Psilocybin, or magic mushrooms as they’re more colloquially known, have been at the center of discussions on psychedelics since the first conversations happened. Psilocybin, the active ingredient in magic mushrooms, was one of the first classical psychedelics to be properly introduced to the West. This came after amateur mycologist R. Gordon Wasson’s visit to the curandera Maria Sabina in Mexico several decades ago.
The LIFE magazine article sparked conversation in many circles, with some individuals going off for their own experiences, and some starting to look into the West’s own historical and traditional use of psychedelic compounds.
In the clinical context, psilocybin has also made a name for itself through its efficacy in treating a host of conditions and ailments, as has been documented since psychedelic therapy studies first began. Psilocybin was used in the classic “Good Friday” experiment, the landmark smoking cessation study, and the mystical experience & psychedelics study. Psilocybin has a strong recreational, mystical, and clinical history behind it —and for good reason.
In this resource, we’re going to explore the subtle yet profound distinctions between ketamine and psilocybin, including the neurobiology of the compound and the phenomenological differences of the experiences.
To begin, it’s worth noting that possession or use of psilocybin is currently illegal in most of the world.
As they are more commonly referred to, magic mushrooms are a Schedule 1 substance as classified by the U.S. Drug Enforcement Agency (DEA), which means they are not formally recognized or approved for medical value, among other designations. Despite its DEA classification, the U.S. Food and Drug Administration (FDA) has designated psilocybin as a “Breakthrough Therapy,” an expedited approval process, which in the case of psilocybin is evaluating treatment for major depressive disorder (MDD) and treatment-resistant depression.
Psilocybin has become a central point in the discussions around psychedelic therapy and psychedelic medicine, largely due to its ability to systematically and reliably induce a psychedelic experience in an individual. Mushrooms do have some physiological benefits to them, but the true value of the experience for individuals seeking psychedelic therapy with psilocybin is the mental and emotional healing that it seems to accommodate.
The psilocybin experience itself is longer than other medicines like ketamine or other psychedelics like MDMA, generally lasting for about six to eight hours depending on the individual and the dosing protocol. Effects typically onset at about 45 minutes to one hour after ingestion, and booster doses are rarely used in practice.
A full psilocybin experience tends to include many of the classic hallmarks of a psychedelic experience. This includes distortions of time and space, out of body experience, an ineffable quality, noetic importance, and levels of visions, visuals, or hallucinations that accompany the subjective experience. In general, though not always, psilocybin experiences tend to focus on the natural world: the body, the environment, the people, and the planet. This is more pronounced than what is reported in a DMT (N,N-Dimethyltryptamine) or LSD (lysergic acid diethylamide) experience, for example.
Psilocybin is often favored over other compounds like LSD in psychedelic therapy protocols due to the length of the experience. Whereas LSD experiences can be upwards of 10+ hours for the full experience, psilocybin/magic mushrooms tend to run about 6 hours for the complete experience. This accommodation helps the clinicians and researchers better accommodate and facilitate these experiences.
This is in juxtaposition to ketamine, where the experiences are often 60-90 minutes in length, with a rest and comedown period afterwards. While the ketamine experience does contain many similarities to the psychedelic experience, psilocybin experiences do not always provide the same level of dissociation as ketamine. This distinction can be important for the future if psilocybin becomes legally available to clients.
Psilocybin’s Effects in Comparison to Ketamine
As a classical psychedelic compound, psilocybin acts most directly on the 5HT2A serotonin receptor in the brain. This is largely responsible for the phenomenology of the experience, though there are other neurobiological mechanisms present in the psilocybin experience.
To a lesser extent, this includes increasing the presence of dopamine in the basal ganglia, while also inducing some region-dependent alterations in glutamate levels, which may contribution to the ego-dissolution experiences that are common with psilocybin and the psychedelic experience.
One of the core neurobiological correlates that happens with psilocybin is the dampening of the Default Mode Network (DMN). This also happens with ketamine. This is a significant neurobiological feature because the DMN generally creates the sense of self in the present moment. As activity here begins to quiet down, the subject-object distinction that most people live within begins to dissolve. A sense of merging with the world, or a more expansive sense of Self shines forth, and this brings in itself a level of healing and peace that is prominent in many client stories.
In some of the early psilocybin studies, participants rated the psilocybin psychedelic experience as one of the most important experiences in their entire lives, alongside their marriage, or the birth of a child.
Alongside the neurobiological effects, there are several physical effects that come from ingesting psilocybin:
- Pupil dilation
- Changes in heart rate (increase and/or decrease)
- Changes in blood pressure (increase and/or decrease)
- Increased energy levels
This presents many of the classic contraindications that would be present for individuals working with ketamine or other psychedelic medicines. A mental health screening, and a physical screening that include but are not limited to heart health and blood pressure are essential to ensure the safety of clients and efficacy of the experience.
One of the largest benefits to working with psilocybin are its low toxicity levels. Psilocybin’s LD-50 —the active dose that would be fatal to 50% of the population— is low compared to other compounds: 280 milligrams per kilogram (mg/kg). Heroin, alcohol, marijuana, caffeine all have higher LD-50s. Psilocybin is matched in its low toxicity by LSD. It also has low possibilities for dependencies to form, despite the current Schedule 1 classification from the FDA.
With low dependency potential, and given the psychedelic experience's ability to assist individuals working through addictive behavioral patterns, psilocybin seems positioned to be net-beneficial for individuals dealing with substance use disorders. Though more research will need to be conducted to demonstrate this.
The phenomenology of the psilocybin experience aligns very closely with the hallmarks of a classical psychedelic experience. Indeed, it was through the use and study of psilocybin experiences that the original characteristics of a psychedelic experience were able to be distilled.
As everyone’s experience and healing process is unique, these may not apply to all individuals in all circumstances. Some broad categories or types of experiences are common in the psilocybin experience are:
- Space/Time Distortion: The individual perception of space and time may distort or become unintelligible.
- Ego Dissolution: A calming of the ego as the center of identity. A sense of merging with the environment.
- Visions/Visuals: Geometric patterns, color gradients, or visual illustrations may occur while eyes are closed.
- Entity Encounters: There can be a distinct experience of interacting with entities/beings that are not the individual.
- Ineffable: It is extremely difficult to put in words and language what happened in the experience and why it was meaningful.
- Noetic Quality: A sense of accessing a “more true” reality, or a world/knowledge that was previously inaccessible in regular waking consciousness.
- Cognitive Distance: A sense of distance from the individual’s thoughts, identity, and body. Taking a 3rd-person perspective or getting a “view from above.”
The combination of these characteristics is what often generates the meaning and significance of the psilocybin/psychedelic experience. Clients have a direct, embodied experience of a new way of viewing themselves and the world. They may receive insights into personal patterns or traumas, and be able to reframe their life and tell themselves a new story moving forward.
This ability to rewrite narrative views of self, others, and the world is a profound potential present in all psychedelic therapy. When paired with trained clinicians and skilled practitioners individuals are able to make significant progress on their healing journey with the support of these compounds.
Important Differences Between Psilocybin and Ketamine
There are several distinctions that can be drawn between psilocybin and ketamine as psychedelic medicines. However, it’s worth noting that both are powerful in their own right.
Both have strong scientific and clinical evidence supporting them, and both compounds have countless client stories that demonstrate the healing and supportive power of these experiences.
When drawing distinctions between psilocybin and ketamine, there are a number of key differences.
Ketamine is a Schedule 3 substance as designated by the DEA and is available for on and off-label prescription. Psilocybin is currently Schedule 1, and is not available for prescription. However, there are studies moving through FDA clinical trials right now to make psilocybin a legal and accessible medicine.
Length of Experience
Psilocybin experiences can be significantly longer than ketamine experiences. Ketamine experiences tend to last around 90 minutes including a “landing” period as the medicine slowly dissipates, while Psilocybin tends to last several hours with a comedown period. This impacts accessibility for clients, and is a more significant undertaking for clinicians and facilitators who assist in the experience.
Mechanism of Action
There are neurobiological differences between the compounds and how they act. Psilocybin is largely active on the serotonin 5HT2 receptors, while Ketamine is most active in the glutamate system.
Matching Individual Needs
Depending on the condition and the individual, sometimes a more dissociative experience is needed, in contrast with a more mystical experience.
Ketamine has the distinction of providing a dissociative experience, whereas psilocybin does not as reliably induce this state. In the future if psilocybin becomes clinically available, matching the medicine to the individual's needs will become more and more central in the discussions.
While there are several core distinctions to be made, at the time of this writing ketamine remains the only legal and accessible option for individuals seeking psychedelic therapy immediately.
There are several promising studies underway at various stages of the approval process for psilocybin, but this requires more time before it becomes clear what conditions psilocybin can be used for and whether it becomes a legal medicine.
There is hope that psilocybin can become a legal and available psychedelic medicine for individuals in the near future. Several studies addressing depression, eating disorders, smoking cessation, and other conditions have been conducted or are currently happening —and the early results have been promising.
There are several major institutions and organizations currently working on standardizing treatment care plans for psilocybin therapy, and the future looks bright for this medicine and treatment option.
Psychedelic therapy is gaining momentum, it is building legitimacy and proving its efficacy with each new client that works with it. The introduction of additional medicines like psilocybin, LSD, DMT, or MDMA can help expand the options available to clients while helping address the exact conditions and concerns each client has.
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This article is for informational purposes only and is not intended to be a substitute for professional medical advice. Always talk to your doctor about the risks and benefits of any treatment. If you are in a life-threatening situation, call the National Suicide Prevention Line at +1 (800) 273-8255, call 911, or go to the nearest emergency room.
Important FDA Safety Information
Ketamine is not FDA-approved for the treatment of depression or anxiety. Learn more about off-label uses here.
Side effects of ketamine treatment may include: altered sense of time, anxiety, blurred vision, diminished ability to see/hear/feel, dry mouth, elevated blood pressure or heart rate, elevated intraocular or intracranial pressure, excitability, loss of appetite, mental confusion, nausea/vomiting, nystagmus (rapid eye movements), restlessness, slurred speech, synesthesia (a mingling of the senses).
Do not proceed with ketamine treatment if any of the following apply to you:
- Allergic to ketamine
- Symptoms of psychosis or mania
- Uncontrolled high blood pressure
- CHF or other serious heart problem
- Severe breathing problem
- History of elevated intraocular or intracranial pressure
- History of hyperthyroidism
- Other serious medical illness
- Pregnant, nursing, or trying to become pregnant
Ketamine has been reported to produce issues including, but not limited to, those listed below. However, lasting adverse side-effects are rare when medical protocols are carefully followed.
While ketamine has not been shown to be physically addictive, it has been shown to cause moderate psychological dependency in some recreational users.
- In rare cases, frequent, heavy users have reported increased frequency of urination, urinary incontinence, pain urinating, passing blood in the urine, or reduced bladder size
- Ketamine may worsen problems in people with schizophrenia, severe personality disorders, or other serious mental disorders.
- Users with a personal or family history of psychosis should be cautious using any psychoactive substance, including ketamine, and discuss potential risks with your MindBloom® clinician before proceeding with treatment.
- The dissociative effects of ketamine may increase patient vulnerability and the risk of accidents.
To promote positive outcomes and ensure safety, follow these ketamine treatment guidelines:
- Do not operate a vehicle (e.g., car, motorcycle, bicycle) or heavy machinery following treatment until you’ve had a full night of sleep
- Refrain from taking benzodiazepines or stimulants for 24 hours prior to treatment
- Continue to take antihypertensive medication as prescribed
- Avoid hangovers or alcohol intake
- Refrain from consuming solid foods within 3 hours prior to treatment and liquids within 1 hour prior to treatment
- Ketamine treatment should never be conducted without a monitor present to ensure your safety