It’s the summer of 1967, and thousands of young people dressed in bright colors have flocked to the Haight-Ashbury district of San Francisco. These young dreamers have been drawn in by the prospect of glamorized life, utopianism, and the rejection of conservative values [1]. Amidst the sea of artists, musicians, and other hippies are a multitude of people experimenting with a new class of hallucinogenic drugs—psychedelics. This cultural phenomenon, dubbed the “Summer of Love,” marked the peak of the American counterculture movement, an anti-establishment campaign that emerged in the mid 1960s and lasted until the early 1970s. The movement aimed to break down traditional values and social norms in response to the current sociopolitical atmosphere, characterized by an increase in social and political issues [1]. The rise of the Civil Rights Movement and the escalation of the Vietnam War inspired a cultural revolution in the United States, one characterized by the expansion of recreational drug use, most notably psychedelics [2].
Psychoactive drugs, such as LSD (Lysergic acid diethylamide) and psilocybin, can cause changes in perception and consciousness [3]. Psychedelic users often report “trippy” sensations —for example, imagining stationary objects moving or seeing colors more vibrantly [4]. Hippies who took part in the Summer of Love saw these drugs as a way to expand human consciousness and as an avenue to mental and social peace [1]. As strange as the thought of achieving psychological well-being through the use of psychedelics may sound, the latest research on these psychoactive compounds suggests that there might be some truth to it. In fact, research efforts have focused on investigating the potential therapeutic benefits of psychoactive drugs, gathering evidence that these compounds do have some mental healing properties.
A girl stares down pensively with groovy, floral 70s patterns branching from her head like strands of hair.
The History of Psychedelic Research
During the late 1900s, research on psychedelics increased due to interest in their “mind-altering” ability [4]. Investigations into the potential therapeutic uses of these drugs only began in the late 1950s [3]. However, the association of psychedelics with counterculture, as well as their poorly understood effects and concerns over their abuse potential, created a stigma surrounding their use [3]. These negative attitudes towards psychedelics led to strict drug regulation laws that halted ongoing research on these substances [4]. In the United States, the Controlled Substances Act of 1970 established the current scheduling system that classifies drugs into five categories based on their accepted medical uses and abuse potential [3]. Schedule I drugs are defined as having no currently accepted medical uses and are solely used for recreational purposes. Some examples of substances listed under this category include psilocybin, LSD, heroin, marijuana, and MDMA (ecstasy) [3]. Despite emerging evidence that challenges the notion that using these substances is always damaging to health, Schedule I drugs stand out for their lack of accepted medical use, which is determined by the Drug Enforcement Administration (DEA) [3, 5]. This law enforcement agency has the power to change schedule status and regulations for any controlled substance [5]. As soon as a drug is deemed illegal under national code, it becomes harder for researchers to study it [6]. To conduct research involving a controlled substance, investigators often need to obtain approvals that allow them to access, store, and administer it. These approvals may take years to secure, and they do not guarantee that the researchers will receive the necessary funding to continue their investigation. Additionally, obtaining these substances from approved manufacturers and licensed companies can be extremely costly. In the United States, there are very few institutions willing to invest in Schedule I drugs, with mostly specialized organizations—such as the Heffter Institute—providing relatively small grants [6]. Hence, classification of psychedelics as Schedule I drugs creates a multitude of obstacles for researchers trying to study their potentially helpful effects [6].
Despite these obstacles, neuropsychopharmacology research of psychedelics resumed in the 1980s and persists today due to the continued interest in their biomedical potential and the resurgence of their recreational use [3]. Since 1985, the percentage of people who have used psychedelics in the past year has risen from 1.5 percent to 2.2 percent in 2019 [6, 7]. Psychedelic users report increased positive moods, creativity, and well-being, raising questions as to whether these drugs could serve as a novel therapeutic agent for mental health disorders such as depression and anxiety [4]. The need for novel treatments for these illnesses is dire, seeing as 7.8 percent of all U.S. adults have had at least one major depressive episode in 2019 [8]. Emerging research on psilocybin, a hallucinogen found in various “magic” mushrooms, has proven particularly promising [4].
A recent study investigated the anti-depressant effects of psilocybin on patients with major depressive disorder (MDD) [7]. In a randomized clinical trial with 24 participants, researchers gathered evidence to suggest that psilocybin is four times more effective in treating MDD than other commercial antidepressants, such as fluoxetine and sertraline. In fact, psilocybin action was shown to persist for at least four weeks, while ketamine effects usually last for two weeks [7]. Although neither psilocybin nor ketamine is currently approved for depression treatment, their rapid action is impressive when compared to most commercial antidepressants, which often take weeks or even months to start working [8]. Due to the growing evidence supporting the medical use of psilocybin, this substance was the first to be recognized as a “Breakthrough Therapy” by the FDA, allowing it to be used in the management of treatment-resistant depression (TRD) [9]. This designation is meant to accelerate the development and possible approval of drugs intended to treat serious conditions and thus may contribute to the eventual removal of psilocybin from Schedule I [10, 11].
The Science Behind Psilocybin
Psilocybin is a classic serotonergic psychedelic, meaning that it acts on serotonin receptors [4]. These receptors are known for mediating emotions, moods, and other biological and neurological processes including digestion and memory. In the human body, psilocybin is converted into psilocin, which binds to serotonin receptors and mimics the effect of serotonin [4] However, psilocybin has a much stronger effect on serotonin receptors than serotonin itself, allowing it to produce euphoric feelings and hallucinogenic behaviors [4]. Hallucinations are subjective perceptual experiences that are not evoked by stimuli in the outside environment and that can occur in any sensory modality, such as audition and vision [12]. Although hallucinations generally carry a negative connotation, there is evidence that this effect of psilocybin could improve mental health. People who have taken psilocybin often report an increased sense of self-awareness, greater spiritual connections, and persistent happiness [4]. A study conducted at Johns Hopkins University suggests that psilocybin also impacts brain function in the long-term, altering its responses to affective stimuli by increasing emotional and brain plasticity [13]. Following a high dose of psilocybin, the investigators observed significant changes in the neural correlates of affective processing after periods of one day, one week, and one month. That is, brain activity in response to threatening stimuli changed significantly post-treatment compared to pre-treatment. For instance, one month post-psilocybin treatment, the amygdala response to images with negative facial expressions was observed to decrease significantly [13]. This brain structure is known to be involved with the emotional processing of threatening stimuli and high amygdala activity has been implicated in the pathology of depression [14]. Under these conditions, participants showed reduced negative affect, which includes anxiety and depressive symptoms [13]. Hence, this further suggests that psilocybin may be a good candidate for the treatment of mood disorders, as it appears to target brain states characteristic of these conditions [13].
Psychedelic patterns morph into two neurons exchanging information, rendered stylistically with pink and blue tones.
Further studies have also suggested that psilocybin can enhance cognitive performance through its effect on dendrites, the parts of neurons that receive signals from other neurons [15]. In mice, psilocybin has been shown to encourage the growth of dendritic spines, which are protrusions on dendrites that help transmit signals to the rest of the neuron [16]. The formation rate of dendritic spines in a mouse’s frontal cortex after a single dose of psilocybin increased by eight percent in females and two percent in males; after a month, a little more than one-third of the new spines remained with an overall increase in spine density and width [16]. As formation of dendritic spines is vital to cognitive functions such as object recognition and memory, the increased rate of spine formation after psilocybin is implicated in increased brain connections and increased cognitive performance [17]. Psilocybin treatment can facilitate learning and integrate new psychological experiences [16]. Decreased density of dendritic spines is also a defining feature of Alzhiemer's disease, and psilocybin is currently being investigated as a possible treatment for this disease [18,19].
Not only does psilocybin affect the brain's cognitive functions, but it also affects the emotional state of participants. As previously stated, patients given psilocybin have exhibited a decrease in amygdala reactivity characterized by a lower-than-normal amygdala response to negative and neutral pictures [13, 20]. This decrease in amygdala reactivity is theorized to be responsible for the enhanced positive mood that psilocybin users report [20]. However, another study showed that amygdala activity returned to normal a month after treatment, raising concerns about the permanence of psilocybin’s effects [13]. This positive effect on mood is also seen in measures of participants’ emotions. One study investigating psilocybin’s effect on emotions by Kraehenmann et. al. asked participants to report their positive and negative emotions before and after using either psilocybin or a control drug [20]. In this study, psilocybin users had higher scores related to positive emotions and similar or flower scores relating to negative emotions compared to users of the control drug, suggesting that users of psilocybin were overall happier than their control drug counterparts [13, 20].
The Therapeutic Potential of Psilocybin
While the number and breadth of completed studies are limited, multiple studies have suggested that psilocybin can effectively treat mood and anxiety disorders, such as MDD and generalized anxiety disorder (GAD) [3]. Though there are currently available treatments for these disorders, they don't always work for every patient. For example, about 30 to 50 percent of patients with depression don’t respond fully to currently approved pharmacotherapies and ten to 30 percent have treatment-resistant depression [21, 22]. As such, currently unavailable treatment options, most notably ketamine and psilocybin, have been found to be effective as therapies for mood disorders [7, 23].
However, even though there is evidence to back up the effectiveness of psilocybin as a treatment option for depression, very little is known about how this substance exerts its effects in the brain. In this framework, accumulating evidence suggests the existence of a “reset” mechanism as the method by which psilocybin asserts its anti-depressant effects [24]. This reset occurs in the default mode network (DMN)—the large-scale brain network involved in attention, memory, cognitive processing, and mood improvement [25, 26]. Researchers observed decreases in DMN activity immediately after treatment and increases one day after psilocybin treatment, suggesting a pause followed by a quick resumption of normal functioning [25]. This represents a rebooting of the network, which may cause the remission of depressive symptoms seen in patients treated with psilocybin [25]. Further research is needed to fully understand this observed mechanism, as resetting the brain is a drastic change that should only be considered for the treatment of resistant MDD [24]. This evidence suggests the Breakthrough Therapy designation for psilocybin treatment for patients with treatment-resistant depression is justified.
Additionally, since many patients with cancer and other chronic diseases have co-occurring mood disorders, psilocybin has been explored as a supplementary treatment for these groups. As many as 30 to 40 percent of cancer patients in hospital settings meet the criteria for having some combination of mood disorders [27]. Mood disorders are associated with a higher risk of poor outcomes such as adverse prognosis, decreased quality of life, and reduced treatment adherences [28]. Not only do these disorders affect the survival rates for cancer patients, but their management also appears to interfere with the cancer treatment itself [28]. Psilocybin has been shown to decrease anxiety and depression symptoms without any serious adverse effects on patients’ medical and psychiatric conditions [29]. In addition, rapid antidepressant effects were observed after single-dose psilocybin treatment, lasting anywhere from seven weeks to eight months [29]. Hence, this drug appears to mitigate symptoms of depression and/or anxiety, while increasing measures of quality of life and death acceptance for at least six months following the high dose of psilocybin [30]. With promising results, psilocybin may be more effective than current treatments for mood disorders, especially in patients with chronic illness.
As psychedelics have become more popular and their beneficial outcomes more publicized, microdosing, the practice of routinely consuming low doses of psychedelics, has emerged as a novel means of improving one’s mood, focus, and creativity [31]. Despite the growing popularity of this practice, there have not been many studies to investigate these proposed benefits [32]. One study has shown that microdosing lowers dysfunctional attitudes, a set of beliefs that increase negative thoughts and are associated with depression, and negative emotions [32]. At the same time, the practice of microdosing has been demonstrated to increase wisdom, open-mindedness, and creativity, which were all measured using well-established scales [31]. However, just like other prescription drugs, psilocybin should be used with the guidance of a licensed physician rather than by self-medicating. Nevertheless, further studies are necessary to verify the therapeutic potential of psychedelic microdosing [31].
A skeleton spits out psychedelic, floral patterns into the air.
As mentioned before, psilocybin is a Schedule I drug, meaning that it is considered to have a high potential for abuse. When used recreationally, this substance doesn’t always provide the user with a pleasant experience, and its abuse can lead to the so-called “bad trip” [33]. Bad trips may include panic reactions, psychosis, paranoia, nervousness, nausea, increased heart rate, blood pressure and temperature [33]. Among other risks of psilocybin abuse are mushroom toxicity and the possibility of exacerbating pre-existing psychotic symptoms [34]. Even though there is not a high chance of overdosing with psilocybin, mushroom poisoning may lead to organ failure, convulsions, tachycardia, bradycardia, and other symptoms that may require medical intervention [34]. Heart attacks post-psilocybin ingestion have also been observed in groups that are normally considered low risk for heart attacks, such as the case of an 18-year-old man in Poland who suffered one after consuming mushrooms containing psilocybin [35]. Repeated binding to the serotonergic receptors of the brain, specifically the 5-HT2 receptors, has been linked to heart defects, although research into psilocybin’s connection to heart defects and the specific amounts and duration required for these heart defects is still ongoing [36-38].
Limitations on Psilocybin Research
Unfortunately, due to psilocybin’s status as a Schedule I drug and the stigma surrounding psychedelics in general, research on the substance is still in its infancy. Current studies are restricted by sample size, diversity of subjects, types of research performed, and the subjectiveness of psychology research. Sample sizes remain around 20 to 30 participants, which is not enough to extrapolate results to the general population [13]. On top of a small sample size, these samples are not representative of the entire U.S. and worldwide population. For example, the Griffiths and Ross studies included populations that were 94 percent and 90 percent white, respectively, as compared to the U.S. population that is 76.3 percent white [29, 30, 39]. Current studies on psychedelics lack rigorous methods that characterize modern clinical trials, such as placebo or control conditions, blinding, randomization, and stringent patient recruitment [11]. More expansive studies need to be done in order for the effects of psilocybin, both positive and negative, to be properly understood.
Conclusion
Neuropsychopharmacology research is an ever-changing landscape, and psychedelics may be at the forefront of the field. Their potential therapeutic uses have also become more well known. Psychedelics are complex and poorly understood due to a lack of comprehensive research on their mechanisms of action and effects on the human body. Psilocybin, in particular, has not been studied thoroughly enough despite emerging evidence of its potential therapeutic uses. Further research that is representative of the world’s population is needed for the drug to be both destigmatized and approved for medical use. With its enormous potential to help millions of people suffering from depression and other mental health or mood disorders, psilocybin has the power to change lives.
A pair of lips ingesting shrooms melts into a background of serene, peaceful scenery alongside traditional red mushroom iconography.
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