February 28, 2026
preprint
Mescaline, a classic serotonergic psychedelic used ceremonially by Indigenous peoples, shows preliminary safety in healthy humans under controlled conditions, producing dose-dependent subjective effects with moderate, transient autonomic stimulation and no serious medical complications. Adverse effects are generally self-limited, and pooled safety analyses and observational data support an overall favorable safety profile in screened populations. However, there is a lack of controlled clinical trials evaluating mescaline in patient populations, so its safety in individuals with cardiovascular, metabolic, or psychiatric comorbidities remains unclear. Controlled clinical trials are needed to establish its safety and therapeutic potential.
Biomedicines
February 21, 2026
Maximiliano Ganado, Carmen Rubio, Javier Pérez-villavicencio et al.
Psychedelic effects are not solely driven by serotonin receptors. The compound salvinorin A, from Salvia divinorum, produces altered consciousness by directly activating kappa opioid receptors (KORs), bypassing serotonin entirely. This review synthesizes evidence from lab studies, animal models, and human brain imaging. Salvinorin A triggers a specific signaling pathway (β-arrestin bias) that causes rapid receptor desensitization, disrupts thalamocortical communication, suppresses dopamine activity in reward circuits, and fragments large-scale brain networks. Despite being a potent opioid agonist, it has low abuse potential because its aversive effects and dopamine suppression prevent positive reinforcement. Understanding opioid receptor mechanisms expands psychedelic neuroscience beyond serotonin-focused models and may guide development of treatments for depression, addiction, and chronic pain.
Frontiers in Molecular Biosciences
February 18, 2026
Gabriella de Souza Gomes Ribeiro, Beatriz Aparecida Passos Bismara Paranhos, Fabiane Dörr et al.
1 citation
Even modest increases in DMT exposure from ayahuasca may intensify serotonergic effects in individuals taking SSRI antidepressants, suggesting a clinically relevant interaction. The study provides a mechanistic and quantitative framework for assessing interaction risks between ayahuasca alkaloids and SSRIs, supporting clinical decision-making and harm-reduction strategies where controlled drug-drug interaction studies are not feasible.
Translation The University of Toledo Journal of Medical Sciences
February 17, 2026
Amy Hooper, Evelyn K. Lambe
MDMA-assisted psychotherapy shows promise for PTSD, especially when standard treatments like SSRIs and trauma-focused cognitive behavioral therapy have failed. A review of evidence from human and rodent studies examines two main explanations for its effects: a neurobiological model, where MDMA reduces amygdala reactivity, boosts hippocampal connectivity, and alters serotonin and oxytocin signaling to aid fear extinction, memory reconsolidation, and neuroplasticity; and a relational model, where MDMA's prosocial and empathogenic qualities strengthen the therapeutic alliance and patient suggestibility. Rather than being mutually exclusive, these processes likely work together, with MDMA creating a "window of emotional safety" that enables both neurobiological and interpersonal healing. Understanding this dual action is key to refining treatment protocols and therapist training.
Neuropsychopharmacology
February 13, 2026
Fabrizio Ascone, Valeria Buzzelli, Francesca Mottarlini et al.
2 citations
In a rat model of Fragile X Syndrome (FXS), psilocybin microdosing rescued deficits in novel object recognition memory. This benefit persisted even when serotonin receptors (5HT2AR or 5HT1AR) were blocked, but was abolished by blocking the TrkB receptor, indicating that the effect depends on BDNF/TrkB signaling rather than classical serotonergic pathways. At the molecular level, psilocybin normalized mature BDNF, increased TrkB, and restored downstream AKT signaling in the prefrontal cortex—pathways linked to synaptic plasticity and cognition. These results suggest psilocybin microdosing could be a promising therapeutic strategy for neurodevelopmental disorders like FXS and autism spectrum disorder, potentially dissociating therapeutic benefits from hallucinogenic effects.
Molecular Psychiatry
February 12, 2026
Sixtine Fleury, Katherine M. Nautiyal
correction
Research in mice implicates the 5-HT1BR, a nonhallucinogenic serotonin receptor, as a potential mediator of the behavioral and neural effects of psilocybin. The 5-HT1BR influences brain-wide neural changes following psilocybin administration and may contribute to its enduring antidepressant-like effects in mice. However, the data do not address whether 5-HT1BR is sufficient for these effects.
Behavioural Brain Research
February 10, 2026
Kristin A. Felsch, Jessica A. Siegel
MDMA is a psychomotor stimulant drug. Most research has focused on adults, but adolescence is a unique period of brain development where MDMA's effects may differ. This review summarizes 54 studies (48 in rodents, 6 in humans) on acute and repeated adolescent MDMA exposure. Acute high doses generally increase locomotor activity and impair the serotonin system. Repeated exposure shows conflicting results depending on dosing, testing environment, and timing. There is little research on adolescent females. More consistent dosing and female subjects are needed.
Open Access CRIS of the University of Bern
February 9, 2026
Mikael Palner, Elisabeth Kolesnik, Christina Baun et al.
The mammalian brain may contain an endogenous pool of the psychedelic N,N-dimethyltryptamine (DMT), possibly acting as a co-transmitter with serotonin. In rats, inhibiting monoamine oxidase with pargyline did not make endogenous DMT detectable, while probenecid slightly elevated the acidic metabolite 3-indoleacetic acid (3-IAA), suggesting formation from tryptamine, especially in the striatum. After administering DMT plus harmine, peak brain DMT occurred at 45 minutes and peak 3-IAA at 60 minutes, with nearly complete washout by 210 minutes. Escitalopram did not alter exogenous DMT or 3-IAA disposition, and dihydrotetrabenazine slightly increased 3-IAA in some regions. The results do not support an endogenous DMT pool or retention of exogenous DMT in serotonin terminals.
Neuropharmacology
February 9, 2026
Mikael Palner, Elisabeth Kolesnik, Christina Baun et al.
The study tested whether the psychedelic compound N,N-dimethyltryptamine (DMT) exists naturally in the mammalian brain and acts as a co-transmitter with serotonin. In rats, blocking monoamine oxidase with pargyline did not allow detection of endogenous DMT, while blocking acidic metabolite transport with probenecid slightly elevated the DMT metabolite 3-indoleacetic acid, likely from tryptamine. Exogenous DMT was rapidly taken up and cleared from the brain, with peak concentrations at 45 minutes and near-complete washout by 210 minutes. Blocking serotonin reuptake or vesicular monoamine transporters did not alter DMT levels. The results do not support the hypothesis that DMT is an endogenous co-transmitter with serotonin.
Brain Sciences
February 4, 2026
Katarina Savić Vujović, Sonja Vučković, Lara Samardžić et al.
Ketamine and a ketamine-magnesium sulfate combination lower body temperature in rats through serotonergic and adrenergic mechanisms, but not through GABAA receptors. Giving yohimbine, an α2-adrenergic blocker, deepened ketamine-induced hypothermia at doses of 0.5 and 1 mg/kg, while only the highest dose (3 mg/kg) enhanced the combination's effect. Methysergide, a serotonin blocker, had opposite effects depending on dose: 1 mg/kg worsened ketamine hypothermia, whereas 0.5 mg/kg reduced the combination's cooling effect. Bicuculline, a GABAA antagonist, did not change hypothermia from either treatment. These findings clarify neurotransmitter pathways involved in NMDA antagonist-related thermoregulation.
Molecular Psychiatry
February 3, 2026
Pablo Mallaroni, S. Parker Singleton, Natasha L. Mason et al.
The psychedelic phenethylamine 2C-B produces less dysphoria and subjective impairment than the tryptamine psilocybin. In 22 healthy volunteers, 7 Tesla resting-state functional MRI mapped acute effects of matched doses of 20 mg 2C-B, 15 mg psilocybin, and placebo. Both compounds selectively reduced intranetwork static functional connectivity while broadly increasing between-network and subcortical-cortical connectivity. Compared to psilocybin, 2C-B showed less pronounced reductions in between-network dynamic connectivity variability but elevated transmodal static connectivity. Both increased brain complexity similarly. PET density modeling linked neural effects to differences in monoaminergic transporter and serotonergic receptor binding beyond 5-HT2A. Behavioral markers of psychedelic effects reflected decoupling of the transmodal axis of functional brain organization.
Psychedelic Medicine
February 3, 2026
Anton T. Gregersen, Tobias Whelan, Caroline T. Golden et al.
2 citations
Psilocybin, a serotonergic psychedelic, impaired short-term learning and unlearning speeds in rats performing a three-choice visual reversal learning task, though exploratory analysis suggested possible long-term enhancements in learning dynamics. Only five of sixteen Long-Evans rats (31%) successfully completed all six reversal protocols, demonstrating significant learning and unlearning over time. Computational modeling showed low learning rates with no significant differences between psilocybin and placebo conditions on any parameters. The findings indicate a nuanced effect of psilocybin on cognitive flexibility, with potential relevance for its use in neuropsychiatric disorders, but further research is needed on long-term outcomes.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
February 2, 2026
Maya C Gaines-Smith, Justin M Silverman, Michael Fiorillo et al.
3 citations
The drug MDMA, also known as ecstasy, is being studied as a possible aid in psychotherapy for hard-to-treat mental health conditions, but how it works in the brain is not fully understood. In experiments with mice, the S(+) form of MDMA, but not the R(-) form, activated a specific serotonin receptor (5-HT2AR) and caused changes in brain cell connections in the frontal cortex of males. The R(-) form had little effect except for a head-twitch response in females. Blocking the serotonin transporter with fluoxetine prevented these effects, showing that MDMA works indirectly by increasing serotonin levels. These results reveal that MDMA's effects on brain plasticity depend on both the drug's chemical form and the sex of the animal.
Neuropharmacology
February 1, 2026
Giorgia Corli, Fabrizio De Luca, Sabrine Bilel et al.
1 citation
Repeated exposure to the synthetic cannabinoid AKB48 worsens the visual sensorimotor, sensory gating, and motor reactivity response to the hallucinogens 2C-I and 25I-NBOMe in mice. This effect is more prolonged in males than in females. The underlying mechanism involves neuroplastic changes in the cerebellum and cortex, specifically at serotonin 2A receptors and the serotonin transporter. These changes occur more markedly and rapidly in female mice. The findings highlight a significant interaction between synthetic cannabinoids and psychedelic drugs, which may be relevant to long-term effects and psychiatric consequences of their consumption.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
February 1, 2026
Isabel Werle, Francisco S Guimarães, Rafael G Dos Santos et al.
Ayahuasca, a brew containing the psychedelic DMT, helps rodents overcome persistent and generalized fear memories by boosting brain-derived neurotrophic factor (BDNF) signaling in the infralimbic (IL) region of the medial prefrontal cortex. In rats exposed to stress or high-intensity fear conditioning, repeated ayahuasca (0.3 mg/kg DMT) enhanced extinction learning and its retention, and reduced fear generalization. These effects were blocked by infusing an anti-BDNF antibody or a TrkB receptor antagonist into the IL cortex. The reduction in fear generalization depended on BDNF in females but not males. The findings suggest psychedelics may aid in treating difficult-to-extinguish trauma memories, such as those in PTSD.