There have been many trials dedicated to the use of drugs for treating depression. One of such drugs is psilocybin which has the genus Psilocybe as the main active ingredient of hallucinogenic mushrooms. Its action is mainly due to the stimulation of 5-HT2A serotonin receptors. It is known that a violation of the functions of the serotonergic pathways leads to various mental deviations, the most typical of which is clinical depression.
The effectiveness of the treatment of severe depression with psilocybin has already been demonstrated earlier in 2016 and 2020 (Carhart-Harris et al., 2017). What is more, the US Food and Drug Administration (FDA) has awarded the status of a breakthrough therapy to the implementation of psilocybin to cure depression, which should ensure the accelerated introduction of this technique into clinical practice (Hibicke et al., 2020). To date, the turnover of this psychedelic and mushrooms containing it is under strict control in most countries of the world (Hibicke et al., 2020). However, the use of psilocybin is still advised only as the “last option” of therapy in particularly severe and resistant cases of depression. For example, this substance is used to treat depression and anxiety disorders in patients and patients with frequent relapses of mental disorders.
The most common sort of antidepressant is selective serotonin reuptake inhibitors (SSRIs). These drugs have disadvantages, in particular, side effects in the form of headaches, lethargy, and mood swings (Lam, 2018). There are also long-term consequences, such as constant fatigue, insomnia, weight gain, and decreased libido. In addition, antidepressants do not have an instant effect. It usually takes about several weeks or months for the drug to impact one’s health (Lam, 2018). Over time, the impact of the medicines weakens, and they do not help some patients from the very beginning.
The rationale for this literature review is that the scientists suggest enough evidence proving that psilocybin is an effective means of treating depression. Moreover, it is supposed to have a long-lasting effect and takes less time to impact one’s health positively. Hence, this literature review aims to analyze the mechanism of psilocybin, its influence on depression treatment, and its advantages over conventional medicine.
Depression and Conventional Treatment
One of the urgent problems of modern knowledge is the issues of mental health and pathology, aspects of which are reflected from different sides in social, psychological, anthropological, and psychiatric approaches. To date, a vivid example of these problems is a mental state such as depression (Lam, 2018). According to the World Health Organization forecasts, the prevalence of depressive disorders will increase by three times and will take first place in the world among all diseases, overtaking coronary heart disease. The main symptoms of depression are a decrease in motivation and subsequent inactivity. Depression is also accompanied by excess negativity and a lack of positive signs of actions since it is characterized by excessive longing and a lack of positive emotions.
Depression at all stages of the new motivational process is characterized by an excessive fixation on the current state of things; there are long reflections before making a decision. Awareness of longing, anxiety and other depressive emotions can cause the severity of suffering, which can later become a motive for trying to change the depressive state (Lam, 2018). But it should be noted that if a person realizes that there is no rational way to change this state, he may commit suicide or attempt suicide as a significant consequence of overcoming depression. A depressive state is also characterized as a perception disorder (Lam, 2018). Usually, there is a distorted perception of colors; they are perceived as muted, less intense. Sensations sometimes turn out to be distorted, as a rule, unpleasant. For example, a patient may complain that the food has a bitter taste.
A depressive condition for the emotional sphere is characterized by a shift towards anxiety, anger, irritability, apathy, asthenia. Usually, emotional disorders include, in addition to mood changes, a number of other components, for example, psychomotor retardation (Hammen & Watkins, 2018). The problem of depression in psychotherapy has been given little attention for a long time compared to other mental disorders. Still, the growth of interest in this area can be recorded since about 1970, with the rise of two directions of development: the concept of depressive disorders based on behavioral psychology and cognitive psychology (Hammen & Watkins, 2018).
In the course of treatment, two main methods are used: psychotherapeutic and medicinal. Psychotherapy is the basis of successful treatment, which allows you to find contact between the patient and the doctor, determine the cause of the pathology, and form the right attitude to events in life. In rare cases, doctors may use other methods: music therapy, meditation, light therapy, hypnotherapy, etc. Antidepressants are divided into tricyclic antidepressants, double-acting antidepressants, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (IMAO) (Lam, 2018). The different mechanisms of action of antidepressants are based on their other effects on neurotransmitters.
The adaptation of cognitive-behavioral and interpersonal therapeutic methods to the treatment of depression deserves special attention today. Taking into account the multidimensional nature of depressive disorders, both biological and psychological forms of influence are considered in the treatment of depression (Lam, 2018). With the help of psychotherapy, a person can learn to recognize his thoughts in the best way and develop the ability to manage them. They can understand why they think a certain way and find ways to get rid of dangerous ideas (Hammen & Watkins, 2018). There is an understanding of the causes and circumstances of depression. Thus, it becomes possible to overcome grief and difficult situations.
However, these conventional treatments are referred to as long-term, and the effect cannot be ever-lasting. Hence, the researchers have been investigating how various drugs can alleviate the symptoms and restore mental health. The immediate attention was drawn to psilocybin which has undergone multiple tests to prove its efficacy. Therefore, the following part of the literature review will explore its mechanisms and experiments to help in different settings.
Psilocybin Treatment of Depression
Various indigenous communities have implemented the classical psychedelic compounds for several centuries and included them in sacramental recipes. Hence, many psychedelic drugs have a long history of implementation (Johnson & Griffiths, 2017). It has been found that more than 100 species of fungi contain psilocybin, many of which belong to the genus Psilocybe (Johnson & Griffiths, 2017). It is a comparatively small compound based on the structure of tryptamine. It is a prodrug metabolized by dephosphorylation in vivo to psilocin, which is assumed to be an active agent in the central nervous system.
Since the 1990s, neurobiological and psychiatric interest in classical serotonergic psychedelic compounds such as psilocybin, N, N-dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD) has gradually revived after decades of suppression (McCorvy et al., 2016; Misra, 2019). Recent experimental studies indicate the potential of psychedelic therapy to treat conditions such as tobacco and alcohol addiction, obsessive-compulsive disorder, anxiety/depression at the end of life, severe depression, and TRD (Johnson, M.W., & Griffiths, 2017). Interestingly, the therapeutic effect in these trials seems to last for several months – much longer than the pharmacological presence of natural compounds.
Researchers have found that lysergic acid diethylamide (LSD) has a unique effect on brain activity and should relieve patients from mental disorders. It is specified that drugs should be used exclusively as catalysts of perception (Carhart-Harris et al., 2017). Psychotherapists will continue to work with patients suffering from depression. LSD and ketamine should, in particular, help people overcome unpleasant or difficult memories (Brietzke & Zarate, 2020; McCorvy et al., 2016). At the same time, the doses and duration of drug use should remain insignificant. In the course of the research, scientists have found that the anesthetic ketamine, popular in “human” medicine and veterinary medicine, can lift the mood of a person suffering from bipolar depression within a few minutes.
Psilocybin (or mushrooms), LSD, MDMA (or ecstasy) are psychedelic drugs that change a person’s consciousness. Their use is prohibited by law in most countries of the world. However, for example, in the United States, these substances can be studied for medical purposes. Scientists have concluded that drugs known to everyone can be helpful in the treatment of mental disorders (McCorvy et al., 2016). Some evidence suggests that psychedelics are more effective than some antidepressants allowed today in the fight against long-term depression and post-traumatic stress disorder.
During research, scientists did not just give mushrooms or LSD to volunteers. They studied how the human brain reacts to drugs – with the help of special equipment; they study how neurons behave (Carhart-Harris et al., 2017). There were several conditions for psychedelic therapy: the dosage was determined by a doctor; only those who had a clinical diagnosis receive medications; the patient was accompanied by psychotherapists during the course, including the process of taking substances. Psychotherapy sessions are just as important as taking the drug, because the patient must not just go on a trip, but also work out his injuries.
Among the institutions that have opened departments of psychedelic research are Yale University and the University of California, as well as Mount Sinai, one of the oldest hospitals in New York (Carhart-Harris et al., 2017). Also today, there are dozens of startups that are aimed at studying and promoting this type of therapy, as well as engaged in technological developments for it. Private medical companies are also involved. For example, Compass Pathways, with its head office in the UK, is conducting 22 clinical trials in ten countries around the world: experts are studying the effect of psilocybin on patients with depression.
How the brain reacts depends on the substance – psilocybin and LSD act on serotonin receptors, which affects mood. Studies show that these drugs can stimulate the brain’s ability to create new neural connections. According to Vollenweider et al. (1998), a psychiatrist and neurochemist at the University Psychiatric Hospital in Zurich, the drugs activate a therapeutic state similar to sleep, enhance sensory perception, and memories arise like small films. The scientists believe that in this state it is easier for people to get rid of stereotypes of thinking (Vollenweider et al.,1998). The main idea of therapy is to open the door to new ideas about how to think about the past and the future, and consolidate them with the support of a psychotherapist (Vollenweider et al.,1998). Hence, this study proves that the therapeutic effect can be reached by using the mentioned drug.
Researchers from the authoritative Johns Hopkins University Medical School (Johns Hopkins Medicine), in a small study of adults suffering from the so-called major depressive disorder, stated that only two doses of the substance psilocybin in combination with supportive psychotherapy could cause a rapid and significant weakening of depressive symptoms (Carhart-Harris et al., 2017). Moreover, most of the participants in the experiment showed improvement, and half of them achieved remission four weeks after the start of treatment under the supervision of doctors.
The other study concerned with investigating the effects of psilocybin was proposed by Griffith and his colleagues in 206 claiming that psilocybin is beneficial for patients with cancer related depression. According to Griffith et al. (2016), “this randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin” (p. 1181). The study proved that high doses of this drug are useful in decreasing depression symptoms after 6 months of its implementation. However, the researchers established the major limitation – the drug changes the brain cell structure creating long-lasting change in cortical networks which remains to be investigated by others.
The findings suggested in the previous study are supported by those of Davis et al. The researchers established that MDD (major depression disorder) can be mediated by doses of psilocybin (Davis et al., 2021). This randomized clinical trial controlled by a waiting list was carried out among adults aged from 21 to 75 who were exposed to antidepressants treatment (Davis et al., 2021). They were administered different doses of psilocybin and the results of its implementation were disclosed four weeks later. It was found that the majority of participants had remission after only one week of the drug use (Davis et al., 2021). The main advantage of the study is that in encompasses a large sample including people of different ages.
Psilocybin is considered safe in terms of medical use, proven by multiple clinical trials. The drug has been tested for treating resistant depression in the randomized study (Patra, 2016). Psilocybin has a weakening effect on the right amygdala. The amygdala’s reactivity to neutral and negative images decreases, which causes an increase in the positive affective state study (Patra, 2016). The paper also discussed ethical issues of clinical trials with drugs paying attention to safety matters and the possibility of addiction study (Patra, 2016). What is more, the author emphasized that the risk-benefit ratio in treatment-resistant depression should be further established.
The study suggested by Mertens et al. (2020) also proclaimed the idea of the increased amygdala’s responsiveness to psilocybin. The researchers used “psilocybin (25 mg) in 19 patients with treatment-resistant depression” (Mertens et al., 2020, p. 167). They hypothesized that as a result of psilocybin treatment, the amygdalae decrease, affecting the ventromedial prefrontal cortex and positively affecting mental health. According to Mertens et al. (2020), “results showed decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week” (p. 167). The effect was due to changes in communication in response to scared and neutral faces. The results of this research once again proved the efficacy of the drug in curing resistant depression.
Ketamin was also researched as a potentially effective drug for mitigating the symptoms of depression. Rats were used for the experiment to compare and contrast ketamine, psilocybin, and LSD (Hibicke et al., 2020). Hibicke et al. (2020) established that psilocybin is more efficient in reaching remission due to its anxiolytic effect that remains unchanged even after six months. Unlike ketamine and LSD, psilocybin did not have a transient impact but was somewhat permanent.
Johnson and Griffin conducted another analysis increasing the dose of the drug. The study was carried as “a small, open-label study in patients with treatment-resistant depression showed reductions in depression and anxiety symptoms three months after two acute doses” (Johnson & Griffin, 2017, p. 734). The scientists produced promising research since they increased the dose and proved that three months of therapy and psilocybin use could bring significant advances in depression treatment progression.
Recent research suggests that this drug can provide effective outcomes to patients with depression related to life-threatening diseases. The aim of the study was to produce a systematic review of clinical trials to evaluate the potential effect of psilocybin on the chosen population (Vargas et al., 2020). The work showed that given the drug’s safety, patients could be assured of not having mental health implications; yet, there is a need for thorough translational research of the medicine.
There was a debate regarding the addictiveness of the drug. Even though it is mainly utilized as a recreational drug in a number of cultures, recent studies have demonstrated that it does not have addictive effect and can be used in hospital settings. Golberg et al. (2020) conducted meta-analysis with the aim of identifying the influence of psilocybin alongside with behavioral interventions in populations having elevated anxiety and depression symptoms. There were control and placebo groups; the experiment did not indicate any specific fluctuations, or did it find any adverse events. However, the control groups seemed to have an increased level of anxiety. The study has a major limitation – a small number of studies were included in a research. Overall, the results tentatively confirm the necessity of future studies of the drug.
Historical research suggests the indispensability of using psilocybin as a cure against cancer-related anxiety and depression. There was “a double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy” (Ross et al., 2016, p. 1165). Approximately 80% of participants reported that the drug had an anxiolytic effect and led to a better mental state, improving the quality of life, attitude towards death, and eliminating existential crisis (Ross et al., 2016). Therefore, in combination with psychotherapy, this drug was proven to be effective in terms of therapeutic effect provision.
Another research attempted to identify patients’ perceptions of the described drug as a means of fighting depression. Twenty patients participated in an open-label trial, and after six months, they were exposed to an interview (Mahapatra & Gupta, 2017). The researchers used thematic analysis to indicate and compare the results of their treatment with the psilocybin one. As a result, two significant alterations were established in relation to the treatment (Mahapatra & Gupta, 2017). The first change was related to better interaction with oneself and others, during the second concerned increased acceptance. Participants reported that medicine and some psychological treatments tend to increase their feelings of alienation and avoidance, whereas psilocybin use encouraged eliminating these conditions. These results suggest that psilocybin, as a treatment for depression, is able to combat symptoms on its own and in combination with short-term talk therapy.
Conclusion
In summation, it is relevant to mention that drugs are becoming more popular in treating the most severe psychological disorders, including depression. Depression can be considered a plague of the modern century since it causes significant problems for one’s normal functioning. The contemporary literature demonstrates the positive effects of the use of psilocybin in the treatment of depression. Studies analyzed in this review show that small doses of psilocybin can reduce the symptoms of depression. However, several studies have also reported that psilocybin may be associated with increased anxiety. Compared with traditional psychological treatment methods, psilocybin can have similar positive effects, but there is not enough knowledge in the modern literature to eliminate the corresponding risks. Therefore, to better understand the impact of psilocybin, it is recommended to continue studying this issue and conduct more clinical trials.
References
Brietzke, E., & Zarate, C. A. (2020). Ketamine for treatment-resistant depression: Neurobiology and applications. Elsevier Science.
Carhart-Harris RL, Leech R, Williams TM, et al. (2012). Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin. Br J Psychiatry 200: 238–244.
Carhart-Harris, R. L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., & Nutt, D. J. (2017). Psilocybin for treatment-resistant depression: FMRIi-measured brain mechanisms. Scientific Reports, 7(1), 1-11.
Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., & Griffiths, R. R. (2021). Effects of psilocybin-assisted therapy on major depressive disorder: randomized clinical trial.JAMA Psychiatry, 78(5), 481-489.
Goldberg, S. B., Pace, B. T., Nicholas, C. R., Raison, C. L., & Hutson, P. R. (2020). The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis.Psychiatry research, 284, 112749.
Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., & Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.Journal of psychopharmacology (Oxford, England), 30(12), 1181–1197.
Hammen, C., & Watkins, E. (2018). Depression. Taylor & Francis.
Hibicke, M., Landry, A. N., Kramer, H. M., Talman, Z. K., & Nichols, C. D. (2020). Psychedelics, but not ketamine, produce persistent antidepressant-like effects in a rodent experimental system for the study of depression.ACS Chemical Neuroscience, 11(6), 864-871.
Johnson, M.W., & Griffiths, R.R. (2017). Potential therapeutic effects of psilocybin.Neurotherapeutics, 14, 734-740.
Kuypers, K. P. (2020). The therapeutic potential of microdosing psychedelics in depression.Therapeutic Advances in Psychopharmacology, 10, 1-15.
Lam, R. W. (2018). Depression. Oxford University Press.
Mahapatra, A., & Gupta, R. (2017). Role of psilocybin in the treatment of depression.Therapeutic Advances in Psychopharmacology, 54–56.
Mertens, L. J., Wall, M. B., Roseman, L., Demetriou, L., Nutt, D. J., & Carhart-Harris, R. L. (2020). Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. Journal of psychopharmacology (Oxford, England), 34(2), 167–180.
Misra, J. K. (2019). Fungi from different environments. CRC Press.
McCorvy, J. D., Olsen, R. H., & Roth, B. L. (2016). Psilocybin for depression and anxiety associated with life-threatening illnesses.Journal of psychopharmacology (Oxford, England), 30(12), 1209–1210.
Patra S. (2016). Return of the psychedelics: Psilocybin for treatment resistant depression. Asian journal of psychiatry, 24, 51–52.
Roseman, L., Nutt, D. J., & Carhart-Harris, R. L. (2018). Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression.Frontiers in Pharmacology, 8,974.
Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., Mennenga, S. E., Belser, A., Kalliontzi, K., Babb, J., Su, Z., Corby, P., & Schmidt, B. L. (2016). Rapid and sustained symptom reduction following psilocybin Vtreatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. Journal of Psychopharmacology, 30(12), 1165–1180.
Vargas, A. S., Luís, Â., Barroso, M., Gallardo, E., & Pereira, L. (2020). Psilocybin as a New Approach to Treat Depression and Anxiety in the Context of Life-Threatening Diseases-A Systematic Review and Meta-Analysis of Clinical Trials. Biomedicines, 8(9), 331.
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F., Bäbler, A., Vogel, H., & Hell, D. (1998). Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action.Neuroreport, 9(17), 3897-3902.