This paper explores the similarities and differences of classic hallucinogenic drugs and schizophrenia. Anecdotal accounts are provided to give a better understanding of the experiences with hallucinogens and schizophrenia. This paper primarily focuses on the serotonin (5-HT) receptors in the brain and how they relate to both the drug experience and mental illness.
Indoleamine hallucinogens (mescaline, lysergic acid diethylamide [LSD], and psilocybin) bind to the 5-HT2A receptors and produce similar symptoms as those diagnosed with schizophrenia. In addition, anti-psychotics used to treat schizophrenia are able to block the hallucinogenic affects of hallucinogenic drugs and further supports that idea that a connection exists between the two.
Further investigation of the neurotransmitters serotonin, dopamine, and glutamate could provide more information in how to assess and treat schizophrenia. Research is still sparse on hallucinogenic drugs due to strict drug laws in the United States that do not allow researchers access to the drugs for experiments.
It is understandable that there may be confusion about the meanings of the words “hallucinogen” and “hallucination.” Besides looking similar, the Concise Medical Dictionary defines a hallucinogen as “a drug that produces hallucinations,” (Martin, 2010, p. 328) thus linking the two words. The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association [APA], 2013) includes hallucinations as one of the key diagnostic features that define psychotic disorders. Hallucinations are “perception-like experiences that occur without an external stimulus” (APA, 2013, p. 87). They can be visual, auditory, olfactory, tactile, or gustatory. They exist within the context of a range mental disorders and can also be caused by physical disorders affecting the brain (Martin, 2010). Hallucinations are well known for being a symptom of schizophrenia. The definition of hallucinogens can be quite confusing because hallucinogens do not cause actual hallucinations like those seen in psychotic disorders. They cause a pseudo-hallucination because they alter a person’s regular perception and occur with external stimuli. This paper will explore the connectedness of classic hallucinogens and schizophrenia and discuss how they manifest in the brain.
To get a better understanding of the differences between hallucinogens and schizophrenia Kleinman, Gillin, and Wyatt (1977) compiled autobiographical accounts that explained personal experiences with five different hallucinogens and schizophrenia. This paper will only discuss the classic hallucinogens because they are most similar to schizophrenia in the brain.
Mescaline, Psilocybin & LSD Symptoms
Individuals who took mescaline experienced a sense of exhilaration and feelings of increased ability and competency. Individuals described great beauty and splendor and seeing very vivid colors. Visual hallucinations were present and were recalled as pleasant experiences.
Other individuals described a more intense and exclusive attention, only being able to direct attention to one subject at a time. Of important note, individuals described that they knew that their hallucinations were not real (Kleinman et al., 1977).
Those who had experiences with psilocybin described visual and complex hallucinations, illusions, and after-images; they saw geometric patterns and rich colors. Paranoid delusions were also reported. They experienced feelings of novelty, astonishment, and ecstasy. Individuals reported being intellectually alert and expressed a feeling of connection with God. They felt that they could travel backwards and forward in time and felt very connected to those who shared the experience with them (Kleinman et al., 1977).
From the first known report of the ingestion of LSD, Albert Hoffman reported feeling “slight giddiness, restlessness, difficulty in concentration, visual disturbances, and laughing” (Kleinman et al., 1977, p. 566). The effects found throughout all accounts were changes in perception, mood, and attention. Symptoms frequently began with somatic symptoms and progressed to visual illusions and hallucinations. Somatic delusions were most common. Grandiose and religious delusions were rare and paranoid delusions were not reported in the accounts (though possible). Mood changes and perseveration were common. Distortion of time, space, and place were reported.
The individuals who recounted their experiences with schizophrenia had stories that were more involved and different than those recalled during drug-related experiences. The chief complaints were abnormal thoughts, mood disorders, bizarre behaviors, and memory problems. Abnormal thoughts were present in all cases. Delusions were reported in all cases with paranoid delusions being present in all but two. Other delusions were grandiose, somatic, and religious. Hallucinations were predominately auditory and could be accompanied by visual hallucinations.
Loose associations, tangential thinking, “blurred thoughts,” confusion, and depersonalization were also reported. The predominant mood was depression and individuals expressed feelings of helplessness, hopelessness, anxiety, misery, and fear. Unusual and catatonic behaviors were also present and suicidal thoughts were present in about 30 percent of cases (Kleinman et al., 1977).
Though dated, these anecdotes illustrate experiences and symptoms congruent with those of hallucinogenic drugs and schizophrenia described in the literature. It is important to recognize how different the experiences are between hallucinogens and schizophrenia. Visual hallucinations were present in both hallucinogens and schizophrenia. Hallucinogens, however, produced overall positive experiences with the person knowing the “hallucinations” were not real. When negative experiences were reported, they did not last long and only while the drug was present in the person’s system. Auditory hallucinations were more common in individuals with schizophrenia and occurred more frequently than experienced with hallucinogens. This adds increased support for the statement that hallucinogens do not produce true hallucinations.
The most frequent abnormalities of thought content for schizophrenics were paranoid delusions. This was not the case for the hallucinogens; individuals reporting classic hallucinogen use reported mostly somatic delusions. Confused thinking was reported by over half of the schizophrenic individuals and inonlyone case of hallucinogen use. The schizophrenic individuals reported an overall depressed mood with a decline in functioning. Depressed mood was not found in any of the accounts of hallucinogen use and feelings of love and euphoria were expressed overall (Kleinman et al., 1977).
Understanding the known differences between the effects hallucinogens and symptoms of schizophrenia can help in the understanding of these two greatly unknown topics that share some important similarities. Because hallucinogens and schizophrenia act on similar neurotransmitters and areas of the brain, the study of hallucinogens can allow for more insight into the cause of schizophrenia and allow for more effective treatment.
There have been many hypotheses presented over the years to try to understand the pathogenesis of schizophrenia. The dopamine (DA) hypothesis of schizophrenia describes how a dopamine-related imbalance is involved in the etiology and treatment of the disorder. Recent research suggests that serotonin (5-hydroxytryptamine; [5-HT]) may also be involved. Evidence to support 5-HT involvement is as follows:
(a) individuals with schizophrenia have changes in cortical serotonin receptor binding
(b) atypical antipsychotics used to treat the disorder are antagonists at 5-HT2 receptors
(c) classic hallucinogens (lysergic acid diethylamide (LSD), psilocybin, and mescaline) cause schizophrenia-like symptoms by interfering with the serotonin system (Vollenweider, Vollenweider-Scherpenhuyzen, Bäbler, Vogel, & Hell, 1998).
The classic hallucinogens (psilocybin, mescaline, and LSD) are all 5-HT2A receptor agonists. 5-HT2A activation is required to experience the effects of these classic hallucinogens, but it is interesting that not all 5-HT2A agonists cause hallucinogenic effects. It would be interesting to study what makes hallucinogens different from other 5-HT2A agonists; they have an affinity for the 5-HT2A receptors, yet must affect other areas as well for the differences to occur. 5-HT2A are found everywhere in the central nervous system (CNS) and can be found in the ventral striatum and ventral tegmental area which are structures known to be involved in psychosis (González-Maeso et al., 2007).
Vollenweider et al. (1998) tested whether 5-HT2 and/or DA D2 receptors contributed to the psychological effects of indoleamine hallucinogens (psilocybin, LSD). The authors wanted to investigate whether indoleamine hallucinogens mediate their psychological effects through 5- HT2 receptors alone, through a subsequent activation of DA D2 receptors, or through both.
To test their hypotheses, the researchers studied the influence of pretreatment with the 5-HT2A antagonist ketanserin, the D2 antagonist and typical antipsychotic haloperidol, or the mixed 5- HT2/D2 antagonist and atypical antipsychotic risperidone on the psychotomimetic effects of psilocybin (Vollenweider et al., 1998). The antipsychotics haloperidol and risperidone are used in the treatment of schizophrenia; results from this study could increase understanding of the brain chemistry of individuals with schizophrenia.
Altered State of Consciousness Rating Scale
The Altered State of Consciousness rating scale was used to measure the effects of psilocybin on the human subjects. This rating scale uses three subscales which are the following:
(a) OSE (oceanic boundlessness) which measures derealization and depersonalization associated with heightened feelings to sublime happiness, grandiosity, and alterations in the sense of time and space
(b) VUS (visionary restructuralization) which measures illusions, pseudo- hallucinations, and synesthesias
(c) AIA (dread of ego-dissolution) which measures thought disorder, anxious ego-disintegration, loss of control over body and thought, and derealization phenomena associated with arousal and anxiety (Dittrich, 1998).
The results supported the hypothesis that the psychotomimetic effects of indoleamine hallucinogens are a result of a specific activation of the 5-HT2 receptors.
The psychotomimetic effects of psilocybin were completely prevented by either the mixed 5-HT2/D2 antagonist risperidone or the 5-HT2A antagonist ketanserin (dose-dependent), but not the D2 antagonist haloperidol (Vollenweider et al., 1998). 5-HT2 receptor alterations are found in individuals with schizophrenia, which adds support to the hypothesis that serotonin-related hyperactivity may also contribute to the disorder
The typical antipsychotic haloperidol was significantly less effective than the atypical antipsychotic risperidone in blocking the effects of psilocybin even at doses that had comparable effects on D2 receptors. Haloperidol increased AIA scores which indicate that typical antipsychotics would enhance the effects of indoleamine hallucinogens (Vollenweider et al., 1998). This makes it even more important to assess whether or not a patient is presenting with psychotic symptoms related to a mental health disorder or the result of a hallucinogenic drug.
This study offers insight into the pathogenesis of schizophrenia, but more research is needed to support their results. Only 15 participants were used in this study, and it would be interesting to see if the results remained the same with a larger number of subjects.
Effects of Psilocybin Study
Carhart et al. (2012) used fMRI studies to investigate the effects of psilocybin. They found that psilocybin significantly decreased brain blood flow in a way that correlated with the subjective effects of the drug. The study by Vollenweider et al. (1998) described how psilocybin increased brain activity whereas the present study indicated decreased activity in the prefrontal cortex. The authors posited that the stimulation of the 5-HT2A receptors increased GABAergic transmission and pyramidal cell inhibition which might explain the decreases in brain activity. Future research should make use of fMRI technology; it may be an invaluable tool to study the complexity of how hallucinogens interact with the brain.
More recently, Kometer, Schmidt, Jäncke, and Vollenweider (2013) studied the role of 5-HT2A receptors in the pathogenesis of visual hallucinations. The researchers assessed the effects of 5-HT2A receptor activation on the prestimulus oscillatory state of the visual parieto- occipital network. Parieto-occipital α oscillations are involved in visual network excitability and influence visual perception. The researchers hypothesized that using psilocybin to activate the 5-HT2A receptors may modulate α oscillations that regulate cortical excitability which could cause visual hallucinations (Kometer et al., 2013).
The Altered States of Consciousness rating scale (Dittrich , 1998) was used to measure subjective psychological effects of the administration of drugs that included a pretreatment and treatment combination of placebo/placebo, placebo/psilocybin, ketanserin/ placebo, and ketanserin/psilocybin respectively. The researchers found that the activation of 5-HT2A receptors may be increasing the excitability of visual networks in the absence of an external stimulus by decreasing ongoing α oscillations.
The 5-HT2A activation occurs due to a dysbalance between the excitability that occurs in the absence of external stimuli and the excitability that occurs when a stimulus is presented. Visual hallucinations may be caused by this shift away from external stimulus-driven information processing toward internal-driven information processing. The effects of psilocybin were reversed by the ketanserin pretreatment which is a 5-HT2A antagonist (Kometer et al., 2013). Like the previous study, this experiment only contained 17 subjects. Because research studying hallucinogens is sparse, this study is very useful to our understanding of visual hallucinations. It would needed to be replicated with a larger sample size to gain credibility.
Meta-Analysis of Postmortem and Molecular Imaging Study
Selvaraj, Arnone, Cappai, and Howes (2014) conducted a meta-analysis of postmortem and molecular imaging studies that give more insight into the 5-HT receptors and schizophrenia. Fifty post-mortem and molecular imaging studies met inclusion criteria for the meta-analysis. Nine studies reported 5-HT1A receptor measures in the prefrontal cortex. Six out of nine of these found increased 5-HT1A in the prefrontal cortex in patients with schizophrenia as compared to controls. The remaining three studies found no significant difference. Molecular imaging was used in four studies to examine 5-HT1A availability and schizophrenia. Two of the four found no difference between schizophrenic patients and healthy controls. One reported an increase in cortical areas and the other found a decrease in the amygdala in the patients as compared to controls (Selvaraj et al., 2014).
The meta-analysis also investigated the role of 5-HT2A receptors. Six studies were reported that involved LSD or 3H-spiperone. Three out of six studies found decreased 5-HT2A binding which indicates reduced receptor availability. The remaining studies found either an increase in cortical or subcortical regions or no change. In anti-psychotic free patients, two studies found increased binding in the prefrontal cortex which may suggest that anti-psychotic medications change 5-HT2A binding.
Molecular imagining was used to investigate in vivo 5- HT2A in schizophrenic patients. Two of the molecular imaging studies found decreased 5-HT2A binding in the prefrontal cortex. Four studies found no significant difference as compared to controls. It is interesting to note that being at risk of developing psychosis may also affect 5- HT2A binding. It was found in a small group of never-medicated individuals that they had reduced binding in several cortical areas as compared to controls. Those that progressed to develop psychosis had even lower 5-HT2A binding than those that did not progress (Selvaraj et al., 2014).
Overall, these studies demonstrate that there is a reduction in 5-HT2A binding and increased 5-HT1A binding in the prefrontal cortex in patients with schizophrenia. It seems that anti-psychotics play a major role in increased or decreased binding (Selvaraj et al., 2014). There may also be a difference between the patients who were taking atypical or typical antipsychotics because they are known to act on different neurotransmitters. Never-medicated individuals may also present as different to medicated patients. The mixed results found throughout the meta- analysis indicate that schizophrenia is a complicated disease that cannot be explained by serotonin alone. Adding the dopamine hypothesis and examining the effects of both dopamine and serotonin may be helpful for future studies.
Animal Model of Schizophrenia
Marona-Lewicka, Nichols, and Nichols (2011) sought to create a new animal model of schizophrenia. They suggested that previous research about the two phases of LSD should be further explored to understand the nature of psychosis. The phases include the early phase (psychedelic experience) and the second phase (paranoid state).
They used rats to test the effects of chronic LSD treatment. Chronic LSD rats appeared as healthy as control rats in relation to weight and weight gain during treatment. The researchers found that chronic administration of LSD to rats led to a persistent behavioral syndrome after the drug was stopped. The development of this behavioral syndrome is not fully developed until about three months of chronic LSD administration. This behavioral syndrome can be described as a persistent neuroadaptive state that resembles psychosis in the absence of the drug.
The researchers believe that their model may be relevant to investigate the development of psychosis in humans. It is interesting to note that the best atypical antipsychotics are antagonists at both the 5-HT2A and D2 receptors and that LSD is a potent agonist at both of these receptor sites (Marona-Lewicka et al., 2011). This supports the idea of a dopamine-serotonin hypothesis for schizophrenia that should be further explored.
To further complicate things, LSD also elevated extracellular levels of glutamate in the rats. Glutamate levels in the prefrontal cortex remained elevated even after cessation of the drug. In studies with individuals with schizophrenia, it has been found that they have higher levels of glutamate in the prefrontal cortex and hippocampus than non-schizophrenic individuals (Marona-Lewicka et al., 2011). This suggest further investigation into a dopamine- serotonin-glutamate hypothesis of schizophrenia.
How hallucinogens and schizophrenia affect the brain is still widely unknown. The research provided in this paper is just the beginning of what could be learned about the two. Because classic hallucinogens are a schedule I drug in the United States, there are hardly any studies that investigate their effects on the human brain. Because classic hallucinogens are mostly unavailable to use in experiments in the United States, the majority of studies available are being conducted in other countries. Schizophrenia is still a mystery and it impairs the lives of many people every day. Studying the effects of classic hallucinogens on the brain may be the key to unlocking this mystery and helping many people with this chronic mental health disorder.
By: Ashley Przywitowski, Philadelphia College of Osteopathic Medicine
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