According to Gram Research analysis, people experiencing their first psychotic episode have significantly impaired brain chemistry involved in a process called methylation, with SAM levels about 40% lower than healthy people (p < 0.001). This brain chemical imbalance exists before patients start psychiatric medications, suggesting it may be a fundamental feature of psychosis rather than a side effect of treatment. The findings indicate that reduced folate support compounds this methylation problem from the very onset of the illness.
Researchers discovered that people experiencing their first psychotic episode have an imbalance in brain chemicals responsible for making copies of genetic material and supporting brain function. By studying fluid from around the brain and spinal cord, scientists found that patients had lower levels of a key molecule called SAM and reduced support from folate (a B vitamin). Importantly, this imbalance was present before patients started taking antipsychotic medications, suggesting it may be part of what causes psychosis rather than a side effect of treatment. This finding could help doctors understand what goes wrong in the brain during psychosis and potentially lead to new treatments.
Key Statistics
A 2026 cross-sectional study of 34 participants found that drug-naïve patients with first-episode psychosis had markedly lower cerebrospinal fluid SAM levels compared to healthy controls (p < 0.001), indicating severely impaired central methylation capacity at the onset of psychosis.
According to research reviewed by Gram, the SAM/SAH ratio—a measure of methylation efficiency in the brain—was substantially reduced in first-episode psychosis patients (p < 0.001), suggesting the brain’s ability to perform critical chemical processes is compromised from the start of illness.
A 2026 study of 17 drug-naïve psychosis patients found cerebrospinal fluid 5-MTHF (folate) levels were significantly lower than in healthy controls (p = 0.014), indicating reduced folate-dependent support for brain methylation processes.
Research shows that impaired central methylation capacity in first-episode psychosis is present before antipsychotic medication exposure, suggesting metabolic dysfunction may be a root cause rather than a consequence of treatment or chronic illness.
The Quick Take
- What they studied: Whether people with first-episode psychosis have different levels of brain chemicals involved in making and copying genetic material compared to healthy people
- Who participated: 17 men experiencing their first psychotic episode who had never taken antipsychotic medications, compared with 17 healthy men of similar age
- Key finding: Patients had significantly lower levels of a critical brain chemical called SAM (about 40% lower, p < 0.001) and reduced folate support, indicating their brains struggle with a process called methylation that’s essential for normal brain function
- What it means for you: This research suggests psychosis may involve a fundamental brain chemistry problem from the very beginning, not just from medication or long-term illness. This could eventually lead to new treatments targeting these specific chemical imbalances, though more research is needed before clinical applications.
The Research Details
This was a cross-sectional study, which means researchers took a snapshot in time rather than following people over months or years. They collected cerebrospinal fluid (CSF)—the clear liquid that surrounds the brain and spinal cord—from two groups: 17 men experiencing their first psychotic episode who had never taken psychiatric medications, and 17 healthy control men. They measured specific brain chemicals involved in methylation, which is a process where the brain adds chemical tags to DNA to control how genes work. By studying the fluid directly around the brain, researchers could see what’s happening in the central nervous system without the confusing effects of medications or years of illness.
The researchers measured four key chemicals: SAM (the main molecule that does the methylation work), SAH (a byproduct of methylation), the ratio between SAM and SAH (which shows how efficiently methylation is working), and 5-MTHF (a form of folate that helps support methylation). They also measured a broad panel of amino acids—the building blocks of proteins—to understand the overall chemical environment in the brain.
Most previous research on psychosis and brain chemistry relied on blood samples, which can be affected by medications, diet, and other factors outside the brain. By measuring cerebrospinal fluid directly, this study looked at what’s actually happening in the brain itself. Additionally, studying people at their very first psychotic episode before they start medications eliminates the question of whether the chemical imbalances are caused by treatment rather than the illness itself. This timing is crucial for understanding whether these metabolic problems are a root cause of psychosis or a consequence of it.
This study has both strengths and limitations. Strengths include the use of cerebrospinal fluid (a direct measure of brain chemistry), studying drug-naïve patients (eliminating medication effects), and examining people at first episode (capturing the illness at its earliest point). The study was published in a peer-reviewed journal. However, the sample size is relatively small (34 total participants), all participants were male, and the study is cross-sectional rather than following people over time. The small sample means results should be considered preliminary and need confirmation in larger studies.
What the Results Show
The most striking finding was that patients with first-episode psychosis had markedly lower levels of SAM in their cerebrospinal fluid compared to healthy controls (p < 0.001, meaning this difference is extremely unlikely to be due to chance). The SAM/SAH ratio—which indicates how efficiently the brain’s methylation machinery is working—was also substantially reduced in patients (p < 0.001). This means the brain’s ability to perform methylation, a critical process for normal brain function, appears to be impaired from the very start of psychosis.
The study also found that patients had lower levels of 5-MTHF (p = 0.014), a form of folate that helps support methylation. Folate is a B vitamin essential for brain health, and this finding suggests that the brain’s ability to regenerate the molecules needed for methylation is compromised. Interestingly, the absolute levels of SAH (the byproduct) and overall amino acid concentrations were similar between groups, suggesting the problem isn’t a general shortage of building blocks but rather a specific impairment in how the brain uses these building blocks for methylation.
Secondary analyses suggested that the relationships between methylation-related chemicals and certain amino acids were altered in patients with first-episode psychosis compared to controls. This indicates that the methylation problem may involve disrupted coordination between different metabolic systems in the brain. While these secondary findings are less definitive than the primary results, they suggest the metabolic disruption in psychosis is complex and involves multiple interconnected systems rather than a single broken pathway.
Previous research has suggested that one-carbon metabolism (the system that includes methylation) may be involved in psychotic disorders, but most evidence came from blood samples rather than brain fluid. This study provides the first direct evidence from cerebrospinal fluid that methylation capacity is impaired in psychosis. The findings are consistent with earlier research suggesting folate and B vitamins may play a role in psychosis, but this study shows the problem exists in the brain itself at the very onset of illness, before any medication exposure. This strengthens the hypothesis that metabolic dysfunction may be a fundamental feature of psychosis rather than a consequence of treatment.
The study has several important limitations. First, the sample size is small (only 34 participants total), which means results need to be confirmed in larger studies before drawing firm conclusions. Second, all participants were male, so it’s unclear whether findings apply equally to women. Third, the study is cross-sectional, meaning it captures one moment in time and cannot show whether these chemical imbalances cause psychosis or result from it. Fourth, the study doesn’t include information about symptom severity or other clinical details that might help explain the findings. Finally, the study cannot determine whether correcting these chemical imbalances would improve psychotic symptoms, which would be the ultimate test of whether this is clinically important.
The Bottom Line
Based on this research, there are no immediate clinical recommendations for patients or doctors yet. The findings are preliminary and suggest that future treatments targeting methylation capacity or folate metabolism might help people with psychosis, but such treatments don’t yet exist and would need extensive testing. People experiencing psychotic symptoms should continue to work with their doctors on established treatments. However, this research suggests that ensuring adequate folate and B vitamin intake may be worth discussing with healthcare providers, as these nutrients support the methylation processes found to be impaired in this study. Confidence level: Low to moderate—this is early-stage research that needs confirmation.
This research is most relevant to people with psychosis and their families, psychiatrists and mental health professionals, researchers studying the biological basis of psychosis, and pharmaceutical companies developing new psychiatric medications. People with a family history of psychosis may find this research interesting as it helps explain the biological basis of the condition. The findings don’t yet apply to prevention or treatment decisions for the general public.
This is basic research aimed at understanding what goes wrong in psychosis, not a clinical trial testing a new treatment. It will likely take 5-10 years of additional research before any new treatments based on these findings could be available to patients. In the near term (1-2 years), we should expect follow-up studies confirming these findings in larger and more diverse populations.
Frequently Asked Questions
What is methylation and why does it matter for the brain?
Methylation is a process where the brain adds chemical tags to DNA to control how genes work. It’s essential for normal brain function, including mood regulation and thinking. When methylation doesn’t work properly, brain function suffers, which may contribute to psychosis.
Can low folate cause psychosis?
This study shows that people with psychosis have low folate support in their brains, but it doesn’t prove low folate causes psychosis. The relationship is likely complex and involves multiple factors. More research is needed to determine if correcting folate levels helps treat psychosis.
Should people with psychosis take folate supplements?
This research doesn’t yet support folate supplementation as a psychosis treatment. People with psychosis should discuss any dietary changes or supplements with their psychiatrist before starting them, as some supplements can interact with psychiatric medications.
Does this research mean antipsychotic medications don’t work?
No. This study shows that brain chemistry problems exist before medications are started, which doesn’t mean medications don’t help. Antipsychotics work through different mechanisms and remain the primary evidence-based treatment for psychosis.
Could this research lead to new psychosis treatments?
Possibly. Understanding that methylation is impaired in psychosis could eventually lead to new treatments targeting this specific problem. However, this is early-stage research, and it will take years of additional studies before any new treatments become available.
Want to Apply This Research?
- Users could track daily folate and B-vitamin intake (through food or supplements) and correlate with mood, sleep quality, and symptom severity using a simple daily log. This would help identify whether nutritional status relates to symptom patterns, though it won’t prove causation.
- Encourage users to maintain consistent intake of folate-rich foods (leafy greens, legumes, fortified grains) and B vitamins, and log this alongside mood and symptom tracking. Users could set reminders for meals containing these nutrients and track whether they notice any patterns with their symptoms.
- Over 8-12 weeks, users could track weekly averages of folate/B-vitamin intake and correlate with weekly symptom severity scores. This longitudinal tracking within the app could reveal individual patterns, though users should discuss any changes with their healthcare provider before making dietary modifications.
This research is preliminary and has not yet led to clinical treatments. People experiencing psychotic symptoms should work with qualified mental health professionals and continue established treatments. Do not change medications or start supplements based on this research without consulting your psychiatrist. This article is for educational purposes and should not be considered medical advice. The findings apply specifically to the small study population and require confirmation in larger, more diverse studies before broader conclusions can be drawn.
This research translation is published by Gram Research, the science division of Gram, an AI-powered nutrition tracking app.