CNS Drugs
August 17, 2020
Joost J. Breeksema, Alistair Niemeijer, Erwin Krediet et al.
217 citations
This review argues that qualitative research on psychedelic treatments can reveal unique features of different substances and uncover implications for treating specific psychiatric disorders that quantitative methods might miss. By examining subjective experiences, such studies can help tailor therapies to particular conditions and substances, offering insights into how psilocybin, LSD, or other compounds produce distinct psychological effects. The authors suggest that incorporating qualitative findings into clinical practice could enhance treatment precision and patient outcomes, highlighting the value of exploring personal narratives and emotional processes in psychedelic therapy.
CNS Drugs
April 1, 2013
Jerome Sarris, Erica Mcintyre, David A Camfield
154 citations
A narrative review of plant-based medicines with both preclinical and clinical evidence for anxiety identified 21 herbs tested in human trials. Chronic use of Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis, and Echium amoenum showed support for treating various anxiety disorders. Acute anxiolytic activity was found for Centella asiatica, Salvia spp., Melissa officinalis, Passiflora incarnata, and Citrus aurantium. Bacopa monnieri showed anxiolytic effects in people with cognitive decline. Current evidence does not support Hypericum perforatum or Valeriana spp. for any anxiety disorder. Conclusions are tempered by methodological issues like small sample sizes and non-replication.
CNS Drugs
November 17, 2021
Susan Ling, Felicia Ceban, Leanna M.W. Lui et al.
123 citations
Psilocybin, a naturally occurring psychoactive alkaloid found in Psilocybe mushrooms, acts as a non-selective agonist at many serotonin receptors, particularly the 5-HT2A receptor. Its antidepressant and psychedelic effects are thought to involve modulation of the serotonergic system, with downstream changes in gene expression, and indirect effects on dopaminergic and glutamatergic systems. Psilocybin also alters neural circuitry in brain regions implicated in depression, including the default mode network and amygdala. This review synthesizes current understanding of the receptor pharmacology and neuronal mechanisms underlying psilocybin's psychedelic and putative antidepressant properties.
CNS Drugs
November 1, 2024
Roger S McIntyre, Rakesh Jain
58 citations
Glutamate signaling has emerged as a promising target for treating major depressive disorder (MDD), a chronic condition where standard monoamine antidepressants often have delayed effects and low remission rates. This narrative review describes how glutamate dysregulation is linked to depression, based on preclinical evidence and the rapid improvement seen with ketamine in a proof-of-concept trial. While many NMDA-targeted therapies have been investigated in phase 2 or 3 trials, most were discontinued. However, two glutamate-targeted antidepressants are now FDA-approved: nasal esketamine (Spravato) for treatment-resistant depression and MDD with suicidal ideation, and oral dextromethorphan-bupropion (Auvelity) for MDD in adults. These approvals highlight glutamate's role and offer new treatment options.
CNS Drugs
February 14, 2022
Jennifer Swainson, L. Klassen, Stefan Brennan et al.
42 citations
Intravenous ketamine and intranasal esketamine are used for depression but face cost and access barriers. Non-parenteral racemic ketamine (oral, sublingual, intranasal) might improve access, though evidence is limited. Concerns about ketamine's addictive potential have not been examined against available evidence. The authors argue that ketamine misuse risks are similar to those of stimulants or benzodiazepines, and prescribing should balance patient access with misuse concerns. A consortium of mood disorder specialists considers non-parenteral ketamine a reasonable option for select treatment-resistant depression cases and provides practical prescribing recommendations.
CNS Drugs
July 20, 2021
Vera Miriam Ludwig, Cathrin Sauer, Allan H. Young et al.
23 citations
Combining esketamine with the monoamine oxidase inhibitor tranylcypromine in patients with treatment-resistant depression does not cause clinically dangerous blood pressure spikes, despite earlier safety concerns. In a retrospective analysis of 509 esketamine administrations in 43 hospitalized patients, those who also received tranylcypromine showed statistically greater changes in systolic and diastolic blood pressure during the first hour after esketamine administration, but these changes were small (mean systolic increase of 2.96 mmHg versus a decrease of 8.84 mmHg in the non-tranylcypromine group) and not clinically significant. Heart rate was unaffected. A dose-response relationship was observed, with higher tranylcypromine doses linked to larger blood pressure increases, suggesting caution with high doses. The findings indicate that the combination is safe at standard doses.
CNS Drugs
September 1, 2023
Antonio Inserra, Alexandre Piot, Danilo de Gregorio et al.
17 citations
Anxiety disorders are a leading cause of disability, and over half of affected individuals do not respond to standard treatments. This review of preclinical and clinical research on LSD finds that while it can worsen anxiety in the short term, it produces lasting reductions in anxiety. Only two randomized controlled trials combining LSD with psychotherapy have been conducted in patients with anxiety disorders, showing good safety and sustained decreases in anxiety. The effects may involve serotonin receptors and brain networks such as the default mode network. It remains unknown whether LSD works alone or only with psychotherapy, and whether microdosing produces the same long-term benefits as full doses.
CNS Drugs
October 1, 2024
Anton Gomez-Escolar, Daniel Folch-Sanchez, Joanna Stefaniuk et al.
16 citations
Mental health disorders and substance use disorders (SUDs) contribute greatly to the global burden of disease. Psychedelics, including entactogens and dissociative substances, are being explored for SUD treatment but have less clinical evidence than for depression or PTSD. This narrative review discusses current research, therapeutic potential, and safety of psilocybin, LSD, ketamine, MDMA, and ibogaine in SUD treatment. It provides a balanced overview of potential benefits and harms in clinical settings, highlights the need for more research, and points out limitations and challenges to be addressed in future studies.
CNS Drugs
October 1, 2022
Niloufar Pouyan, Zahra Halvaei Khankahdani, Farnaz Younesi Sisi et al.
16 citations
A systematic review of psilocybin research organized by the Research Domain Criteria (RDoC) framework found that psilocybin has beneficial effects across multiple domains, particularly on positive valence systems, negative valence systems, and social processes. Short-term (23 assessments) and long-term (15 assessments) benefits were reported for positive valence systems. For the negative valence system, 12 outcome measures indicated increased fear, 19 showed no significant effect, and 7 parameters indicated lowered sustained threat over the long term. Thirty-four outcome measures revealed short-term alterations in social systems, including enhanced perception and understanding of others and affiliation. Cognitive systems findings mostly reported dyscognitive effects. Seven studies suggested transdiagnostic effects.
CNS Drugs
August 1, 2024
Liliana Patarroyo-Rodriguez, Stefanie Cavalcanti, Jennifer L. Vande Voort et al.
13 citations
Anhedonia, the inability to feel pleasure, is a symptom that appears in many mental disorders beyond just depression and schizophrenia, and it is linked to worse outcomes such as higher suicide risk and poor treatment response. Although brain imaging and biomarkers have improved understanding, the neural basis of anhedonia is still not fully known. Ketamine, a fast-acting antidepressant, also seems to reduce anhedonia through a separate mechanism from its antidepressant effects. Other potential treatments are being explored, but many questions remain, highlighting the need for more research.
CNS Drugs
December 1, 2023
Niloufar Pouyan, Farnaz Younesi Sisi, Alireza Kargar et al.
12 citations
A review of 28 clinical studies with 477 participants examined how lysergic acid diethylamide (LSD) affects reward processing, using the National Institute of Mental Health's Research Domain Criteria (RDoC) framework. LSD produced dose-dependent mood improvement in 20 short-term and 3 long-term studies. Its subjective and neural effects were linked to the 5-HT2A receptor. Animal studies suggested LSD could mildly reinforce conditioned place preference without aversion and reduce responsiveness to other rewards. Findings on reward learning were inconsistent but hinted at potential enhancements in associative learning. Reward valuation measures indicated possible reductions in effort expenditure for other reinforcers. The review identified areas for future research but noted limitations including diverse study designs not initially RDoC-oriented and potential bias from open-label human studies.
CNS Drugs
April 1, 2025
Balwinder Singh
6 citations
Trauma is common, with lifetime exposure estimates from 70% for a single event to 31% for multiple events. Many recover, but some develop post-traumatic stress disorder (PTSD), a debilitating condition with a lifetime prevalence of 6.8%, higher among women and veterans. Only two FDA-approved medications exist, paroxetine and sertraline, alongside psychotherapies like trauma-focused cognitive behavioral therapy and EMDR. Early-phase trials of MDMA-assisted therapy (MDMA-AT) showed promise, leading to FDA breakthrough therapy status in 2017. Phase 3 trials found nearly 70% of participants no longer met PTSD diagnostic criteria. However, in 2024 the FDA voted against approval due to concerns about trial design, blinding failure, missing safety assessments, and potential misconduct. Ongoing research must address blinding, long-term safety, and therapy variability.
CNS Drugs
December 1, 2024
Ruyun Liu, Ning Liu, Lin Ma et al.
5 citations
Major depressive disorder is a severe mental illness whose current medications often work slowly and cause side effects. The N-methyl-D-aspartate receptor (NMDAR), a type of glutamate-gated ion channel, is linked to depression based on preclinical and clinical research. The NMDAR antagonist ketamine produces rapid and lasting antidepressant effects but has psychotomimetic effects and addiction potential that limit its use. Over the past decade, evidence suggests that enhancing NMDAR function, particularly through positive allosteric modulators (PAMs), may offer antidepressant benefits with improved safety. This narrative review presents that approach as a potential novel strategy for treating depression.
CNS Drugs
July 10, 2025
Eric A. Miller, Christy Capone, Erica Eaton et al.
4 citations
Psychedelics have been investigated as a treatment for alcohol use disorder since the 1950s, with over a dozen clinical trials of LSD and recent trials of psilocybin and ayahuasca. Observational studies consistently show promising results, but placebo-controlled trials have produced inconsistent outcomes and methodologies. This review characterizes foundational studies, emphasizing key design factors such as the presence of a placebo (e.g., ephedrine, dextroamphetamine, diphenhydramine, or low-dose LSD) and non-pharmacological factors like treatment setting and psychotherapy. It also examines candidate mechanisms of action through a biopsychosocial lens, spanning cellular neuroplasticity, cognitive neuroscience, subjective experience, and social connection, highlighting findings on efficacy and potential mechanisms to guide future research.
CNS Drugs
November 28, 2025
D J Hirsch, Jace Reed, Aasim Naqvi et al.
2 citations
Eating disorders are complex psychiatric conditions with limited pharmacological treatment options. A review of clinical drug trials from 2010 to 2025 found 43 eligible phase I-IV trials for anorexia nervosa, binge eating disorder, bulimia nervosa, and rumination disorder. Among 24 distinct compounds studied, only lisdexamfetamine dimesylate received FDA approval for an eating disorder during this period. Few agents have shown positive results in late-stage trials, though solriamfetol and psilocybin show promise. There remains a significant lack of evidence-based pharmacological interventions for anorexia nervosa and little progress for bulimia nervosa, highlighting an urgent need for more rigorous clinical trials.
CNS Drugs
October 16, 2025
Gisèle Pickering, Véronique Morel, Marion Voute
2 citations
Ketamine, an anesthetic and sedative drug, is used off-label for chronic refractory pain and can provide significant short-term pain relief, especially for neuropathic pain, and is fairly well-tolerated in patients with severe refractory pain. However, long-term data on efficacy, cognitive impact, addiction risk, and optimal dosing are severely lacking. The intravenous route is the most studied, while alternatives remain underexplored. Ketamine is not a first-line treatment and must be prescribed by trained specialists within a structured standard of care. Future use depends on collaborative research to define optimal administration routes, patient phenotyping, and long-term studies assessing mood, quality of life, and cognitive function.
CNS Drugs
September 1, 2024
Emmanuelle A. D. Schindler
2 citations
Interest in using psychedelics and other psychoactive compounds to treat headache disorders is increasing. Although people have long reported therapeutic benefits from these substances, formal clinical trials have only recently begun. The effectiveness of any treatment depends on the specific headache disorder, the particular drug, and how it is used; no single protocol works for all headaches or drugs. This article discusses the careful considerations needed when evaluating classic psychedelics, ketamine, and cannabinoids as potential headache medicines.
CNS Drugs
January 17, 2026
Gaëlle Rached, Anna Campana, Dimitri Fiani et al.
1 citation
Monoamine oxidase inhibitors (MAOIs) can be used safely in some patients who use psychoactive substances, but certain combinations pose potentially fatal risks. This narrative review of 219 publications found that combining MAOIs with amphetamines, the empathogen MDMA, opioids with strong serotonergic reuptake inhibition (e.g., meperidine, tramadol), or alcoholic beverages high in tyramine can lead to serotonin toxicity, hypertensive emergencies, or death. In contrast, MAOI treatment of patients who use low-tyramine alcohol, caffeine, cannabis, nicotine, sedatives, and some classic hallucinogens can likely be managed with careful monitoring. No robust human data support MAOIs as effective treatments for substance use disorders themselves.
CNS Drugs
June 1, 2025
Sijia Zhang, Houtan Afshar, Peter J Colvonen et al.
1 citation
Repeated ketamine or esketamine sessions significantly reduced depression and PTSD symptoms in veterans. However, those who also had traumatic brain injury (TBI) and severe obstructive sleep apnea (OSA) did not show improvement in depression, suggesting that these comorbidities may require alternative or pre-treatment before starting ketamine or esketamine therapy.
CNS Drugs
July 1, 2026
Omer A. Syed, Valentyn Sobolenko, Sean M. Nestor et al.
Most demographic and clinical variables do not reliably predict who will benefit from ketamine or esketamine for treatment-resistant depression, though a few promising factors—such as early response to treatment and a family history of substance use disorders—warrant further study. This systematic review synthesized 122 studies involving 12,674 participants, finding that the majority of 77 examined predictor variables showed no association with antidepressant outcomes. The review included both unipolar and bipolar treatment-resistant depression, with most studies using intravenous ketamine at a fixed 0.5 mg/kg dose.
CNS Drugs
June 15, 2026
Edward P. Hackett, Aditi Chaudhri -, Linda Hasman et al.
Dextromethorphan (DXM), a common over-the-counter cough suppressant, produces psychedelic effects at high doses that may be useful for treating psychiatric disorders resistant to standard therapies. A systematic review of eight studies with 104 total participants found that psychedelic effects begin at 100 mg, with hallucinatory and mystical experiences intensifying at 300 and 400 mg. Adverse effects such as nausea, vomiting, motor impairment, and cognitive slowing become more prominent above 200 mg. The evidence is too limited to establish true dose-response relationships, and the certainty of evidence is low for most outcomes, highlighting the need for larger, well-designed studies.
CNS Drugs
March 24, 2026
Mathieu Seynaeve, Fiona Dunbar, Chandni Hindocha et al.
A proof-of-concept trial tested intranasal 5-MeO-DMT combined with an SSRI in people with treatment-resistant depression. The treatment was generally well tolerated and showed preliminary signals of antidepressant effects, though the small, uncontrolled design limits conclusions.
CNS Drugs
February 1, 2026
Matheus G Marques, Liliana Patarroyo-Rodriguez, Balwinder Singh
Bipolar disorder affects about 40 million people worldwide, with depression as its most disabling phase. Current treatments often work slowly, prompting interest in psilocybin, a psychedelic compound being studied in clinical trials combined with psychotherapy. Early research in bipolar II disorder (19 participants) shows encouraging results, but evidence is limited. Safety concerns include risk of mood switching and drug interactions. Regulatory hurdles, infrastructure needs, and uncertainties about the role of the psychedelic experience, especially with common bipolar medications, remain. Cautious research is needed to assess psilocybin's safety and efficacy for bipolar depression, particularly for bipolar I disorder and long-term outcomes.
CNS Drugs
May 1, 2024
Libat Weizman, Haggai Sharon, Lior Dayan et al.
In male patients with chronic radicular neuropathic pain, a single sublingual dose of THC (0.2 mg/kg) shifted autonomic balance toward increased parasympathetic tone, as shown by a reduced low/high frequency heart rate variability ratio, and improved the body's ability to inhibit pain, measured by conditioned pain modulation. These changes correlated with increased functional connectivity between brainstem and prefrontal cortex regions, suggesting THC exerts top-down regulatory effects that may normalize multiple aspects of supraspinal pain dysregulation.
CNS Drugs
October 1, 2023
Dania Akbar, Taeho Greg Rhee, Felicia Ceban et al.
A systematic review of five studies found that AXS-05, a combination of dextromethorphan and bupropion, rapidly reduces depression severity in adults with major depressive disorder who do not respond to standard antidepressants. Depressive symptoms measured on the MADRS scale decreased significantly compared to placebo as early as one week and compared to an active control at two weeks. The treatment effect was maintained for up to 12 months, with an average 23-point reduction from baseline. The therapy was well-tolerated with only transient side effects. These results support the role of glutamatergic and sigma-1 signaling pathways in depression.