Key Insights

• Schizophrenia remains a challenging condition with limited effective treatments, particularly for its negative and cognitive symptoms. Psychedelic research offers a promising avenue to fill this treatment void by exploring novel mechanisms of neuroplasticity and connectivity.
• Early studies using psychedelics like LSD and mescaline provided initial ‘models of psychosis’, paving the way for a deeper understanding of schizophrenia’s neurobiology. Today, modern research investigates controlled, low-dose protocols and microdosing strategies to harness the therapeutic potential of these substances.
• Biotech companies are actively developing non-hallucinogenic psychedelic analogues and other compounds inspired by classic psychedelics, aiming to improve patient outcomes and reduce side effects. Continued interdisciplinary research and advanced neuroimaging techniques are expected to drive the next wave of breakthroughs in personalised treatments for schizophrenia.

Authors: Beatrisse Fender & Chiara Corpetti. This page was made possible by Chiara Corpetti, PhD, in Pharmacology and Toxicology, and Beatrisse Fender, a student at Bristol University of Psychology and Neuroscience.

Schizophrenia

Schizophrenia is a chronic mental health disorder that severely disrupts a person’s thoughts, perceptions, emotions, and social interactions. It is defined by episodes of psychosis—periods during which individuals lose touch with reality and experience hallucinations, delusions, and disorganised speech. Although the term is often misunderstood, schizophrenia does not mean having a “split personality” but rather a splitting between thought and reality.

According to the World Health Organization, schizophrenia affects about 24 million people worldwide—roughly one in every 300 individuals [1]. In the UK, it is estimated that around one in 100 people will experience an episode in their lifetime.

Symptoms and Diagnosis

While the exact cause remains unknown, schizophrenia is understood to arise from a combination of genetic, neurobiological, and environmental factors. Neuroimaging studies reveal structural and functional abnormalities in the brain, particularly in the prefrontal cortex and dopamine pathways [2]. Environmental triggers, including stress, trauma, and substance use, may also contribute to its onset [3].

The symptoms of schizophrenia are generally grouped into three main categories [4]:

• Positive Symptoms: These are behaviours or experiences that are added to a person’s normal functioning. Hallucinations (usually auditory), delusions, and disorganised or incoherent speech fall under this group.
• Negative Symptoms: These involve a reduction or absence of normal functions. They include diminished emotional expression, lack of motivation, and social withdrawal.
• Cognitive Symptoms: Many individuals experience impairments in memory, concentration, and decision-making, which can further complicate daily living.

According to the DSM-5 (a manual for assessing and diagnosing mental disorders), schizophrenia is typically diagnosed when symptoms such as persistent delusions, hallucinations, disorganised speech, and cognitive impairments are present for at least six months and significantly interfere with daily life [5].

Neurobiology and Brain Abnormalities

Advanced imaging techniques have uncovered several key brain abnormalities in individuals with schizophrenia [2]:

• Structural Changes: Many studies reveal reduced grey matter volume in the prefrontal cortex and temporal lobes. These structural deficits are associated with impaired cognition and poor executive function.
• Neurotransmitter Dysregulation: The classic dopamine hypothesis remains central—overactivity in dopamine pathways is linked to positive symptoms such as hallucinations. However, modern research also implicates glutamate and serotonin systems, indicating a more complex neurochemical imbalance.
• Functional Connectivity: Disruptions in the way different brain regions communicate (for example, within the default mode (DMN) and salience networks) further contribute to the cognitive and perceptual disturbances observed in schizophrenia.

The serotonin system, particularly 5-HT2A receptors, plays a crucial role in schizophrenia’s pathophysiology. These receptors modulate cortico-subcortical circuits, affecting perception, mood, and cognition. Research has revealed important interactions between 5-HT2A receptors and glutamate receptors, specifically mGlu2. Dysfunction in the 5-HT2A–mGlu2 receptor complex may contribute to hallucinations and delusions. Moreover, schizophrenia is characterised by disrupted connectivity and reduced synaptic integration, partly due to synaptic pruning—a process involving the loss of synapses and dendritic spines that further impairs neuronal network efficiency.

Impact on Daily Life

Schizophrenia often has a profound effect on everyday functioning. Individuals may struggle with:

• Social Isolation and Occupational Challenges: Difficulties in maintaining relationships and holding a job are common. Many experience long-term social and economic hardships.
• Physical Health and Mortality: The disorder is associated with a higher incidence of physical health issues and reduced life expectancy.
• Stigma and Misunderstanding: Despite its prevalence, schizophrenia remains highly stigmatised, which can hinder access to effective treatment and social support.

Although antipsychotic medications combined with psychotherapy and social rehabilitation can improve outcomes, many patients continue to experience persistent symptoms that impact their quality of life.

Current Treatments and Challenges

Current treatment for schizophrenia typically involves a combination of antipsychotic medications, psychological therapies, and social rehabilitation [6]. Antipsychotic drugs—both first-generation and second-generation—remain the cornerstone for managing acute psychotic symptoms such as hallucinations and delusions. However, most medications primarily target dopamine pathways and often do little to improve negative and cognitive symptoms. This means that while patients may experience a reduction in overt psychotic episodes, issues like lack of motivation, social withdrawal, and impaired memory often persist. Moreover, the side effects associated with these medications, including weight gain, metabolic disturbances, and movement disorders like tardive dyskinesia, can reduce adherence and overall quality of life.

In addition to medication, psychological interventions such as cognitive behavioural therapy (CBT) and family support programmes play a key role. These therapies help patients develop coping strategies, manage stress, and rebuild social skills, which are critical for long-term recovery. Despite these approaches, challenges remain: many patients continue to experience residual symptoms, and some develop treatment-resistant schizophrenia. Access to specialised mental health services is often limited, leading to delays in diagnosis and intervention. This issue is starkly illustrated by the fact that whilst 50% of individuals hospitalised in psychiatric institutions receive a schizophrenia diagnosis, many lack access to adequate specialised care [8]. The economic burden is substantial, with high treatment costs, loss of productivity, and heavy reliance on informal caregiving creating additional barriers to treatment [9]. These systemic challenges, combined with persistent stigma and discrimination, significantly exacerbate social isolation and hinder recovery.

Recent developments in novel treatments—such as drugs targeting alternative neurotransmitter systems (e.g. the muscarinic system) and emerging approaches from neuroscience research—offer hope for more comprehensive symptom management. However, the high cost of new medications and systemic issues in mental healthcare delivery remain significant barriers. As a result, the search for therapies that effectively address the full spectrum of schizophrenia symptoms continues to be a major focus of research and clinical practice.

Psychedelics in Schizophrenia Research

Psychedelics have played a complex role in schizophrenia research, fundamentally linked by shared neurobiological mechanisms. Classic serotonergic psychedelics interact with the same 5-HT2A receptors implicated in schizophrenia, affecting both presynaptic and postsynaptic neurons in the cortex. Historically, early studies explored how classic hallucinogens could mimic aspects of psychosis—providing researchers with a model for understanding the disturbed perceptions and thought processes seen in schizophrenia. More recently, controlled clinical research has re-examined these substances not as treatments for schizophrenia per se but as tools to uncover the underlying neurobiology of psychotic states, with the hope of inspiring novel, safer therapeutic approaches.

Early Psychedelic Research as a Model for Psychosis

Early in the 1950s and 1960s, researchers explored the use of classic psychedelics such as LSD and mescaline both as a model for psychosis and as potential therapeutic agents in schizophrenia. Pioneering figures like Humphry Osmond and Albert Kurland administered these substances to patients with schizophrenia, observing that the transient, drug-induced state produced hallucinations, delusions, and disorganised thinking that bore a superficial resemblance to the symptoms of schizophrenia.

Early clinical investigations yielded mixed and often contradictory results. A significant 1952 study examining the effects of mescaline (0.4-0.6g) and LSD (10-120μg) in schizophrenia patients found that these substances typically aggravated existing symptoms and further disrupted psychic integration compared to healthy individuals. However, when LSD was studied in different contexts, such as a 1970 investigation of alcoholism treatment involving 75 patients, researchers observed that individuals without schizophrenia responded more favourably to the treatment than those with schizophrenia comorbidity.

The theoretical understanding of these substances evolved significantly over time. By 1976, researchers were investigating N,N-dimethyltryptamine (DMT) as a potential ‘schizotoxin’, hypothesising that it might play a role in the development of schizophrenia symptoms. Whilst DMT produced psychedelic effects in healthy subjects, researchers ultimately concluded that the psychological changes it induced did not closely mirror schizophrenia symptoms.

A breakthrough came in 1998 when researchers identified psilocybin’s primary mechanism of action through the serotonin (5-HT2A) receptor system, rather than solely through dopaminergic pathways. This study demonstrated that psilocybin’s psychotomimetic effects could be blocked by serotonin-2A antagonists, suggesting a potential role for serotonin-2A overactivity in schizophrenia’s pathophysiology.

Despite some studies suggesting improvements in symptoms like social interactions, empathy, and cognitive abilities, these early experiments were significantly limited by methodological challenges, including small sample sizes, lack of control groups, and non-standardised protocols. Nevertheless, they were instrumental in establishing the concept that altered states of consciousness induced by psychedelics could serve as a model for understanding the neurochemical and perceptual disturbances seen in psychotic disorders, laying the groundwork for subsequent research into the neurobiology of psychosis.

Current Research on LSD

Modern research on LSD has shifted away from its use as a direct treatment for schizophrenia due to the risk of exacerbating psychotic symptoms. Instead, studies focus on understanding how LSD affects brain connectivity and receptor activity, particularly its action on serotonin (5-HT) 2A receptors. Post-mortem research has revealed that untreated schizophrenia patients show a two-fold higher density of these receptors in their active configuration, as measured by LSD radioligand binding, compared to those receiving antipsychotic medication.

Recent neuroimaging studies have provided crucial insights into the distinct neural mechanisms of psychedelic states versus schizophrenia. While both LSD administration (75μg) in healthy volunteers and schizophrenia patients show increased neural signal diversity, the conditions differ in their processing of sensory information. Schizophrenia uniquely increases the precision weighting of sensory information, suggesting that despite superficial similarities in symptoms, the underlying neural mechanisms are fundamentally different.

These findings demonstrate LSD’s value as a research tool for probing altered states of consciousness and identifying neural pathways implicated in schizophrenia. Advanced neuroimaging techniques continue to reveal important distinctions between psychedelic states and psychosis, potentially informing the development of more targeted therapeutic approaches.

Current Research on Psilocybin

Psilocybin, a naturally occurring psychedelic found in certain mushrooms, has been studied both historically and in contemporary research for its psychotomimetic properties. Early observations noted that psilocybin induced hallucinations and altered thought patterns similar to those observed in schizophrenia.

Research has revealed significant parallels between psilocybin-induced states and schizophrenia symptoms, particularly in sensory processing. A study showed that psilocybin impairs prepulse inhibition (a startle reflex) in a dose-dependent manner, mimicking the inability to filter out unnecessary sensory information observed in schizophrenia patients. Furthermore, investigations into cognitive function have suggested that both 5-HT2A and NMDA receptors may play crucial roles in the cognitive deficits characteristic of schizophrenia.

While these findings highlight psilocybin’s utility as a model for studying psychosis, contemporary research also explores its potential therapeutic applications. Scientists are particularly interested in psilocybin’s ability to promote neural connectivity and plasticity, investigating whether carefully controlled administrations might help address cognitive and negative symptoms of schizophrenia. However, such therapeutic applications remain experimental and require robust clinical trials to establish safety and efficacy.

Current Research on MDMA

Although MDMA is traditionally classified as an entactogen rather than a classical psychedelic, it has attracted attention for its potential to improve social functioning and alleviate negative symptoms in various psychiatric disorders. Recent research is exploring MDMA’s capacity to enhance emotional processing and reduce social withdrawal in patients with schizophrenia.

Clinical trials are underway to assess whether MDMA, when administered in a controlled, therapeutic environment alongside psychotherapy, can offer benefits for the negative symptom spectrum of schizophrenia. A study assessing its tolerability in individuals with schizophrenia found that low doses were generally well tolerated, though further research is needed to determine its therapeutic efficacy.

“While MDMA demonstrates potential in addressing social deficits associated with schizophrenia, its clinical application remains highly experimental and requires further investigation.” – Anya Bershad 

Current Research on Ketamine

Ketamine, a dissociative anaesthetic with psychedelic properties, is widely recognised for its rapid antidepressant effects and is being studied for its potential to address cognitive deficits and negative symptoms in schizophrenia. Unlike classical psychedelics that primarily act on the serotonin system, ketamine functions as an NMDA receptor antagonist, thereby modulating glutamate transmission in the brain.

This unique mechanism is being investigated to determine whether ketamine can improve working memory and executive function in patients with schizophrenia. Research suggests that ketamine-induced deficits in context-dependent processing mirror cognitive impairments observed in schizophrenia, offering insights into the disorder’s underlying mechanisms. However, its clinical application remains controversial, as ketamine may also induce or exacerbate psychotic symptoms in vulnerable individuals.

Integrating Past and Present

Early research with psychedelics helped establish a model for psychosis, while modern studies leverage advanced neuroimaging and computational modelling to explore how these substances alter brain connectivity and promote neuroplasticity. Despite these insights, current evidence does not support the use of psychedelics as a direct treatment for schizophrenia. Studies have explored their pharmacological effects in schizophrenia-spectrum disorders, but concerns regarding their potential to trigger psychotic episodes remain significant.

By studying how these compounds affect neural circuits, scientists hope to identify new molecular targets and develop novel antipsychotic agents that can more effectively address the full spectrum of schizophrenia symptoms.

Psychedelic Industry and Future Research

The resurgence of interest in psychedelics has spurred considerable investment and innovation within the pharmaceutical industry. Although their application in treating schizophrenia remains experimental, biotech companies and research initiatives are developing novel compounds that harness the neuroplastic and therapeutic benefits of psychedelic agents while minimising the risk of exacerbating psychotic symptoms.

This dynamic field is underpinned by advances in neuroimaging, molecular biology, and computational modelling, which together offer a promising pathway towards safer, more targeted treatments for schizophrenia. The following sections highlight current industry efforts and future research directions.

Companies with Ongoing Studies

One of the most significant industry efforts comes from Delix Therapeutics, which is developing non-hallucinogenic psychedelic analogues designed to promote neuroplasticity without triggering psychotic symptoms. These compounds aim to provide the therapeutic benefits of psychedelics without the risks associated with classic hallucinogens.

MindMed, a leader in psychedelic drug development, is also exploring next-generation serotonergic compounds for neuropsychiatric conditions, including schizophrenia. MindMed’s research into LSD analogues and selective 5-HT2A receptor modulators aims to harness the neurobiological effects of psychedelics while avoiding their hallucinogenic properties.

The RL-007 clinical trial from Recognify Life Sciences (a subsidiary of Atai) is another example of psychedelic-inspired pharmacology in schizophrenia research. This compound, designed to enhance cognitive function, is being evaluated for its ability to improve working memory and social cognition in individuals with schizophrenia.

In addition, Compass Pathways, best known for its work with psilocybin therapy in depression, is investigating innovative drug development pathways to target schizophrenia-related deficits. While psilocybin itself is not being explored for schizophrenia due to its potential to exacerbate symptoms, modified serotonergic compounds inspired by its mechanism of action remain a focus.

With ongoing research and clinical trials into psychedelic-inspired compounds, the potential for new treatments addressing cognitive and negative symptoms in schizophrenia continues to grow. While classical psychedelics may not be viable for schizophrenia treatment, the industry is actively working towards safe and effective neuroplasticity-enhancing alternatives.

Emerging Clinical Trials

A number of clinical trials are underway to evaluate the safety and efficacy of psychedelic-inspired compounds in neuropsychiatric disorders, including schizophrenia. Trials such as those exploring low-dose psilocybin microdosing and the use of MDMA to ameliorate negative symptoms are beginning to shed light on their potential benefits when combined with psychotherapy. Early-phase studies are focusing on refining dosing protocols and establishing reliable biomarkers of response, while more advanced trials are being designed to test these compounds in larger patient cohorts.

Future Research Directions

Several promising strategies are being explored to harness the neuroplastic benefits of psychedelics whilst minimising psychotic risk in schizophrenia patients [7]. Researchers are investigating non-hallucinogenic derivatives, sub-psychedelic or microdosing protocols, and the potential entourage effects present in psychedelic mushroom extracts. Additional studies are examining methods to block 5-HT2A receptor-mediated hallucinogenic effects whilst preserving therapeutic benefits.

These approaches could potentially address the cortical atrophy associated with negative symptoms, which remains one of the most challenging aspects of treatment. However, extensive preclinical studies using appropriate animal models will be essential before progressing to carefully designed clinical trials. This methodical approach could open new frontiers in psychopharmacology and significantly impact the treatment of this severely debilitating psychiatric disorder.

With increased investment and a growing evidence base, it is anticipated that within the next decade, innovative treatments based on psychedelic-inspired compounds may offer significant improvements in managing the complex symptomatology of schizophrenia, particularly for those patients who do not respond adequately to current antipsychotic medications.

External references for Schizophrenia and Psychedelics

All resources available on Blossom are directly linked on this topic page. Find even more background about this topic with these external references.

1. World Health Organization. (2022). Schizophrenia fact sheet. https://www.who.int/news-room/fact-sheets/detail/schizophrenia

2. Van Os, J., & Kapur, S. (2009). Schizophrenia. The Lancet, 374(9690), 635-645. https://doi.org/10.1016/S0140-6736(09)60995-8 

3. Murray, R. M., Englund, A., Abi-Dargham, A., et al. (2017). Cannabis-associated psychosis: neural substrate and clinical impact. Neuropharmacology, 124, 89-104. https://doi.org/10.1016/j.neuropharm.2017.06.017 

4. Tandon, R., Gaebel, W., Barch, D. M., et al. (2013). Definition and description of schizophrenia in the DSM-5. Schizophrenia Research, 150(1), 3-10. https://doi.org/10.1016/j.schres.2013.05.028

5. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.

6. Leucht, S., Cipriani, A., Spineli, L., et al. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet, 382(9896), 951-962. https://doi.org/10.1016/S0140-6736(13)60733-3 

7. Wolf, G., Singh, S., Blakolmer, K., Lerer, L., Lifschytz, T., Heresco-Levy, U., … & Lerer, B. (2023). Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation. Molecular Psychiatry, 28(1), 44-58. https://www.nature.com/articles/s41380-022-01832-z

8. Chong, H. Y., Teoh, S. L., Wu, D. B. C., Kotirum, S., Chiou, C. F., & Chaiyakunapruk, N. (2016). Global economic burden of schizophrenia: a systematic review. Neuropsychiatric disease and treatment, 357-373. https://pmc.ncbi.nlm.nih.gov/articles/PMC4762470/

9. Olesen, J., Gustavsson, A., Svensson, M., Wittchen, H. U., Jönsson, B., CDBE2010 Study Group, & European Brain Council. (2012). The economic cost of brain disorders in Europe. European Journal of Neurology, 19(1), 155-162. https://onlinelibrary.wiley.com/doi/10.1111/j.1468-1331.2011.03590.x

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