Frontiers in pharmacology
January 1, 2018
Deborah C Mash, Linda Duque, Bryan Page et al.
109 citations
A single oral dose of ibogaine, administered under medical supervision, diminishes opioid withdrawal symptoms and reduces drug cravings in people seeking to detoxify from opioids or cocaine. In an open-label case series of 191 human volunteers, no significant adverse events occurred at doses effective for blocking withdrawal. Pharmacokinetic measures from whole blood assays tracked ibogaine's metabolism and clearance. Multi-dimensional craving questionnaires showed reduced heroin and cocaine cravings during inpatient detoxification. One-month follow-up data suggested some persistence of craving reduction outside the inpatient setting. The results support developing ibogaine as a treatment for opioid withdrawal during medically supervised detoxification to transition individuals toward abstinence.
Frontiers in pharmacology
January 1, 2019
Soledad Marton, Bruno González, Sebastián Rodríguez-bottero et al.
71 citations
A single injection of ibogaine in rats increased the expression of neurotrophic factors in brain regions containing dopamine neurons, with effects depending on dose and brain area. At 24 hours, the higher dose (40 mg/kg) selectively raised GDNF in the ventral tegmental area and substantia nigra, while both doses boosted BDNF transcripts in the nucleus accumbens, substantia nigra, and prefrontal cortex. NGF mRNA increased across all regions after the higher dose. Protein levels showed GDNF rise only in the ventral tegmental area at the higher dose, and proBDNF increased in the nucleus accumbens for both doses. These changes may help explain ibogaine's reported ability to reduce drug-seeking behavior.
Frontiers in pharmacology
January 1, 2021
Johannes Reckweg, Natasha L Mason, Cees Van Leeuwen et al.
58 citations
Vaporized 5-MeO-DMT (GH001) produces dose-dependent increases in psychedelic experience intensity in healthy volunteers, with individualized dose escalation yielding maximal effects on peak experience, mystical experience, ego dissolution, and altered states of consciousness. Higher single doses (6, 12, 18 mg) significantly increased ratings compared to 2 mg on all measures except challenging experiences. Cognition, mood, and well-being were unaffected. Vital signs remained stable, and adverse events were mild and self-resolving. Individualized dose escalation may be preferable for clinical applications aiming to maximize the psychedelic experience for therapeutic response.
Frontiers in pharmacology
January 1, 2022
Daniel Perkins, Broc A Pagni, Jerome Sarris et al.
53 citations
Fifty-three first-time ayahuasca users (32 women, 21 men) completed questionnaires before and one month after a facilitated ceremony. Depression, anxiety, stress, alcohol and cannabis use, body dissociation, self-alienation, impulsivity, and negative affect significantly decreased, while positive mood, self-efficacy, authentic living, extraversion, agreeableness, open-mindedness, spirituality, and relationship satisfaction increased. Baseline traits—especially high negative emotionality and body dissociation, and low self-efficacy—strongly predicted improvements in mental health and substance use, whereas the intensity of the mystical experience had little predictive value. The findings suggest ayahuasca may produce broad mental health benefits and that personal traits could guide personalized treatment.
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
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
January 1, 2023
Dario A 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
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 1, 2025
Agnieszka Zelek-Molik, Ewa Litwa
19 citations
Mood disorders like major depressive disorder and bipolar disorder are leading causes of disability worldwide, characterized by depressed mood, anhedonia, sleep disturbances, appetite changes, fatigue, cognitive impairment, and feelings of worthlessness. A growing number of patients experience treatment resistance, even with long-term therapy, creating an urgent need for rapid-acting and safe antidepressants. This review summarizes trends in novel antidepressant research, focusing on drugs with multi-directional mechanisms and high efficacy for treatment-resistant depression. Animal models of depression remain essential for predicting therapeutic strategies and understanding the physiological effects of new compounds, guiding the development of innovative treatments.
Frontiers in pharmacology
January 1, 2023
Klemens Egger, Frederik Gudmundsen, Naja Støckel Jessen et al.
17 citations
Co-administration of harmine with DMT in rats increased brain DMT levels by inhibiting its metabolism to indole-3-acetic acid, yet no significant occupancy of serotonin 5-HT2A receptors by DMT was detected, even at brain DMT concentrations up to 11.3 µM. Low doses of DMT and/or harmine did not significantly alter brain glucose metabolism as measured by [18F]FDG-PET. These preliminary findings suggest that the role of MAO-A inhibition in potentiating DMT's psychedelic effects may be more complex than previously assumed, and further dose-response studies are needed.
Frontiers in pharmacology
January 1, 2025
Jing Wang, Yulei Hao, Di Ma et al.
14 citations
Recreational abuse of six addictive drugs—methamphetamine, cocaine, synthetic cathinones, ketamine, nitrous oxide, and heroin—damages the nervous system through shared toxic pathways, including oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. Psychostimulants disrupt monoaminergic signaling, causing cognitive impairment and neurovascular damage. Dissociative anesthetics impair glutamatergic transmission and mitochondrial function, worsening excitotoxicity and neuronal death. Opioids target the brain's reward system, inducing oxidative stress and neuroinflammation. Current treatments focus on symptom management and behavioral therapy; emerging options like antioxidants and NMDA receptor modulators need further validation.
Frontiers in pharmacology
January 1, 2023
Leah M Salinsky, Christina R Merritt, Joshua C Zamora et al.
14 citations
Opioid misuse and overdose deaths are a major public health problem involving prescription opioids and potent fentanyl derivatives. Repeated overdose events indicate opioid use disorder (OUD). Opioids reduce pain by activating µ-opioid receptors (MOR) in the central nervous system, and dysregulation of reward circuitry underlies OUD. Serotonin (5-HT) contributes to opioid pharmacology and OUD. There is renewed interest in psychedelic compounds acting through the 5-HT2A receptor (5-HT2AR) for treating substance use disorders. Emerging data suggest MOR and 5-HT2AR crosstalk at cellular levels and in OUD circuitry, offering opportunities for novel pharmacological intervention. This review discusses the opportunities and challenges of using 5-HT2AR agonists as therapeutics for OUD.
Frontiers in pharmacology
January 1, 2024
Carla Soares, Gisela Lima, Marta Lapo Pais et al.
13 citations
A pharmacoimaging study in eleven healthy experienced users found that inhaled DMT increases functional connectivity between brain regions involved in social cognition and emotional processing. Specifically, DMT strengthened connections between the supramarginal gyrus and the precuneus, posterior cingulate gyrus, amygdala, and orbitofrontal cortex, as well as between the amygdala and orbitofrontal cortex. These changes occurred in socio-emotional and affective-value circuits, offering insight into how psychedelics may alter brain function and potentially contribute to therapeutic effects in disorders involving social and reward processing deficits.
Frontiers in pharmacology
January 1, 2024
Senbing Zhang, Yanzhu Pu, Jianning Liu et al.
12 citations
(R)-ketamine shows promise for treatment-resistant depression with fewer psychomimetic and dissociative side effects than (R,S)- or (S)-ketamine, but a recent small randomized controlled trial found its antidepressant efficacy did not surpass placebo in adults. The compound may also have applications in cognitive disorders, stroke, Parkinson's disease, multiple sclerosis, osteoporosis, substance use disorders, inflammatory diseases, COVID-19, and organophosphate poisoning. This review covers (R)-ketamine's mechanisms and antidepressant research, highlighting its potential and need for further verification.
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
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
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 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.