Translational psychiatry
November 8, 2021
Manoj K Doss, Michal Považan, Monica D Rosenberg et al.
343 citations
Psilocybin therapy increased cognitive flexibility for at least four weeks in 24 patients with major depressive disorder, though these improvements were not linked to antidepressant effects. One week after treatment, glutamate and N-acetylaspartate concentrations decreased in the anterior cingulate cortex (ACC), and functional connectivity dynamics increased between the ACC and posterior cingulate cortex. Surprisingly, larger increases in this neural flexibility were associated with smaller gains in cognitive flexibility. Baseline brain connectivity from the ACC predicted cognitive flexibility improvements, with greater baseline connectivity linked to better baseline flexibility but less improvement. The findings suggest that while some increase in neural dynamics may help shift from rigid states, larger persisting increases may be less beneficial.
Translational psychiatry
May 23, 2023
Severin B Vogt, Laura Ley, Livio Erne et al.
85 citations
Intravenous DMT can produce a psychedelic state that is short-lasting and controllable. A double-blind, placebo-controlled crossover trial with 27 healthy participants tested five DMT regimens: low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus plus low infusion (15 mg + 0.6 mg/min), and high bolus plus high infusion (25 mg + 1 mg/min). Bolus doses induced very intense effects within 2 minutes, with more negative feelings and anxiety than infusions. Infusions produced slowly increasing, dose-dependent effects that plateaued after 30 minutes. All effects subsided within 15 minutes of stopping the infusion. Acute tolerance developed, with stable subjective effects from 30 to 90 minutes despite rising plasma concentrations. Intravenous DMT infusion is a promising tool for tailored psychedelic therapy.
Translational psychiatry
May 31, 2016
M Belgers, M Leenaars, J R Homberg et al.
64 citations
Ibogaine, a naturally occurring substance used informally to reduce craving and relapse in substance use disorders, was evaluated in a systematic review and meta-analysis of 27 animal studies. Ibogaine reduced drug self-administration, especially within the first 24 hours after dosing, but did not affect drug-induced conditioned place preference. It caused motor impairment in the first day and cerebral cell loss persisting for weeks. Data on cardiac effects and neuropharmacological mechanisms were limited. The findings support further clinical research into ibogaine's efficacy for reducing craving and substance use in patients, but close monitoring is recommended due to potential toxic effects.
Translational psychiatry
May 10, 2023
Sandeep Singh, Alexander Botvinnik, Orr Shahar et al.
54 citations
Psilocybin reduced marble burying in mice, a behavior used to model obsessive-compulsive disorder, but this effect did not depend on the serotonin 2A or serotonin 1A receptors typically associated with psychedelic effects. The 5-HT1A agonist 8-OH-DPAT also reduced marble burying, and its effect was additive with psilocybin, while the 5-HT1A partial agonist buspirone reduced marble burying without adding to psilocybin's effect. Blocking 5-HT1A receptors with WAY100635 did not attenuate psilocybin's effect. A staggered psilocybin regimen over 3.5 hours had no effect, and the effect of a single injection was not persistent. Co-administration of buspirone blocked psilocybin's head twitch response, a rodent correlate of psychedelic effects, suggesting buspirone might block psychedelic effects without impairing anti-obsessional effects.
Translational psychiatry
April 8, 2023
D P Effinger, S G Quadir, M C Ramage et al.
49 citations
Psilocin, the active metabolite of psilocybin, produces sex-specific and lasting changes in central amygdala (CeA) activity and reactivity to an aversive stimulus in mice. Acutely, psilocin increased CeA activity in both sexes and increased stimulus-specific CeA reactivity in females but not males. Over time, psilocin decreased CeA reactivity in males from 2 to 28 days after administration, while no such decrease occurred in females. Behavioral responses to the aversive stimulus also showed sex-dependent changes in threat responding, without affecting exploratory behavior or locomotion. These findings indicate that a single dose of psilocin induces enduring, sex-specific alterations in CeA function and threat-related behavior.
Translational psychiatry
February 12, 2024
Cheng Jiang, Ralph J DiLeone, Christopher Pittenger et al.
37 citations
A single dose of ketamine produces antidepressant-like effects in rats only when the brain's own opioid system is active in the medial prefrontal cortex (mPFC). Blocking opioid receptors with naltrexone—either throughout the body or directly in the mPFC—eliminates ketamine's behavioral effects. Ketamine rapidly increases levels of the opioid β-endorphin and expression of the μ-opioid receptor gene in the mPFC, and boosts production of β-endorphin's precursor in the hypothalamus. Neutralizing β-endorphin in the mPFC with a specific antibody also abolishes ketamine's behavioral and molecular effects, demonstrating that β-endorphin and opioid receptor activation in the mPFC are necessary for ketamine's antidepressant-like actions.
Translational psychiatry
July 30, 2020
Ashish K Sahib, Joana Ra Loureiro, Megha M Vasavada et al.
37 citations
Ketamine produces rapid antidepressant effects even in people with treatment-resistant depression, but how it alters brain function is not fully understood. In this study, 47 patients with treatment-resistant depression and 32 healthy controls performed a brain-imaging task measuring response inhibition. After one and then four intravenous ketamine infusions, 37 patients repeated the task. Brain activation decreased in regions involved in inhibitory control, including prefrontal and parietal areas and visual cortex, following repeated treatment. Patients who achieved remission had lower activation in the supplementary motor area before treatment, which then normalized toward control levels after ketamine. These changes in the supplementary motor area during response inhibition were linked to reduced depressive symptoms and may predict treatment outcome.
Translational psychiatry
November 29, 2024
Gustavo C Medeiros, Isabella Demo, Fernando S Goes et al.
32 citations
Treatment-resistant depression accounts for a large share of the burden of major depressive disorder. Intravenous ketamine and intranasal esketamine are rapid-acting antidepressants that can effectively treat this condition, but response varies. Reliable predictors of response are urgently needed. Clinical predictors of a robust response to ketamine include a family history of alcohol use disorder and a history of childhood trauma. A promising brain-based biomarker is an increase in gamma power in frontoparietal regions measured by EEG. Blood-based biomarkers have shown limited usefulness, with small-effect increases in BDNF being the most consistent indicator. Dissociative symptoms during treatment are not typically associated with response. Most predictors have modest effect sizes, so multivariate models will be needed.
Translational psychiatry
June 10, 2024
ZuoYao Shen, DaiQuan Gao, Xue Lv et al.
31 citations
Ketamine rapidly reduces suicidal thoughts in people with depression, with effects lasting through the full treatment cycle. A network meta-analysis of 14 studies (1,380 participants) found that within the first day after treatment, suicidal ideation dropped significantly (risk ratio 10.02). Repeated doses produced greater improvement after the last dose than after the first (risk ratio 0.56). By the end of treatment, recovery was significantly better with ketamine than with placebo (risk ratio 4.29 at day 26). This is the first network meta-analysis to demonstrate ketamine's role in alleviating suicidal ideation and to compare drug effects at different time points.
Translational psychiatry
September 30, 2024
Aaron Klaiber, Yasmin Schmid, Anna M Becker et al.
27 citations
Mescaline produces dose-dependent subjective and physiological effects in healthy people, with doses above 100 mg increasing blood pressure and heart rate. Subjective effects lasted from 6.4 hours at 100 mg to 14 hours at 800 mg, and the drug reached peak concentration in blood after about 2 hours with a half-life of 3.5 hours. Nausea and vomiting were common at the highest dose. Blocking serotonin 5-HT2A receptors with ketanserin reduced the effects of 800 mg mescaline to levels similar to lower doses, indicating that mescaline's acute effects are primarily mediated by these receptors.
Translational psychiatry
May 25, 2024
Marta Valenza, Roberta Facchinetti, Carola Torazza et al.
26 citations
Acute stress triggers a rapid response from glial cells—astrocytes and microglia—in the prefrontal cortex of rats, activating the NF-κB pathway and increasing inflammatory cytokines IL-18 and TNF-α. In vulnerable animals, this response persists alongside altered levels of glial proteins S100B, CD11b, and CX43, brain trophic factors BDNF and FGF2, and synaptic proteins MAP2 and PSD95. A single subanesthetic dose of ketamine given 24 hours after stress reversed many of these changes, suggesting it helps restore brain homeostasis. Reactive astrogliosis, changes in trophic factors, and neuronal damage appear to be key determinants of vulnerability to acute traumatic stress, and ketamine shows therapeutic potential against stress-related psychiatric disorders.
Translational psychiatry
December 4, 2024
Kenneth Shinozuka, Katarina Jerotic, Pedro Mediano et al.
17 citations
Serotonergic psychedelics such as LSD, psilocybin, and DMT alter consciousness and may help treat depression and addiction, but their mechanisms remain unclear. A systematic review and meta-analysis across three levels—subjective experience, neuroimaging, and molecular pharmacology—reveals that medium and high doses of LSD produce stronger visionary restructuring than psilocybin. Neuroimaging shows psychedelics generally strengthen connectivity between brain networks while weakening connectivity within networks. Pharmacologically, LSD triggers more inositol phosphate formation at the 5-HT2A receptor than DMT or psilocin, but no significant differences exist in receptor selectivity among the drugs. The analysis finds high heterogeneity and risk of bias, calling for standardized methods and more research.
Translational psychiatry
July 15, 2024
Nadia R P W Hutten, Conny W E M Quaedflieg, Natasha L Mason et al.
16 citations
Repeated low doses of LSD (15 mcg) affect arousal, attention, and memory depending on a person's baseline cognitive state. In a randomized placebo-controlled trial with 53 healthy participants, LSD reduced resting-state EEG delta, theta, and alpha power (indicating stimulation) and enhanced pre-attentive processing during acute dosing sessions. LSD also blunted visual long-term potentiation (a marker of perceptual learning and memory) by the fourth dosing session. Stimulatory effects were strongest in individuals with low baseline arousal and attention, while inhibitory effects on memory were strongest in those with high baseline memory performance. Some EEG changes persisted at a one-week follow-up, suggesting possible neuroadaptations from repeated low-dose LSD.
Translational psychiatry
June 4, 2024
Elizabeth D Ballard, Deanna Greenstein, Philip T Reiss et al.
16 citations
Ketamine, a drug that modulates the glutamate system, is linked to changes in sleep, depression, and suicidal thoughts. In a randomized, double-blind, crossover trial, 36 people with treatment-resistant major depression and 25 healthy volunteers underwent polysomnography before and after receiving ketamine or placebo. At baseline, those with depression had less total sleep time and shorter REM latency. Ketamine increased slow-wave (delta) brain activity early in the night and both alpha and delta activity later, compared to placebo. However, ketamine did not significantly alter sleep arousal metrics or mediate its antidepressant or anti-suicidal effects through sleep changes. The findings suggest sleep-related variables are part of broader neurobiological shifts after ketamine.
Translational psychiatry
September 4, 2024
Patrick Vizeli, Erich Studerus, Friederike Holze et al.
15 citations
LSD dose is the strongest predictor of the drug's subjective and autonomic effects, but non-pharmacological factors also play a significant role. Pre-drug mood states—such as well-being, emotional excitability, and anxiety—predict subjective effects, heart rate, and body temperature. The personality trait openness to experiences correlates with stronger mystical-type effects and oceanic boundlessness. Prior hallucinogen use is linked to less anxious ego dissolution and a less intense overall altered state. Acute anxiety relates negatively to the functionality of the Cytochrome 2D6 enzyme. Sex and body weight do not significantly influence the drug experience.
Translational psychiatry
April 15, 2024
Nathan Allen, Aron Jeremiah, Robin Murphy et al.
15 citations
Microdosing LSD (10 µg every third day for six weeks) increased sleep duration in healthy adult male volunteers. On nights after dosing, the LSD group slept an extra 24.3 minutes per night compared to placebo, with no change in sleep on dosing days. Sleep stage proportions and physical activity remained unchanged. The findings indicate that microdosing LSD modifies physiological sleep requirements, and the objective changes are unlikely to be a placebo effect.
Translational psychiatry
September 30, 2024
Elizabeth L Fisher, Ryan Smith, Kyna Conn et al.
14 citations
Psilocybin treatment in rats performing a reversal learning task led to more rewards through increased task engagement, driven by changes in forgetting rates and reduced loss aversion. Computational modeling suggests psilocybin may induce an optimism bias by altering how beliefs are updated, which could have implications for clinical conditions marked by pessimism.
Translational psychiatry
August 9, 2024
Yiheng Pan, Maria P Gorenflo, Pamela B Davis et al.
14 citations
Ketamine prescriptions are linked to a lower risk of suicidal thoughts in people with recurrent major depressive disorder compared to other common antidepressants. Analyzing electronic health records from over 500,000 patients, the risk of suicidal ideation was 37% lower within the first week, 33% lower within the first month, and 22% lower over nine months. The protective effect was strongest in adults over 24, females, males, and White patients. This real-world evidence suggests ketamine's long-term benefits for reducing suicidal ideation, though optimal dosing and mechanisms need further study.
Translational psychiatry
July 27, 2024
Rubén Herzog, Florentine Marie Barbey, Md Nurul Islam et al.
13 citations
Ketamine increases redundancy in brain dynamics—copies of the same information retrievable from three or more electrodes—most notably in the alpha frequency band, as measured by portable low-density EEG. In a double-blind crossover trial with 30 male adults, racemic ketamine compared to saline infusion produced greater redundancy during resting state, linked to dissociative shifts in consciousness. During an auditory oddball task, the effect was stronger for predictable standard stimuli than for deviant ones. Associations between ketamine's high-order interactions and experiences of derealization were observed, suggesting these measures capture pharmacological alterations in consciousness.
Translational psychiatry
September 12, 2024
Christopher R Nicholas, Matthew I Banks, Richard C Lennertz et al.
10 citations
Psilocybin, a serotonergic psychedelic, can relieve symptoms in several psychiatric disorders and improve well-being, but it was unclear whether these benefits arise during the acute experience or depend on later memory of it. In 8 healthy participants, psilocybin (25 mg) was co-administered with the amnestic benzodiazepine midazolam at a dose that allowed a conscious psychedelic experience while partially impairing memory for it. Higher midazolam doses and greater memory impairment tended to associate with lower salience, insight, and well-being from psilocybin. These results suggest memory plays a role in therapeutically relevant behavioral effects of psilocybin.
Translational psychiatry
February 24, 2024
Rachael L Sumner, Rebecca L McMillan, Anna Forsyth et al.
7 citations
Ketamine's antidepressant effects may be driven by acute changes in brain connectivity and GABA receptor dynamics, not primarily by NMDA receptor blockade. In 30 patients with major depressive disorder, resting-state EEG was recorded before and during a 0.44 mg/kg ketamine infusion. Computational modeling revealed a significant increase in parietal-to-frontal AMPA-mediated connectivity and a significant decrease in the frontal GABA time constant. Both changes correlated with antidepressant response. NMDA receptor changes did not survive correction and were not correlated with symptom improvement. The findings suggest that acute fronto-parietal connectivity and GABA-A/AMPA receptor dynamics mediate ketamine's antidepressant properties.
Translational psychiatry
December 5, 2024
Bettina Habelt, Dzmitry Afanasenkau, Cindy Schwarz et al.
6 citations
Alcohol use disorder (AUD) impairs prefrontal control mechanisms, leading to reduced inhibitory control and increased relapse risk. Using a biocompatible neuroprosthesis in a rat model of alcohol addiction, researchers measured neural oscillations and event-related potentials during abstinence. Alcohol-dependent rats showed reduced amplitudes of P1N1 and N1P2 components and attenuated event-related oscillatory activity, along with a dominance in higher beta frequencies indicating hyperarousal prone to relapse. Treatment with psilocybin or LY379268 restored these electrophysiological impairments, with psilocybin particularly counteracting the hyperarousal state. These prefrontal markers may serve as indicators of relapse vulnerability and treatment response, especially for psychedelic drugs.
Translational psychiatry
August 6, 2024
Chengyu Wang, Xiaofeng Lan, Weijian Liu et al.
6 citations
Non-improvement after four ketamine infusions, or three consecutive non-improvements after three infusions, reliably predicts overall non-response to a six-dose course of intravenous ketamine for depression. Among 135 individuals with major depressive or bipolar disorder in a current depressive episode, sensitivities for predicting non-response exceeded 90% using these early non-improvement criteria. Those who did not improve by these points showed no significant reduction in depressive symptoms from subsequent infusions. The findings suggest that early non-improvement can guide clinicians to discontinue treatment, avoiding ineffective continued dosing.
Translational psychiatry
November 9, 2024
Tianwen Huang, Yangyang He, Ruijuan Cheng et al.
5 citations
In mice with cisplatin-induced acute kidney injury (AKI), a single dose of ketamine reduced kidney damage, pathological changes in other organs, and depression-like behaviors. The beneficial effects were reversed by blocking the TrkB receptor, and analysis implicated the TrkB and ERK-CREB signaling pathways and blood metabolites like C16-ceramide. The findings suggest ketamine may alleviate both kidney injury and associated depressive symptoms, though the role of the kidney-brain axis remains unclear.
Translational psychiatry
January 19, 2024
Judit Biosca-Brull, Genis Ona, Lineth Alarcón-franco et al.
5 citations
A single oral dose of ibogaine significantly alters gene expression in the frontal cortex of mice four hours after administration. Genes involved in hormonal pathways and synaptogenesis were upregulated, while genes associated with apoptosis and endosomal transport were downregulated. Validation via qPCR did not fully confirm the hormonal pathway changes, possibly due to the specific brain region sampled. Female mice showed more pronounced gene expression changes than males, and high variability was observed across individual animals. These findings advance understanding of ibogaine's molecular actions and highlight sex differences that may influence its effects.