYP2C9, and CYP3A4 metabolizer status—reliably predicted treatment response. Adjunctive psychotherapy was the only factor significantly associated with remission. Most patients received the standard 84 mg dose, so nominal dosing explained little of the outcome variability. Exploratory analyses suggested that metabolic phenotype and concomitant pharmacotherapy may contribute to inter-individual differences. The findings support a multidimensional, clinically oriented approach to optimizing esketamine treatment rather than relying on a single predictor. The small sample size may have limited the ability to detect modest associations, so results are exploratory.
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.
Frontiers in Pharmacology
December 1, 2025
Tiejia Jiang, Rui Zhao
Esketamine provides relatively good pain control after surgery and is linked to a lower risk of postpartum depression, but this finding is not stable. In pregnant women over 30, esketamine may increase the risk of dizziness. The study was conducted entirely in China, which limits how broadly the results apply.
Frontiers in Pharmacology
November 19, 2025
Yan Du, Qing Ma, Xingcui Gao et al.
No Summary
Frontiers in Pharmacology
January 1, 2024
Luan Oliveira Ferreira, Esther Padilha da Silveira, Clarissa A Paz et al.
Ketamine, increasingly used illicitly alongside alcohol, alters brain activity in ways that depend on dose. In late-adolescent male rats, ketamine alone increased delta, theta, beta, and gamma brainwaves, most strongly at 30 mg/kg, while reducing alpha waves. Alcohol alone reduced all brainwaves. Combined, ketamine enhanced alcohol's depressant effect on alpha waves at all doses. A low ketamine dose (10 mg/kg) boosted alcohol's reduction of theta and beta waves, whereas a high dose (30 mg/kg) produced neuronal hyperexcitability, increasing delta, theta, beta, and gamma bandpower. The intermediate dose (20 mg/kg) reversed alcohol-induced reductions in theta and gamma waves.
Frontiers in Pharmacology
January 1, 2016
Bokor, Petra, Frecska, Ede, Winkelman, Michael
Ayahuasca, an Amazonian psychoactive brew containing β-carboline and tryptamine derivatives, remains central to healing ceremonies among indigenous and mestizo populations in South America and is increasingly used worldwide. A growing number of studies indicate that its psychotherapeutic potential is based largely on strong serotonergic effects, while the sigma-1 receptor agonist effect of its active ingredient dimethyltryptamine may allow scientific verification of the diversity of conditions treated in ethnomedical observations. In appropriate therapeutic or ritual settings with proper preparation, mindset, and integration, ayahuasca has proven effective for treating substance dependence. The article argues that therapeutic effects are best understood from a bio-psycho-socio-spiritual model, and that ayahuasca may act against chronic low-grade inflammation and oxidative stress via the sigma-1 receptor.
Frontiers in Pharmacology
July 25, 2024
Yasunori Aoki, Malcom Rowland, Yuichi Sugiyama
Intra-Target Microdosing (ITM), a Phase 0 clinical approach, can engage targets at levels similar to systemically administered therapeutic doses for certain compounds, but its probability of success notably decreases when the predicted therapeutic dose exceeds 10 mg. Key factors influencing ITM success include lower dissociation constants, higher systemic clearance, and optimal receptor abundance in the target organ. Target tissues with relatively low blood flow rates and high drug clearance capacities are more conducive to successful ITM. The findings highlight the need to consider each drug's unique pharmacokinetic and pharmacodynamic properties alongside the physiological characteristics of the target tissue when determining ITM suitability.
Frontiers in Pharmacology
July 16, 2024
H. Markus Weiss, Yuichi Sugiyama, Esther van Duijn
Phase 0 microdosing—testing compounds at subtherapeutic doses in humans—enables early decisions in drug development with a reduced preclinical safety package. Its uptake has been slow despite advantages such as better decisions informed by early human data, reduced animal experiments, and access to vulnerable populations. Intratarget microdosing (ITM) enhances this approach by assessing safety or efficacy-related biomarkers beyond pharmacokinetics, including target expression via Positron Emission Tomography. The CIVO platform, an injectable device for surface-accessible tumors, can microdose up to eight drugs simultaneously and generate human pharmacodynamic data safely, improving translation over animal efficacy data.
Frontiers in Pharmacology
January 1, 2024
Jack M Ognibene, Rajeev I Desai, Praveen P Kulkarni et al.
Mice exposed daily to vaporized cannabis (10.3% Δ9-THC) for ten days showed a blunted brain response to Adderall, with decreased positive and increased negative BOLD signals in regions including the prefrontal cortex, accumbens, ventral pallidum, caudate/putamen, and thalamus. After a two-week washout without cannabis, the difference in Adderall response between cannabis-exposed and placebo groups disappeared. The findings suggest that short-term daily cannabis inhalation, comparable to recreational use, reduces sensitivity to the psychostimulant Adderall, particularly in dopaminergic circuitry, raising concerns about potential escalation of psychostimulant use.
Frontiers in Pharmacology
April 18, 2023
María Salud García-Gutiérrez, Daniela Navarro, Amaya Austrich-Olivares et al.
Cannabidiol (CBD) produced faster anxiolytic and antidepressant-like effects than sertraline in male mice exposed to chronic mild stress. CBD showed effects in the light-dark box and tail suspension tests after 4 and 7 days, respectively, while sertraline required 14 days. CBD also improved cognitive impairment and anhedonia more effectively than sertraline. Combining CBD with sertraline produced similar effects to CBD alone in some tests but worse outcomes in cognitive and social interaction tests. CBD reversed all stress-induced molecular changes in the brain, whereas sertraline and the combination failed to restore certain receptors and neurotrophic factors in the hippocampus.
Frontiers in Pharmacology
January 1, 2022
Chongguang Chen, Peng Huang, Kathryn Bland et al.
Selective kappa opioid receptor (KOR) agonists are promising for treating pain and itch but often cause side effects like dysphoria and sedation. This study tested whether conditioned place aversion (CPA), a measure of dysphoria, is linked to KOR phosphorylation and internalization—markers of β-arrestin recruitment—in male mice. Using four KOR agonists at doses that maximally reduce pain and scratching, the authors found that U50,488H, MOM-SalB, and 42B, but not nalfurafine, induced KOR phosphorylation and internalization in brain regions. Yet, prior work showed that U50,488H and MOM-SalB cause CPA, while nalfurafine and 42B do not. These results indicate no connection between CPA and these β-arrestin-related processes.
Frontiers in Pharmacology
January 1, 2022
Kelly F Paton, Dan Luo, Anne C La Flamme et al.
Kappa opioid receptor (KOR) agonists, including analogues of Salvinorin A, reduced pain in a mouse model of chemotherapy-induced neuropathic pain. 16-Ethynyl SalA was more potent than morphine at reducing mechanical allodynia, and SalA, 16-Ethynyl SalA, and EOM SalB were more potent at reducing cold allodynia. Sex differences appeared in mechanical allodynia testing: U50,488 was more potent in males, SalA more potent in females, but no sex differences occurred in cold allodynia. Chronic U50,488 (10 mg/kg) restored mechanical and cold pain responses to healthy levels over 23 days. KOR agonists may be developed to treat this condition.