LSD revisited: Mechanisms of action and therapeutic potential in mental health

Major depressive disorder (MDD) is one of the most prevalent psychiatric conditions worldwide, affecting over 350 million people. Standard treatments, primarily antidepressants targeting serotonin, noradrenaline, and/or dopamine, are based on the monoamine hypothesis, which links depression to imbalances in these neurotransmitters. A sizable fraction of patients, however, does not get enough relief, which highlights the limits of current drug treatments. Treatment-resistant depression (TRD), a mainly intractable subtype of MDD, affects around 30 % of MDD sufferers, therefore it is imperative that better effective therapies be found. Recent research has focused on psychedelic medicines including lysergic acid diethylamide (LSD), which affects serotonergic as well as glutamatergic systems. These drugs have demonstrated potential to induce rapid and long-term antidepressant responses, possibly by the facilitation of neuroplasticity and adjustment of long-term neural communication, even after the drug is cleared from the body. Ongoing clinical trials are testing the efficacy and safety of LSD in TRD and simultaneously resolving problems of placebo design and risk minimization. This narrative review examines the neurobiological mechanisms of LSD, assesses its potential as an antidepressant and anxiolytic agent, and discusses the safety issues associated with its utilization. Although still experimental, psychedelic therapies could demonstrate a significant shift in psychiatric treatment, offering new hope for patients who have not responded to conventional antidepressants. Sustained research is essential to validate these results and guide their integration into clinical practice.

Treatment of major depressive disorder (MDD) including treatment-resistant depression (TRD) remains a major unmet need. Although there are several classes of dissimilar antidepressant drugs approved for MDD, the current drugs have either limited efficacy or are associated with undesirable side effects and withdrawal symptoms. The efficacy and side effects of antidepressant drugs are mainly attributed to their actions on different monoamine neurotransmitters (serotonin, norepinephrine, and dopamine). Development of new antidepressants with novel targets beyond the monoamine pathways may fill the unmet need in treatment of MDD and TRD. The recent approval of intranasal Esketamine (glutamatergic agent) in conjunction with an oral antidepressant for the treatment of adult TRD patients was the first step toward expanding beyond the monoamine targets. Several other glutamatergic (AXS-05, REL-1017, AV-101, SLS-002, AGN24175, and PCN-101) and GABAergic (brexanolone, zuranolone, and ganaxolone) drugs are currently in different stages of clinical development for MDD, TRD and other indications. The renaissance of psychedelic drugs and the emergence of preliminary positive clinical trial results with psilocybin, Ayahuasca, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and lysergic acid diethylamide (LSD) may pave the way towards establishing this class of drugs as effective therapies for MDD, TRD and other neuropsychiatric disorders. Going beyond the monoamine targets appears to be an effective strategy to develop novel antidepressant drugs with superior efficacy, safety, and tolerability for the improved treatment of MDD and TRD.

Introduction A new era of treatment for adults with treatment-resistant depression (TRD), which involves psychedelic substances, is dawning. Emerging evidence indicates that psychedelics can exert antidepressant effects through multiple neurobiological and psychological mechanisms. However, it remains to be seen if these new treatments will revolutionize the treatment of TRD. Areas covered The present review focuses on the efficacy of serotoninergic psychedelics psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), ayahuasca, 5‐methoxy‐N,N‐dimethyltryptamine (5-MeO-DMT) and mescaline (3,4,5-trimethoxyphenethylamine), as well as 3,4-methylenedioxymethamphetamine (MDMA), for TRD. A systematic search was conducted for psilocybin in TRD as emerging trials had not yet been subject to review. A narrative review summarized findings on other psychedelics. Expert opinion Psychedelic therapy has created a paradigm shift in the treatment of TRD, as it can maximize therapeutic benefits and minimize potential risks. Psilocybin holds promise as a potential game-changer in the treatment of TRD, with initial evidence suggesting a rapid antidepressant effect sustained for some responders for at least 3 months. Nevertheless, further adequately powered, double-blind, comparator-controlled trials are required to explore and clarify the mechanisms of action and long-term effects of psychedelics in TRD. Psychedelics also hold promise for other psychiatric conditions, such as bipolar depression and post-traumatic stress disorder.

Vagus nerve stimulation: An update on a novel treatment for treatment-resistant depression

ObjectiveIntranasal (IN) esketamine represents a novel add-on treatment for treatment-resistant depression (TRD) with reported favourable effects on insomnia. IN esketamine treatment might similarly reduce the incidence of insomnia as an adverse event (AE). The present meta-analysis therefore investigated whether IN esketamine relative to placebo is associated with a lower incidence of insomnia as an AE in adults with TRD.MethodsData were retrieved from seven randomised placebo-controlled trials evaluating the safety and efficacy of IN esketamine combined with a monoaminergic antidepressant in the treatment of TRD that reported data on insomnia as an AE. The study population (n = 1,311) comprised adult patients (aged ≥ 18 years) with a primary diagnosis of major depressive disorder. A mixed-effects logistic regression model was employed to compare the incidence of insomnia as an AE between the IN esketamine and placebo group.ResultsInsomnia as an AE was reported by 52 patients (7.3%) in the IN esketamine group relative to 40 (6.7%) in the placebo group. IN esketamine compared to placebo was not associated with the odds of insomnia as an AE (OR = 1.07; 95% CI = 0.68−1.69; p = 0.76). There was no evidence for heterogeneity between the included trials.ConclusionIN esketamine does not affect the occurrence of insomnia as an AE in the treatment of TRD. This contrasts previous findings demonstrating beneficial effects of esketamine on insomnia severity relative to placebo, although AE reporting may not capture insomnia improvements in a population with frequent baseline insomnia.

Spectral signatures of psilocybin, lysergic acid diethylamide (LSD) and ketamine in healthy volunteers and persons with major depressive disorder and treatment-resistant depression: A systematic review

EMBO Reports (2018) e47118 “It felt like being in a pod […], like a little boat, going along through rooms [that had] white breathing walls.” This is how American standup comedian Neal Brennan described his experience with ketamine, a psychoactive drug also known as Special K in the club scene, in an interview with fellow comedian Joe Rogan. “I just couldn't get over the fact that this was happening in a doctor's office,” he said about taking ketamine as a medication against depression. > One may argue that treating psychologically unstable patients with an addictive drug that has psychedelic side effects is not a good idea. Ketamine was introduced commercially in the United States in 1970 as an anesthetic. At lower doses, it causes dissociations, out‐of‐body experiences, and hallucinations, which explains its career as club drug. But during the past two decades, it has also gained attention as a fast‐acting antidepressant. Its antidepressant effect was first noted by researchers at Yale University in the 1990s, and the effect was reproduced in a larger double‐blind, placebo‐controlled trial at the US National Institute of Mental Health, published in 2006. A number of studies have since shown the effectiveness of ketamine in treating patients with depression, suicidal ideation, and post‐traumatic stress disorder [1]. Researchers have called it the biggest breakthrough in depression research in half a century. Ketamine is not yet approved by regulatory agencies, but is widely used off‐label by private so‐called ketamine clinics. New medications to treat depression are urgently needed. The last significant innovation—Prozac, the first selective serotonin reuptake inhibitor (SSRI)—is now 30 years old, and SSRIs and many me‐too drugs of similar structure and function still dominate the treatment of depression. They are, however, anything but satisfactory. It takes 6–8 weeks for their effect to kick in, and …

Major depressive disorder (MDD) is a prevalent and disabling condition affecting over 350 million individuals worldwide. Although conventional antidepressants targeting serotonin, dopamine, and noradrenaline pathways provide benefit for many, a substantial proportion of patients experience inadequate response. Treatment-resistant depression (TRD), defined by failure to respond to at least two antidepressant trials, affects approximately 30% of patients with MDD and poses significant clinical challenges. Emerging research is exploring novel therapeutics such as psychedelics, notably LSD (lysergic acid diethylamide). Unlike standard antidepressants that target singular pathways, LSD modulates both the serotonin system, particularly the 5-HT2A receptor, and the glutamatergic system, which are critical in neurocircuitry underlying mood regulation. This dual mechanism may enhance neuroplasticity, potentially accounting for the rapid and sustained antidepressant effects observed in preliminary studies. Ongoing clinical trials aim to evaluate the efficacy and safety of LSD-assisted therapy in MDD, especially TRD. Methodological challenges include designing appropriate placebo controls and ensuring rigorous psychological support to manage the acute psychedelic experience. While still investigational, LSD-assisted therapy represents a promising avenue that may complement existing treatments. Further research is necessary to confirm its clinical utility and establish protocols for safe integration into psychiatric practice.

BackgroundDepressive disorders affect about 280 million people worldwide, with many struggling to find effective relief. Conventional antidepressants are widely prescribed but often lack efficacy and have side effects, leaving many patients dissatisfied or untreated. Concurrently, psychedelic therapies have gained momentum in both research and ‘in the wild’, with emerging evidence supporting their potential in alleviating depressive symptoms. Among these, lysergic acid diethylamide (LSD) microdosing – the practice of consuming sub-hallucinogenic doses over a period of weeks or months – presents a promising option for conditions like major depressive disorder (MDD). However, there is little qualitative investigation into the effect of LSD microdosing on depression in clinical trials. Also, few studies have explored LSD microdosing for depression with researcher-supplied, controlled doses taken in natural settings. Most research is either lab-based or relies on unregulated, self-administered doses.Aims & ObjectivesThe aim of the present study was to gain a comprehensive understanding of the experiences of individuals who took part in an open label trial of LSD microdosing to treat their MDD.MethodThis research presents analysis of semi-structured interviews from an open label trial of LSD microdosing for individuals with MDD. After completing an 8-week regimen of LSD microdosing, taking 15 doses in their home and one in the clinic, 17 participants undertook semi-structured interviews. These interviews involved discussion of their experiences and any changes in symptoms. The data were analyzed using thematic analysis.ResultsThemes were grouped into five categories: Increased Connectedness (to self, others and world/nature), Behavioral Activation (motivated for activities, cognitive, social), Improved Mental Health (better mood, cumulative positive change), Better Coping (internal, external) and Negative Effects (no change, side effects).Discussion & ConclusionsThe present study underscores the importance of qualitative research in psychedelic and clinical studies. Microdosing of LSD for participants with MDD seemed to provide cumulative mental health change by increasing broad range connectedness, improving mood and increasing behavioral activation over 8 weeks. This seems to be a bidirectional positive feedback loop which each aspect effecting and improving the others leading to overall positive change. The improvement in these areas also seemed to enhance participants ability to cope with negative situations if they occurred. For some participants however the LSD caused side effects or failed to change their depressive symptoms. These findings indicate that implementing a titration protocol could help reduce side effects and enhance efficacy. With observed increases in behavioral activation contributed to mood improvements and greater connectedness, these results also suggest that encouraging individuals to incorporate psychologically beneficial activities while microdosing can maximize therapeutic benefits. Overall, this study advances our understanding of treatments for depression.

While psychedelics may have therapeutic potential for treating mental health disorders such as depression, further research is needed to better understand their biological effects and mechanisms of action when considering the development of future novel therapy approaches. Psychedelic research could potentially benefit from the integration of metabonomics by proton nuclear magnetic resonance (1H NMR) spectroscopy which is an analytical chemistry-based approach that can measure the breakdown of drugs into their metabolites and their metabolic consequences from various biofluids. We have performed a systematic review with the primary aim of exploring published literature where 1H NMR analysed psychedelic substances including psilocin, lysergic acid diethylamide (LSD), LSD derivatives, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and bufotenin. The second aim was to assess the benefits and limitations of 1H NMR spectroscopy-based metabolomics as a tool in psychedelic research and the final aim was to explore potential future directions. We found that the most current use of 1H NMR in psychedelic research has been for the structural elucidation and analytical characterisation of psychedelic molecules and that no papers used 1H NMR in the metabolic profiling of biofluids, thus exposing a current research gap and the underuse of 1H NMR. The efficacy of 1H NMR spectroscopy was also compared to mass spectrometry, where both metabonomics techniques have previously shown to be appropriate for biofluid analysis in other applications. Additionally, potential future directions for psychedelic research were identified as real-time NMR, in vivo1H nuclear magnetic resonance spectroscopy (MRS) and 1H NMR studies of the gut microbiome. Further psychedelic studies need to be conducted that incorporate the use of 1H NMR spectroscopy in the analysis of metabolites both in the peripheral biofluids and in vivo to determine whether it will be an effective future approach for clinical and naturalistic research.

S-Adenosyl-L-Methionine (also called SAMe) was first discovered in Italy in 1952 and soon became popular in Europe and the USA. SAMe is an important physiologic compound, widely distributed throughout the body tissues and fluids. It plays a central role as precursor molecule in several biochemical reactions involving enzymatic transmethylation. Numerous studies have shown that SAMe may affect the regulation of various critical components of monoaminergic neurotransmission involved in the pathophysiology of major depressive disorder (MDD). Some evidence has confirmed its antidepressant effect. These findings have suggested that SAMe may have therapeutic potential in treating MDD. Moreover, SAMe has a very favourable side-effect profile, comparable with that of placebos. Therefore, it may offer considerable advantages as an alternative to antidepressant drugs or as an adjunctive therapy in the treatment of MDD and/or treatment-resistant depression (TRD). A summary of the literature evidence available so far on efficacy of SAMe as monotherapy or as an adjunctive drug in the treatment of MDD and TRD was here provided.

Background Psychedelic and dissociative drugs, including psilocybin, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), and ketamine, have garnered significant interest for their therapeutic potential in treating various mental health disorders. However, their psychoactive properties pose substantial risks when used in contexts requiring unimpaired cognitive and motor functions, such as driving. Psychedelics are known for their ability to induce profound alterations in sensory perception, thought patterns, and emotions. Dissociative drugs can produce a sense of detachment from the body and surroundings, leading to an altered reality and a range of experiences, from mild dissociation to complete anesthesia. This study aimed to determine the prevalence, type, and concentration of psychedelic and dissociative drugs, including phencyclidine (PCP), which is not currently being investigated for medical purposes, in suspected driving under the influence of drugs (DUID) cases. Methods Blood specimens from suspected DUID cases submitted to NMS Labs between January 2024 and December 2024 were evaluated for the presence of psychedelic and dissociative drugs. Toxicological analyses were performed as a screen with subsequent confirmation. The screening and confirmation reporting limits for the psychedelic and dissociative drugs are in parentheses. Specimens were screened by High Performance Liquid Chromatography/Time of Flight/Mass Spectrometry (LC/TOF/MS) for ketamine (10 ng/mL), LSD (2 ng/mL), psilocin (active hallucinogenic component of psilocybin, 10 ng/mL), and/or Enzyme-Linked Immunosorbent Assay (ELISA) for MDMA (20 ng/mL) and PCP (10 ng/mL). Confirmation testing was performed using High-Performance Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS) for ketamine (20 mg/mL), LSD (0.2 ng/mL), psilocin (10 ng/mL), MDMA (5 ng/mL), and PCP (5 ng/mL). Results During 2024, NMS Labs detected psychedelic and dissociative drugs in 328 suspected DUID cases: ketamine (n = 22), LSD (n = 2), PCP (n = 220), psilocin (n = 5), and MDMA (n = 81). Because LC/TOF/MS screening was performed only at the client’s request, ketamine, LSD, and psilocin positivity may be underestimated. The psychedelic and dissociative drug concentrations ranged from 25 to 880 ng/mL for ketamine (mean: 272 ng/mL, median: 61 ng/mL), 3 to 9.8 ng/mL for LSD (mean/median: 6.4 ng/mL), 6 to 270 ng/mL for PCP (mean: 50 ng/mL, median: 44 ng/mL), and 5.5 to 850 ng/mL for MDMA (mean: 124 ng/mL, median: 44 ng/mL). Psilocin concentrations were not determined due to analyte instability. Two drivers had more than one psychedelic or dissociative drug present in their blood samples. Additionally, most cases were positive for other substances that could further impact psychomotor function, including other CNS depressants. Conclusion While the future of psychedelic drugs for mental health treatments looks promising, it also raises important considerations for driving. The altered states induced by psychedelics and dissociatives can impair cognitive functions, motor skills, and judgment, thereby affecting a person’s ability to operate a vehicle safely. The data from this study can help inform future health and public safety considerations as psychedelic therapies become available to the public.

Background:Depressive disorders affect approximately 280 million globally, with many finding treatments ineffective or limited by side effects. Growing evidence suggests that psychedelic therapies may help alleviate depressive symptoms. Among these, lysergic acid diethylamide (LSD) microdosing shows promise for major depressive disorder (MDD). However, research on LSD microdosing in clinical populations remains limited.Objectives:This study aimed to understand the experiences of individuals participating in an open-label trial of LSD microdosing for MDD.Design:Open-label pilot trial in target population (MDD; phase IIa).Methods:Seventeen participants with MDD completed an 8-week LSD microdosing regimen, dosing twice weekly. Following the intervention, participants underwent semi-structured interviews regarding their experiences. Data were analysed using thematic analysis.Results:Themes were grouped into five categories: enhanced self-determination, increased connectedness, improved cognitive processing, better emotional well-being, and negative effects.Conclusion:Reported effects appeared to reinforce one another; that is, self-determination led to feeling more connected, which enhanced cognitive processing and ultimately improved emotional well-being and reduced depressive symptoms. However, this effect was not universal; some individuals reported negative effects or no significant improvement from microdosing LSD. This variability may be due to individual differences in response, insufficient dosage, or the treatment’s lack of effectiveness for some individuals. The presence of side effects highlights the need for a careful titration protocol, while the lack of symptom improvement in some cases reinforces that microdosing is not a guaranteed solution, and expectations should remain realistic. The absence of a placebo control represents a key limitation as it precludes attribution of observed changes specifically to LSD.Trial registration:ANZCTR, ACTRN12623000486628. Registered on 12 May 2023 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385758).

Background Alcohol Use Disorder (AUD) is a widespread condition with serious health, social, and economic impacts, often marked by relapse despite the availability of FDA-approved treatments. Recent studies suggest that psychedelic substances, such as psilocybin, Lysergic acid diethylamide (LSD), ayahuasca, etc. may offer novel therapeutic potential in treating AUD by modulating neurotransmission and promoting neuroplasticity. Ketamine is a dissociative psychedelic, and it works primarily by blocking NMDA receptors (a type of glutamate receptor in the brain) compared to Classic psychedelics (like LSD, psilocybin, mescaline) work mainly by activating serotonin 5-HT2A receptors hence ketamine was not the focus of this review. This narrative review aims to synthesize existing evidence on the effectiveness of psychedelic-assisted therapy for AUD. Methods A systematic literature search was conducted across PubMed and Google Scholar, yielding 186 articles. Following inclusion and exclusion criteria, 71 studies were selected for review, including randomized controlled trials, observational studies, and meta-analyses. These studies assessed the use of psychedelics (e.g. LSD, psilocybin) in individuals with AUD, focusing on therapeutic outcomes, neurobiological mechanisms, and safety profiles. Results Findings from clinical trials and observational studies suggest that psychedelic therapies, particularly those involving psilocybin and LSD, are associated with significant reductions in alcohol consumption, enhanced emotional regulation, and sustained improvements in mental health over follow-up periods ranging from 6 to 32 weeks. These effects are thought to be mediated by serotonin 2A receptor agonism, which promotes neuroplasticity in regions such as the prefrontal cortex, enhancing cognitive and emotional processes. A meta-analysis of six trials revealed that a single dose of LSD outperformed traditional pharmacotherapies like naltrexone and acamprosate in promoting long-term abstinence from alcohol. Conclusion This review emphasizes the potential of psychedelic-assisted therapy as a promising alternative or adjunctive treatment for AUD. Psychedelic substances, particularly when combined with behavioral therapies such as Motivational Enhancement Therapy (MET), show significant promise in reducing alcohol misuse and fostering long-term recovery. Despite the promising results, further research is needed to assess the safety, long-term efficacy, and optimal treatment protocols, particularly regarding patients with underlying psychiatric conditions. Future studies should focus on large-scale, controlled trials with neuroimaging and long-term follow-up to fully elucidate the neurobiological mechanisms underlying these therapeutic effects and to establish best practices for clinical use.

The need for publicly funded research on therapeutic use of psychedelic drugs.