Psychedelics and Schizophrenia

Emerging theories propose that psychedelic drugs may operate through a “brain resetting” mechanism, potentially treating the underlying neuronal circuitry issues, thus benefiting psychiatric disorders like schizophrenia. As a result, psychedelics are now seen as promising research tools for the development of new treatment approaches for various psychiatric disorders, including schizophrenia.

The dopamine and serotonin theories remain critical in schizophrenia research and antipsychotic medication development, but our understanding of schizophrenia continues to evolve with new hypotheses surfacing. Notably, the effects of psychedelic drugs bear significant similarities to some primary symptoms of schizophrenia. Both some atypical antipsychotic drugs (APDs) and substances like LSD act on the same targets, the serotonin 5HT2A receptors. Moreover, these psychedelic drugs, including newer second-generation ones and glutamatergic APDs, are believed to exert their pharmacological effects through a shared pathway, involving a complex interaction between serotonin and glutamate receptors in certain brain neurons. 

Recent studies have indicated a close link between serotoninergic and glutamatergic neurotransmissions in response to psychedelic compounds and antipsychotic medication. 

Understanding Psychedelics

Psychedelics are a class of drugs that cause significant alterations in perception, thought, and emotion. These effects are primarily attributed to their interaction with serotonin 5-HT2A receptor subtypes in the brain. An emerging trend is the practice of psychedelic microdosing, which involves the administration of sub-hallucinogenic doses of psychedelics on a regular basis. This practice has been reported to potentially lower depression and anxiety, improve cognitive function, and promote social interaction.

Clinical studies have found psychedelic compounds to be well-tolerated and efficacious in regulated doses, suggesting potential applications in treating a variety of neurological disorders, including schizophrenia, resistant depression, anxiety, posttraumatic stress disorder, and substance use disorders. Psychedelic compounds have also been found to aid in de-addiction to substances like tobacco and alcohol.

Recent studies suggest that psychedelic compounds, including psilocybin and LSD, may have superior efficacy compared to traditional antidepressants. These findings have led to a shift in focus from rectifying “chemical imbalances” to achieving selective modulation of neural circuits. The FDA in the United States has recognized the potential of these substances, granting psilocybin and MDMA the status of breakthrough medicine.

Psychedelic compounds can be grouped into two categories: tryptamines, which chemically resemble the neurotransmitter serotonin, and phenethylamines. Tryptamines include psilocybin, LSD, and DMT, while phenethylamines include mescaline. Newer analogues of DMT include N, N-diethyltryptamine (DET) and N, N-dipropyltryptamine (DPT).

Understanding Schizophrenia

Definition of Schizophrenia

Schizophrenia is a chronic, severe mental disorder that affects how a person thinks, feels, and behaves. It is characterized by distortions in thinking, perception, emotions, language, sense of self, and behavior. People with schizophrenia may seem like they have lost touch with reality, which can be distressing to the individual, as well as to their family and friends.

Symptoms and Types of Schizophrenia

• Schizophrenia symptoms are typically separated into three categories: positive, negative, and cognitive.
• Positive symptoms are psychotic behaviors not seen in healthy individuals. These include hallucinations, delusions, thought disorders, and movement disorders.
• Negative symptoms are associated with disruptions to normal emotions and behaviors, which may present as the “loss” of normal functions. These can include reduced expression of emotions, reduced feelings of pleasure in everyday life, difficulty beginning and sustaining activities, and reduced speaking.
• Cognitive symptoms involve problems with thought processes. These might be subtle, but can also be severe. They can include poor executive functioning (the ability to understand information and use it to make decisions), trouble focusing or paying attention, and problems with working memory (the ability to use information immediately after learning it).
• There are several subtypes of schizophrenia that were previously recognized, including paranoid schizophrenia, disorganized schizophrenia, and catatonic schizophrenia, among others. However, the latest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) no longer separates schizophrenia into these subtypes.

Traditional Treatments for Schizophrenia

• Treatment for schizophrenia focuses on eliminating the symptoms of the disease, as there is currently no cure. Treatments include:
• Antipsychotics: These are usually taken daily in pill or liquid form, and some antipsychotics are injections given once or twice a month.
• Psychosocial Treatments: This can help with the everyday challenges of schizophrenia such as dealing with illness, self-care, work, and forming and keeping relationships. Learning and using coping mechanisms to address these issues allows individuals with schizophrenia to attend school, work, and socialize.
• Coordinated Specialty Care (CSC): This is a team approach to treating schizophrenia when the first episode occurs, and combines medication, psychosocial therapies, case management, family involvement, and supported education and employment services.
• Hospitalization: This can be necessary to treat severe episodes of schizophrenia, ensuring safety, proper nutrition, adequate sleep, and basic hygiene.
• Electroconvulsive Therapy (ECT): While not a first-line treatment, ECT may be considered in cases where medication and psychosocial treatment are ineffective.
• Self-management strategies and education: This includes learning about schizophrenia, managing its symptoms, making informed decisions about treatments, setting life goals, and using relaxation and stress-reducing strategies.

The Link Between Psychedelics and Schizophrenia

Historical studies exploring the relationship between psychedelic drugs and schizophrenia began in 1947, with the first trial conducted by Stoll at the University of Zurich. This initial research used escalating doses of LSD on six treatment-resistant schizophrenia patients, revealing that they required significantly higher doses (up to 130μg) to achieve an effect, compared to healthy volunteers who responded to a 30μg dose. Moreover, the onset of the effects was slower, and the visual and euphoric effects were less pronounced in patients with schizophrenia.

Subsequent studies by Condrau and Katzenellenbogen and Fang echoed these findings, with the latter demonstrating that emotional ventilation seemed more marked with LSD. These studies, despite their limitations and lack of clear therapeutic effects on core schizophrenia symptoms, served as a foundation for further research in the 1950s and 60s, exploring the use of psychedelic drugs in conjunction with psychotherapy for various psychiatric conditions, including schizophrenia.

Research from this era often reported similar findings, highlighting a diminished response to psychedelic drugs in schizophrenia patients and a need for higher doses to achieve an effect. Some studies also observed either a reversal of accustomed behavior or intensification of symptomatology and behavior patterns. It was suggested that LSD and mescaline accentuated symptoms in acute schizophrenia patients, while deteriorated schizophrenics showed minimal response. A hypothesis emerged from Abramson et al, suggesting that LSD could facilitate identification of schizophrenic patients with healthy volunteers in group therapy settings and reported increased communication by patients after receiving LSD compared to a placebo.

Psychedelics as a Potential Treatment for Schizophrenia

Investigating the possible use of psychedelic drugs for schizophrenia treatment, particularly in patients with recent onset disease and noticeable negative symptoms, is both fascinating and demanding. Current treatments are largely ineffective for this patient group, making the potential of psychedelics to promote neurogenesis and synaptic plasticity particularly attractive due to the link between negative symptoms and cortical atrophy. 

A significant amount of preclinical research is necessary to determine whether the proposed psychedelic treatment plans could intensify psychosis or prove effective in negative symptom models. 

Treatments that neither trigger psychosis nor effectively alleviate negative symptom-like features should undergo testing in meticulously planned phase 1 studies. A thorough investigation in this field could dramatically impact the treatment of one of the most severe and socially disabling psychiatric disorders, marking an exhilarating new chapter in psychopharmacology.

The idea that serotonin, a chemical in our brain, plays a part in schizophrenia has helped scientists develop many of the newer drugs used to treat this condition. Researchers found that drugs like ritanserin, which can stop the effects of LSD (a strong psychedelic drug) on certain serotonin receptors in our brain, could be useful in treating schizophrenia.

Studying hallucinogenic drugs gives us important clues about schizophrenia, especially why people with this condition might see or hear things that aren’t there (psychosis). Psychedelic drugs have complex effects on the brain, but by studying them in detail, using things like computer models and mouse studies, we can learn a lot about how they work.

Research into drugs that have effects like LSD and PCP (another strong psychedelic drug) has given us new ways to think about creating better medicines for schizophrenia. It also points to a possible link between two major ideas about what causes schizophrenia: one related to serotonin and another related to a different brain chemical, glutamate.

The next big challenge is to see how these ideas fit with a third theory, which suggests that dopamine, yet another brain chemical, plays a key role in schizophrenia.

Overall, studying psychedelic drugs has been really useful in developing better treatments for schizophrenia. Even though there’s still a lot we don’t know, this research is really promising and could lead to big improvements in how we understand and treat mental health problems.

Current pharmacological approaches to treating negative schizophrenia symptoms

Up until now, only a handful of treatments for schizophrenia negative symptoms (NS) have undergone testing, and the results have been moderately successful at best. The lack of a universal definition of NS among both researchers and pharmaceutical regulatory bodies has led to inconsistencies in the criteria used for including participants in these clinical trials. This inconsistency hampers the ability to draw robust conclusions. 

Cariprazine has demonstrated effectiveness in preliminary models of anhedonia, a condition characterized by the inability to feel pleasure, and it has proven more effective than risperidone in treating schizophrenia patients with predominant NS. This suggests a potentially promising new direction for treating NS. Nevertheless, there is an urgent need for more trials to enhance our current understanding of NS treatment, as well as increased efforts in discovering and developing new drugs.

Future Directions in Research

In the world of medical research, there’s a surprising shortage of trials focusing on the link between psychedelics and schizophrenia. However, a few brave studies are stepping up to fill the gap.

One such study is examining the tolerability of MDMA, also known as Ecstasy, in people diagnosed with schizophrenia. This study could be a real game-changer in understanding how this group of people reacts to the drug.

Another exciting trial is delving into whether cannabidiol, or CBD, can reduce the effects of THC intoxication in individuals with schizophrenia. THC is the active ingredient in cannabis that can cause a ‘high,’ while CBD is another cannabis component often used for its potential health benefits. This double-blind, randomized, placebo-controlled study could shed new light on how these two components interact in individuals with schizophrenia.

Lastly, a study is probing the cannabinoid system in people with a family history of psychosis. By understanding this system better, researchers hope to gain insights that could eventually lead to improved treatments for schizophrenia.

It’s early days for these studies, but they could pave the way for breakthroughs in our understanding and treatment of this complex mental health condition.

FDA Approval Greenlights MDMA Trial for Schizophrenia

The U.S. Food and Drug Administration (FDA) has given the green light to a clinical trial investigating the use of MDMA in patients with schizophrenia. This experimental medical product (IMP) has been developed by PharmAla Biotech, a Canadian firm, and the trial will be conducted by researchers at the University of California, Los Angeles (UCLA).

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References

1. “Therapeutic Potential of Psychedelics in Schizophrenia” (2022). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9147282/ 

2. “Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Underlying Psychoactive Drug-Induced Perceptual Alterations” (2022). Retrieved from https://www.nature.com/articles/s41380-022-01832-z 
3. “Hallucinogens and Schizophrenia.” Retrieved from https://fairmountbhs.com/patients-families/resources/hallucinogens-and-schizophrenia/ 
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5. “Psychedelics and Schizophrenia: A Review of the Evidence” (2021). Retrieved from https://www.frontiersin.org/articles/10.3389/fpsyt.2021.727117/full 
6. “Investigating the Neural Correlates of Psychedelic Drugs: Linking Schizophrenia and Psychedelic States” (2022). Retrieved from https://www.sciencedirect.com/science/article/pii/S105381192200739X 
7. “Psychedelics and Schizophrenia.” Retrieved from https://encyclopedia.pub/entry/23790
8. “Clinical Reactions and Tolerance to LSD in Chronic Schizophrenia” (1955). Retrieved from https://journals.lww.com/jonmd/Citation/1955/09000/Clinical_Reactions_and_Tolerance_to_Lsd_in_Chronic.1
9. Abramson, H. A., Hewitt, M. P., Lennard, H., Turner, W. J., O’neill, F. J., & Merlis, S. (1958). The Stablemate Concept of Therapy as Affected by LSD in Schizophrenia. Journal of the American Psychoanalytic Association, 6(1), 32-46. doi: 10.1080/00223980.1958.9916241
10. PharmAla Biotech. (2023, June). USFDA approves Laneo (MDMA) for clinical trial use in the United States. Retrieved June 16, 2023, from https://pharmala.ca/media/2023/06/usfda-approves-laneo-mdma-for-clinical-trial-use-in-the-united-states