Frontiers in Pharmacology
April 29, 2024
Jan Thomann, Oliver V Stoeckmann, Deborah Rudin et al.
52 citations
Psilocybin is rapidly converted to psilocin in the body, which causes psychedelic effects by binding to the 5-HT2A receptor. Psilocin is mainly broken down by glucuronidation or conversion to 4-hydroxyindole-3-acetic acid (4-HIAA). In laboratory experiments with human liver microsomes, about 29% of psilocin was metabolized, while specific enzymes CYP2D6 and CYP3A4 metabolized nearly 100% and 40%, respectively. Monoamine oxidase A produced small amounts of 4-HIAA and 4-hydroxytryptophol (4-HTP), but 4-HTP appeared only in lab tests and neither metabolite showed activity at serotonin receptors. Two new potential metabolites were found: norpsilocin in mice and an oxidized form in humans, though CYP2D6 genotype did not affect psilocin levels in people. These findings help understand drug interactions and psilocybin's therapeutic use.
Frontiers in Pharmacology
January 1, 2016
Andrew R. Gallimore, Rick J. Strassman
51 citations
The state of consciousness induced by DMT is extraordinary, with users reporting a complete replacement of normal experience by a novel alternate universe filled with complex visual content and sentient beings. The short duration of DMT effects (under 20 minutes) limits single-dose studies. Using pharmacokinetic modeling and blood sampling data, the authors demonstrate that DMT's rapid onset and lack of acute tolerance make it suitable for target-controlled intravenous infusion, a technology used to maintain stable anesthetic levels during surgery. Simulations show this approach can induce a stable, prolonged DMT experience, enabling careful observation of psychological contents, extended accounts, functional neuroimaging, and potential psychotherapeutic applications.
Frontiers in Pharmacology
July 7, 2022
Songbai Xu, Xiaoxiao Yao, Bingjin Li et al.
50 citations
Ketamine, a drug that blocks N-methyl-D-aspartate receptors, produces rapid and lasting antidepressant effects in people with major depressive disorder and in animal models, but its use is limited by side effects like dissociation and psychosis-like experiences. The drug may work by enhancing signaling through another receptor type, AMPA receptors, in brain cells, possibly by reducing inhibition or blocking spontaneous NMDAR activity. It also activates pathways linked to brain plasticity and synapse formation, such as BDNF/TrkB and mTOR signaling. These processes may help restore the balance of excitatory and inhibitory signals in brain circuits disrupted in depression. Understanding these mechanisms could guide development of safer, more effective treatments.
Frontiers in Pharmacology
May 29, 2018
Elisangela Gouveia Cata-Preta, Yasmim A. Serra, Eliseu Da Cruz Moreira-Junior et al.
50 citations
Ayahuasca, a hallucinogenic beverage containing DMT and β-carbolines, can reduce ethanol reward in male mice without itself being rewarding at certain doses. An intermediate dose of ayahuasca induced conditioned place preference (CPP), while higher doses and its plant components Banisteriopsis caapi (Bc) and Psychotria viridis (Pv) did not. Pretreatment with ayahuasca blocked the development of ethanol-induced CPP, whereas Bc and Pv alone had no effect. Post-conditioning treatment with ayahuasca, Bc, or Pv in the ethanol-paired environment blocked expression of ethanol-induced CPP; treatment in the saline-paired compartment also blocked expression for intermediate ayahuasca and Bc doses, and for Pv. The environment influences these therapeutic effects.
Frontiers in Pharmacology
May 4, 2021
Ido Hartogsohn
49 citations
The psychedelic experience is profoundly shaped by psychological, social, and cultural factors—a concept known as set and setting. The Santo Daime religion in Brazil uses a rich tapestry of ordering principles, techniques, symbology, aesthetics, and music to direct the effects of the hallucinogenic brew ayahuasca. This paper systematically describes these elements and the mechanics of entheogenic initiation within the tradition, providing a template for future studies on how context influences psychedelic experimentation.
Frontiers in Pharmacology
October 7, 2022
Katarzyna Stachowicz, Magdalena Sowa-Kućma
48 citations
Depression is a severe mental health problem that affects people regardless of social status or education, is associated with changes in mood and behavior, and can result in suicide attempts. Current therapy relies mainly on drugs discovered in the 1960s and early 1970s, with SSRIs and SNRIs as frontline treatments. Esketamine, approved by the FDA in 2019, is an important compound for suicide and drug-resistant depression, acting as an NMDA receptor antagonist with additional effects on AMPA receptors, HCN channels, L-VDCC, opioid receptors, and monoaminergic receptors. However, treatment is burdened with severe side effects and often ineffective. This review discusses new research directions and proposes a new perspective on depressive therapies, emphasizing the need for antidepressants with different mechanisms of action.
Frontiers in Pharmacology
January 27, 2022
Athanasios Markopoulos, Antonio Inserra, Danilo de Gregorio et al.
44 citations
Psychedelic compounds such as LSD, psilocybin, and DMT show empathogenic and prosocial effects, suggesting potential therapeutic benefit for behavioral traits in autism spectrum disorder (ASD), including reduced social behavior and co-occurring anxiety and depression. The review examines dysregulated neurobiological systems in ASD—synaptic function, serotonergic signaling, prefrontal cortex activity, and thalamocortical signaling—that may underlie or limit these effects. Clinical studies from the 1960s and 70s using psychedelics in children with ASD reported positive outcomes like enhanced mood and social behavior, but also adverse effects including increased aggression, dissociation, and psychosis. Further studies are needed to weigh benefits against risks and determine if the 5-HT 2A receptor could be a target for social-behavioral disorders.
Frontiers in Pharmacology
July 13, 2022
Patrick Vizeli, Isabelle Straumann, Urs Duthaler et al.
43 citations
A single 125 mg dose of MDMA, given to 30 healthy men after fear conditioning and two hours before extinction learning, reduced skin conductance responses to a conditioned fear cue during both extinction learning and its recall the next day, compared with placebo. The drug did not affect fear-potentiated startle responses. Subjective feelings of trust and openness during extinction learning were linked to poorer discrimination between danger and safety cues during recall. MDMA raised oxytocin levels fourfold, but this increase did not correlate with fear extinction outcomes. The findings suggest MDMA can accelerate fear extinction learning and retention, at least for some physiological measures of fear, which may help explain its therapeutic benefit in PTSD.
Frontiers in Pharmacology
April 15, 2021
Meiying Cui, Wanlin Dai, Jing Kong et al.
43 citations
Major depressive disorder involves inflammation and immune processes, including alterations in cytokine levels and immune cell function. Th17 cells, a proinflammatory T cell subset, accumulate and disrupt the Th17/Treg balance, contributing to depression and depressive-like behaviors in animal models. Ketamine is an effective rapid-acting antidepressant, but its mechanisms are not fully understood. This review suggests that ketamine's antidepressant effects may involve immune modulation of Th17 cells and the Th17/Treg balance. Exploring these mechanisms could enhance ketamine's benefits and reduce side effects.
Frontiers in Pharmacology
October 7, 2020
Ilana Berlowitz, Ernesto García Torres, Heinrich Walt et al.
43 citations
In the Peruvian Amazon, tobacco—particularly Nicotiana rustica—is used as a potent medicinal plant, applied topically or ingested to treat conditions including mental health issues, respiratory problems, parasitic infections, gout, and spiritual-energetic ailments. A transdisciplinary field study interviewed a Maestro Tabaquero (traditional healer specializing in tobacco) to document preparation methods, indications, contraindications, effects, and risks. The most common remedy was a liquid taken orally, producing acute psychoactive effects and physiological responses like vomiting. Safe treatment requires a skilled healer knowledgeable in dosing and managing adverse effects. This work contributes to research on Amazonian medicine and psychedelic-assisted therapies.
Frontiers in Pharmacology
January 4, 2023
Kenneth Alper, Janelle Cange, Ria Sah et al.
39 citations
A single dose of psilocybin reduces voluntary ethanol consumption in male mice for three days afterward, but has no effect in female mice. The reduction is dose-related and occurs at 0.5 mg/kg or higher, but does not persist when ethanol is reintroduced after two days of withdrawal. The effect is not due to altered taste perception, motor effects, or nonspecific changes in drinking behavior. These findings suggest sex-dependent effects of psilocybin on alcohol drinking and indicate that the C57BL/6J mouse may be useful for studying sex differences in alcohol use disorder and the neurobiology of psychedelics.
Frontiers in Pharmacology
May 5, 2021
Débora González, Jordi Cantillo, Irene Hidalgo Pérez et al.
39 citations
People who took part in an Indigenous Shipibo healing program involving ayahuasca ceremonies showed significant increases in psychological well-being, happiness, and quality of life that lasted up to 12 months. A subgroup analysis indicated the improvements were due to the program rather than the passage of time. A relationship was found between decentering—the ability to observe thoughts and feelings objectively—and enhanced psychological well-being.
Frontiers in Pharmacology
January 1, 2021
Leor Roseman, Yiftach Ron, Antwan Saca et al.
39 citations
Ayahuasca ceremonies involving Palestinians and Israelis can foster peacebuilding through intersubjective and intercultural relational processes. Analysis of 31 in-depth interviews identified three types of shared experiences: unity-based connection, where participants felt a sense of shared humanity that dissolved national and religious identities; recognition and difference-based connection, where awe and reverence arose from encountering the other culture's music or prayers; and conflict-related revelations, where personal or historical traumatic elements of the conflict emerged in visions triggered by the presence of the other. These findings suggest that psychedelic ceremonies may contribute to peacebuilding not only by dissolving identities but also by enabling shared spiritual experiences and revealing links between personal psychological states and the broader sociopolitical context.
Frontiers in Pharmacology
December 3, 2020
Daniela Dudysová, Karolína Janků, Michal Šmotek et al.
37 citations
Psilocybin, a serotonergic psychedelic with antidepressant potential, altered sleep architecture in healthy volunteers the night after administration. In a randomized, double-blinded trial, 20 healthy adults (10 women, ages 28–53) received psilocybin or placebo. Psilocybin prolonged REM sleep latency and showed a trend toward reduced total REM sleep duration, with no changes in NREM sleep or whole-night EEG power spectra. Contrary to expectations, psilocybin suppressed slow-wave activity in the first sleep cycle, providing no evidence for sleep-related neuroplasticity. The findings suggest that psilocybin's antidepressant properties may involve sleep changes, possibly through different mechanisms than those of classical antidepressants.
Frontiers in Pharmacology
August 31, 2018
Kenneth Alper, Bin Dong, Relish Shah et al.
37 citations
A single high dose of LSD (50 μg/kg) reduced alcohol consumption by an average of 17.9% in adult male mice over 46 days, with no change in total fluid intake or activity. A lower dose (25 μg/kg) had no effect. The findings suggest classical hallucinogens warrant further animal research for addiction neurobiology and drug discovery.
Frontiers in Pharmacology
June 21, 2017
Rafael Naime Ruggiero, Matheus Teixeira Rossignoli, Jana Batista de Ross et al.
37 citations
Research on the endocannabinoid system in schizophrenia has largely relied on rodent behavioral measures such as prepulse inhibition and open-field locomotion, often combined with neurochemical or drug challenge methods. These approaches help map sensorimotor gating, hyperlocomotion, social interaction, and underlying neurotransmitter disturbances. However, greater use of neurophysiological tools like electrophysiology and optogenetics is needed to clarify how exogenous cannabinoids—THC worsening symptoms and CBD ameliorating them—affect hallucinations, delusions, and cognitive deficits. Recent evidence also highlights a complex interplay between the endocannabinoid and endovanilloid systems, particularly anandamide's influence on cognitive variables like aversive memory extinction, with TRPV1 receptors emerging as promising therapeutic targets.
Frontiers in Pharmacology
September 29, 2021
João Castelhano, Gisela Lima, Marta Teixeira et al.
34 citations
Tryptamine psychedelics such as LSD, psilocybin, DMT, and ayahuasca alter brain activation and connectivity in regions that match the distribution of 5HT2A and 5HT1A receptors, including visual cortex, cingulate cortex, medial prefrontal cortex, temporal cortex, and the right amygdala. These effects involve areas supporting mental imagery, theory of mind, and emotional regulation, suggesting potential therapeutic applications. The analysis confirms that changes occur in regions with high 5HT2A receptor density, but also in other areas like the dorsolateral prefrontal cortex. However, too few PET studies exist to meta-analyze receptor occupancy directly.
Frontiers in Pharmacology
April 24, 2019
Dino Luethi, Melanie Walter, Xun Zhou et al.
33 citations
Halogenated derivatives of amphetamine-type stimulants, such as 4-fluoroamphetamine and 4-chloroamphetamine, inhibit the norepinephrine transporter at submicromolar concentrations and the dopamine transporter at low micromolar concentrations. As the size of the para-substituent increases, selectivity shifts from dopamine to serotonin transporter inhibition, resulting in potent serotonin uptake inhibition. All tested compounds deplete cellular ATP at lower concentrations (0.25–2 mM) than they cause cell membrane integrity loss (≥0.5 mM), indicating mitochondrial toxicity. The toxicity rank order for para-substituents is chloride > fluoride > hydrogen. Para-halogenation increases the risk of serotonergic neurotoxicity and may heighten hepatic toxicity through mitochondrial impairment.
Frontiers in Pharmacology
July 11, 2017
Drew J. Puxty, Johannes G. Ramaekers, Rafael de la Torre et al.
33 citations
A single 75 mg dose of MDMA produces a dissociative state, marked by feelings of depersonalization and derealization, in healthy recreational users. Blocking the 5-HT2 receptor with ketanserin did not prevent this effect, indicating that the 5-HT2 receptor does not mediate MDMA-induced dissociation. Heart rate correlated with the dissociative state after MDMA alone, but not when ketanserin was given, suggesting heart rate changes do not directly cause dissociation. Cortisol levels and MDMA blood concentrations showed no clear relationship with dissociation. The exact neurobiological mechanism remains unknown and may be relevant to MDMA's therapeutic use.
Frontiers in Pharmacology
January 1, 2023
Dario Dornbierer, Laurenz Marten, Jovin Mueller et al.
32 citations
Ayahuasca, an Amazonian plant medicine containing DMT and harmine, shows promise for mental health disorders but its oral use causes gastrointestinal side effects and unpredictable drug levels. This study tested new ayahuasca-analogue formulations in 10 healthy men: an oral capsule of purified DMT and harmine versus a combined oromucosal harmine tablet with intranasal DMT spray. The combined buccal/intranasal route significantly reduced variations in systemic exposure and attenuated common side effects like nausea, vomiting, and diarrhea compared to traditional oral ayahuasca. All preparations were well tolerated. This approach may enable safer, patient-friendly DMT/harmine administration for affective disorders.
Frontiers in Pharmacology
May 2, 2022
Ilana Berlowitz, Klemens Egger, Paul Cumming
32 citations
Monoamine oxidases (MAOs) are enzymes that break down biogenic amines like serotonin, dopamine, and tyramine in the brain and body. Beta-carboline alkaloids, such as harmine and harmane, are MAO inhibitors found in plants including tobacco and Banisteriopsis caapi, a key ingredient in the Amazonian ayahuasca brew. These beta-carbolines may boost the bioavailability of the hallucinogen DMT and might have antidepressant properties. However, the level of MAO inhibition needed to affect neurotransmitter signaling is not yet known. Unlike synthetic antidepressant MAO inhibitors that cause complete and irreversible inhibition, beta-carbolines are reversible and competitive, making complete inhibition unlikely. Many medicinal plants contain MAO inhibitors, but their pharmacological relevance often remains unclear.
Frontiers in Pharmacology
January 1, 2018
Joaquín González, José P Prieto, Paola Rodríguez et al.
31 citations
Ibogaine, a psychedelic alkaloid with anti-addictive properties, acutely increases wakefulness and suppresses REM sleep in rats. In a study with polysomnographic recordings over six hours, rats given ibogaine (20 or 40 mg/kg) spent more time awake and less time in slow wave sleep and REM sleep compared to controls. REM sleep latency increased with the higher dose. The wake-promoting and slow wave sleep effects occurred in the first two hours, while REM suppression lasted throughout the recording. Lower doses increased locomotion; higher doses caused tremor and flat body posture. Head shake response, linked to 5HT2A receptor activation, was unchanged. The findings suggest ibogaine produces a waking state with prolonged REM suppression and a dose-dependent motor profile.
Frontiers in Pharmacology
January 28, 2020
Esther Papaseit, Clara Pérez‐mañá, Elizabeth B. de Sousa Fernandes Perna et al.
27 citations
Combining mephedrone with alcohol amplifies cardiovascular effects and intensifies euphoria and well-being compared to either drug alone, while mephedrone reduces the sedative effects of alcohol. In a double-blind, placebo-controlled trial with 11 male volunteers, the combination increased blood pressure, heart rate, and subjective feelings of euphoria. Mephedrone alone and alcohol alone were also tested. The results suggest that the abuse liability of mephedrone is greater when taken with alcohol, similar to other psychostimulants like amphetamines and MDMA.
Frontiers in Pharmacology
February 17, 2023
Lourdes Poyatos, Clara Pérez‐mañá, Olga Hladun et al.
26 citations
Methylone, a common synthetic cathinone used as a substitute for MDMA, produces similar acute effects in humans. In a controlled trial with 17 experienced psychostimulant users, a single 200 mg oral dose of methylone increased blood pressure and heart rate and induced pleasurable effects including stimulation, euphoria, wellbeing, enhanced empathy, and altered perception. Methylone's effect profile resembled MDMA's but with a faster onset and earlier disappearance of subjective effects. The findings suggest methylone's abuse potential is comparable to that of MDMA in humans.
Frontiers in Pharmacology
May 19, 2021
Brian Rush, Olivia Marcus, Sara Mallén García et al.
26 citations
This paper describes the protocol for the Ayahuasca Treatment Outcome Project (ATOP), which evaluates addiction treatment services at the Takiwasi Center in the Peruvian Amazon. The project aims to assess outcomes and understand therapeutic mechanisms of an ayahuasca-assisted, integrative treatment model for addiction rehabilitation. The protocol emphasizes the importance of treatment setting in designing and delivering a program involving the psychedelic tea ayahuasca. A mixed-methods approach to data collection and analysis is used to understand why, how, and for whom the treatment is effective across various outcomes.