Molecular Psychiatry
March 13, 2018
P. Zanos, T. Gould
1,112 citations
A single low dose of the anesthetic ketamine can rapidly and lastingly relieve depression, but its abuse potential and dissociative side effects limit widespread use. This review examines proposed molecular mechanisms for ketamine's antidepressant action, including inhibition of specific N-methyl-D-aspartate receptors (NMDARs), effects on GABAergic interneurons, and suppression of burst firing in the lateral habenula. It also discusses downstream pathways involving brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mTOR, and GSK-3, as well as the roles of ketamine's (R)-ketamine enantiomer and the metabolite (2R,6R)-hydroxynorketamine. These mechanisms likely work together to trigger lasting changes in synaptic plasticity that underlie the antidepressant effects.
Molecular Psychiatry
October 3, 2018
M. Fava, M. Freeman, M. Flynn et al.
438 citations
Intravenous ketamine at 0.5 mg/kg and 1.0 mg/kg produces rapid antidepressant effects in adults with treatment-resistant depression, with most improvement seen one day after a single 40-minute infusion. Lower doses (0.1 mg/kg and 0.2 mg/kg) did not show consistent benefit. The study compared four ketamine doses against an active placebo (midazolam) in 99 outpatients across six U.S. sites. Higher doses caused more dissociative symptoms and temporary blood pressure increases, but infusions were generally well tolerated. The findings indicate a range of effective subanesthetic doses, with no clear advantage for doses below 0.5 mg/kg.
Molecular Psychiatry
April 15, 2021
J. Bonaventura, Sherry Lam, Meghan L. Carlton et al.
266 citations
Ketamine, a mixture of two mirror-image molecules called (S)-ketamine and (R)-ketamine, is used as an anesthetic and, more recently, as an antidepressant, but it carries a risk of abuse. The (S)-form is FDA-approved for treatment-resistant depression, while the (R)-form shows promise in animal models but has not been tested in people. In rats and mice, (S)-ketamine, but not (R)-ketamine, produced behaviors linked to abuse potential, such as self-administration, increased movement, and preference for places where the drug was given. (S)-ketamine also boosted activity and dopamine levels in a brain region called the medial prefrontal cortex, partly by activating opioid receptors. These findings indicate that the abuse liability of racemic ketamine stems mainly from its (S)-enantiomer.
Molecular Psychiatry
February 27, 2018
A. Nugent, Elizabeth D. Ballard, T. Gould et al.
254 citations
In a double-blind, placebo-controlled, randomized cross-over trial with 35 unmedicated people with major depressive disorder (MDD) and 25 healthy controls, ketamine (0.5 mg/kg) improved depressive symptoms in MDD subjects but caused modest, temporary increases in depressive symptoms in healthy controls. Both groups showed increased resting gamma power measured by magnetoencephalography. Among MDD subjects, gamma power did not directly predict the size of the antidepressant effect. However, baseline gamma power moderated the link between post-ketamine gamma and response: higher post-ketamine gamma was tied to better response in those with low baseline gamma, but the opposite pattern appeared in those with high baseline gamma. This suggests biological subtypes based on homeostatic dysregulation and cautions against inferring ketamine's mechanism solely from studies of healthy controls.
Molecular Psychiatry
May 7, 2021
Wei Yan, Lijia Chang, Kenji Hashimoto
242 citations
The antidepressant effects of the drug (R,S)-ketamine, a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), are not primarily due to blocking the N-methyl-D-aspartate receptor (NMDAR), despite initial assumptions. Preclinical studies in rodents show arketamine has more potent and longer-lasting antidepressant-like effects than esketamine, even though arketamine binds less strongly to NMDAR. Clinical trials with other NMDAR-blocking compounds failed to produce robust antidepressant effects in humans, indicating rodent findings do not always translate. The exact molecular mechanisms remain unclear. This review covers recent findings on these mechanisms, the possible roles of the brain-gut-microbiota and brain-spleen axes, and arketamine's potential for treating cognitive impairment, Parkinson's disease, osteoporosis, inflammatory bowel diseases, and stroke.
Molecular Psychiatry
November 24, 2021
W. Yao, Qianqian Cao, Shilin Luo et al.
208 citations
In a mouse model of depression, (R)-ketamine produces longer-lasting antidepressant effects than (S)-ketamine. The study identifies a molecular pathway in microglia—cells in the brain's medial prefrontal cortex—that mediates these effects. (R)-ketamine activates the ERK-NRBP1-CREB-BDNF signaling cascade in microglia, increasing BDNF transcription. Blocking this pathway with specific inhibitors or depleting microglia prevented (R)-ketamine's antidepressant-like effects and its ability to restore reduced dendritic spine density. These findings suggest that microglial signaling is essential for (R)-ketamine's antidepressant actions.
Molecular Psychiatry
September 14, 2020
A. Mkrtchian, Jennifer W. Evans, C. Kraus et al.
110 citations
Ketamine increased fronto-striatal functional connectivity in people with treatment-resistant major depression toward levels seen in healthy volunteers, while shifting connectivity in healthy volunteers toward a state similar to depressed participants under placebo. These effects occurred largely without changes in inflammatory markers (C-reactive protein) and were associated with both acute and sustained symptom improvements in the depressed group. Ketamine thus normalized reward-related brain circuitry in depression but disrupted it in healthy individuals, highlighting the potential importance of this circuitry in ketamine's mechanism of action for motivational symptoms.
Molecular Psychiatry
May 25, 2021
Ju Lu, Michelle Tjia, Brian Mullen et al.
87 citations
A single dose of the psychedelic analog tabernanthalog (TBG) reduces anxiety and reverses stress-induced deficits in sensory processing and cognitive flexibility in mice exposed to unpredictable mild stress. TBG promotes regrowth of dendritic spines lost during stress, lowers baseline neuronal activity, and enhances whisking-related modulation in the somatosensory cortex. In a texture discrimination task, novel textures activate a greater proportion of cortical neurons than familiar ones; this differential response is diminished by stress and restored by TBG. The findings indicate TBG combats stress effects by modulating basal and stimulus-dependent neural activity in cortical networks.
Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
Molecular Psychiatry
January 20, 2023
Jie Guo, Di Qiu, Han-Wen Gu et al.
46 citations
Perioperative intravenous ketamine reduces postoperative depression scores and pain scores on the first day after surgery but increases the risk of adverse effects including nausea, vomiting, headache, hallucination, and dizziness. The analysis of 15 randomized controlled trials with 1697 patients receiving ketamine and 1462 controls showed a reduction in depression scores on postoperative days 1, 3, and 7 and over the long term. Pain scores were lower only on the first postoperative day. The authors conclude that ketamine's benefits for postoperative depression and pain must be weighed against its increased adverse effects.
Molecular Psychiatry
April 27, 2024
K Conn, L K Milton, K Huang et al.
44 citations
Psilocybin, currently in clinical trials for anorexia nervosa (AN), may improve cognitive inflexibility, a core feature of AN. Using the activity-based anorexia rat model, psilocybin post-acutely improved body weight maintenance in female rats and facilitated cognitive flexibility, specifically through better adaptation to reversed reward contingencies. The cognitive enhancing effects involved serotonin 5-HT1A and 5-HT2A receptor signaling; blocking 5-HT1A negated these benefits. Psilocybin transiently increased cortical Htr2a transcription and decreased Htr1a transcription, with further Htr2a reduction in anorexic rats. These findings suggest psilocybin could ameliorate cognitive inflexibility in AN and highlight therapeutic mechanisms beyond 5-HT2A receptor binding.
Molecular Psychiatry
January 17, 2024
Dotan Braun, Ayelet M Rosenberg, Elad Rabaniam et al.
32 citations
Psilocybin, a psychedelic serotonin receptor agonist, has two behavioral effects in larval zebrafish: it stimulates spontaneous exploration and prevents irregular swim patterns that normally follow stress exposure, indicating an anxiolytic effect. These effects resemble those of ketamine, not SSRIs. Neural imaging suggests psilocybin inhibits serotonergic neurons in the dorsal raphe nucleus by activating local GABAergic neurons, a mechanism consistent with findings in mammals.
Molecular Psychiatry
October 11, 2024
Michal Brownstien, Michal Lazar, Alexander Botvinnik et al.
23 citations
In mice lacking the SAPAP3 gene, which display excessive self-grooming and anxiety similar to human obsessive-compulsive disorder, a single injection of psilocybin or psychedelic mushroom extract reduced self-grooming by about 15-19% over 21 days, while vehicle-treated mice showed a 119% increase. The effects lasted up to 7 weeks in responsive mice, and non-responsive mice later treated with psilocybin also improved. The mushroom extract was superior for reducing head-body twitches and anxiety. These results support clinical trials of psilocybin for OCD.
Molecular Psychiatry
March 14, 2024
Pol Puigseslloses, Gabriel Ketsela, Nicola Weiss et al.
23 citations
All tested 5-MeO-tryptamines selectively bind to 5-HT1A receptors over 5-HT2A receptors, with computational docking predicting better interaction in the 5-HT1A binding pocket. These compounds also interact with the serotonin transporter (SERT), where molecular size of the amino group influences affinity. 5-MeO-pyr-T acts as the most potent partial 5-HT releaser. All tryptamines elicit the head twitch response in mice, indicating potential hallucinogenic effects primarily mediated by 5-HT2A receptors, but 5-HT1A activation attenuates this response. Tryptamines producing stronger hypothermic responses via 5-HT1A tend to show lower hallucinogenic effects, highlighting opposing roles of the two receptors. Some compounds with low hallucinogenic effects remain potent 5-HT2A agonists, offering insight into non-hallucinogenic therapeutic ligands.
Molecular Psychiatry
October 21, 2024
Gabriele Floris, Mary Tresa Zanda, Konrad Dabrowski et al.
19 citations
A single dose of psilocybin given to rats 4–24 hours before a relapse test reduced cue-induced heroin seeking, though it did not alter actual heroin taking. Blocking the serotonin 2A receptor with antagonists worsened relapse. Psilocybin regulated about twice as many genes in the prefrontal cortex at a higher dose, with ketanserin blocking over 90% of these gene changes, including the IL-17a cytokine receptor. Psilocybin also regulated four chemokine/cytokine genes, and selectively inhibiting IL-17a in the prefrontal cortex was enough to reduce heroin relapse. The findings suggest psilocybin reduces heroin relapse and point to IL-17a signaling as a possible downstream pathway.
Molecular Psychiatry
February 6, 2024
Merima Šabanović, Alberto Lazari, Marta Blanco-Pozo et al.
17 citations
A single dose of the psychedelic compound (±)-DOI increased brain volume in sensory and association areas of young adult mice and improved cognitive flexibility one week later. Treated mice adapted faster to a reversal in a probabilistic learning task and began learning from reward omissions, a strategy mice normally do not use. The effects depended on the timing between drug administration and the reversal, as well as on intervening experiences. These findings suggest that psychedelics may aid treatment of conditions involving rigid thinking, such as depression or addiction, by enhancing neuroplasticity and enabling new learning strategies.
Molecular Psychiatry
February 17, 2022
Guang Chen, G. Mannens, Marlies de Boeck et al.
14 citations
An open-label study of (R)-ketamine for depression cannot establish efficacy due to expectancy biases and large placebo effects, even in treatment-resistant patients. One patient showed clinically meaningful dissociation. The antidepressant efficacy and optimal dose of (R)-ketamine must be determined in randomized controlled trials. A study in healthy volunteers found that (R)-ketamine and (S)-ketamine produced similar frequency and character of dissociative and other central nervous system adverse effects when compared at doses equipotent for NMDAR antagonism.
Molecular Psychiatry
November 29, 2024
Adrian Hase, Gregor Hasler, Abigail E. Calder
12 citations
A meta-analysis of 29 studies found no evidence that psychoplastogens—including ketamine, LSD, psilocybin, and MDMA—elevate peripheral brain-derived neurotrophic factor (BDNF) levels in humans. The overall effect size was negligible (SMD = 0.024) and not statistically significant. This null result held across different drugs, doses, blood fractions, participant ages, and psychiatric diagnoses. Better-controlled studies showed even smaller effects. The findings suggest that peripheral BDNF may not be a useful biomarker for rapid neuroplasticity changes in humans, or that preclinical findings on psychoplastogen-induced neuroplasticity may not translate to humans. More precise methods, such as neuroimaging, are recommended for future translational research.
Molecular Psychiatry
March 1, 2026
Tyler G. Ekins, Chloe Rybicki-Kler, Tao Deng et al.
9 citations
Classic psychedelics can strengthen connections in the retrosplenial cortex, a brain region important for memory and spatial orientation that is impaired in Alzheimer's disease, even though its neurons lack the serotonin 2A receptors thought necessary for such effects. Using a new genetic tool in mice, the research shows that this strengthening depends on presynaptic serotonin 2A receptors on incoming nerve fibers from the anterior thalamus, not on the postsynaptic receptors of the retrosplenial cortex itself. The finding suggests psychedelics may have broader therapeutic potential than currently recognized, possibly aiding conditions like Alzheimer's disease and post-traumatic stress disorder by boosting retrosplenial circuit function.
Molecular Psychiatry
August 23, 2025
Adam J. Drewko, Ron L. P. Habets, Tibor M. Brunt
4 citations
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Molecular Psychiatry
April 26, 2025
Rebecca Harding, Neomi Singer, Talma Hendler et al.
4 citations
Psilocybin therapy reduces anhedonia more than the SSRI escitalopram in major depressive disorder, yet escitalopram dampens emotional responses to musical surprises while psilocybin therapy preserves them. Escitalopram increases brain activity in memory and emotion regions during musical surprises, whereas psilocybin therapy decreases activity in the ventromedial prefrontal cortex and angular gyrus and increases sensory region activation. These contrasting neural and behavioral effects suggest fundamentally different treatment mechanisms: psilocybin may maintain subjective responses by reducing the salience of prediction errors or strengthening hedonic expectations, while escitalopram may weaken hedonic priors.
Molecular Psychiatry
August 26, 2025
Ross J. Purple, Rahul Gupta, Christopher W. Thomas et al.
2 citations
After a therapeutically relevant dose of psilocybin, high-frequency oscillations at 100 Hz appear in the infralimbic cortex of rats, lasting about an hour, while overall neuron firing rates and spike-train complexity decrease. These acute effects are stronger when the animal is at rest than during a sustained attention task. Over the following days, power in beta and low-gamma frequencies (20–60 Hz) gradually increases in the infralimbic cortex. The findings point to infralimbic network oscillations as potential markers of psychedelic-induced plasticity that unfold over multiple days, revealing details not easily seen in human brain imaging.
Molecular Psychiatry
April 6, 2025
2 citations
A study in a mouse model of obsessive-compulsive disorder (OCD)-like behaviors tested a psychedelic mushroom extract (PME) for potential therapeutic benefits. The research used SAPAP3 knockout mice, which exhibit compulsive grooming and other OCD-like behaviors. The findings suggest that PME may reduce these behaviors, indicating possible therapeutic effects. This work underscores the need for well-designed preclinical studies in the growing field of psychedelic research for psychiatric disorders.
Molecular Psychiatry
April 8, 2026
Johannes G. Ramaekers, Kim P. C. Kuypers, Franz X. Vollenweider
1 citation
MDMA, originally developed for military purposes and later used recreationally, is now being tested in clinical trials for PTSD. A narrative review of placebo-controlled single-dose studies in healthy volunteers found that 75-125 mg of MDMA acutely enhances mood, empathy, trust, and arousal while transiently impairing memory encoding through increased serotonin signaling. Motor coordination and cognitive flexibility decline modestly, but inhibitory control and executive function remain largely intact. Post-acutely, fatigue and low mood may occur. These effects may support trauma processing by facilitating fear extinction and disrupting negative memory reconsolidation, though they also complicate trial design by compromising blinding and inflating expectancy.
Molecular Psychiatry
March 5, 2026
1 citation
About 30% of people with depression have treatment-resistant depression (TRD). Ketamine can help, but how it works in the human brain was unclear. Using a PET tracer that shows AMPAR density, researchers found that AMPAR density was lower in patients with more severe TRD, and its distribution differed from healthy people. After ketamine, changes in AMPAR density in certain brain areas correlated with antidepressant effects, partially restoring normal AMPAR patterns. AMPAR dynamics underlie ketamine's antidepressant effect in TRD.