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In psychedelic therapy, two substances are drawing significant attention: ketamine and psilocybin (the active compound in “magic” mushrooms), both of which are considered psychedelic drugs.
Both show promise in treating mental health conditions such as depression, anxiety, and trauma. Yet, they differ fundamentally in their mechanisms, effects, therapeutic use, and accessibility. These substances are among the emerging treatment options for mental health.
At Essence Institute, we’re often asked: “What’s the difference between ketamine and psilocybin?” and “Which one is right for me?”
This article explores both options across five key areas: effects, therapeutic potential, safety, legality, and user experience. Our aim is not to promote one over the other but to provide clear, balanced insights for those considering psychedelic-assisted therapy or simply wanting to learn more.
Psilocybin is classified under the Controlled Substances Act in many countries, which significantly affects its legal status and accessibility.
Introduction to Psychedelic Therapy
Psychedelic therapy is an innovative approach to mental health treatment that uses psychoactive substances—most notably ketamine and psilocybin—to help alleviate depressive symptoms and address a range of mental health challenges. Unlike traditional therapies, psychedelic therapy is gaining momentum for its potential to treat conditions that are often resistant to standard interventions, such as treatment-resistant depression, major depressive disorder, and anxiety disorders.
The World Health Organization has highlighted the urgent need for new solutions in mental health, as millions worldwide continue to struggle with mood disorders and other psychiatric conditions. In this context, ketamine and psilocybin have emerged as promising tools. Both substances have demonstrated the ability to produce rapid and sometimes sustained antidepressant effects, offering hope to those who have not found relief with conventional antidepressant medications.
By harnessing the unique properties of these psychoactive substances, psychedelic therapy is opening new doors for individuals seeking to alleviate depressive symptoms and improve their overall mental health. As research continues, the role of ketamine and psilocybin in modern mental health treatment is becoming increasingly significant.
Ketamine vs Psilocybin
What is ketamine?
Ketamine is a synthetic compound originally developed as an anesthetic. Ketamine is available in several forms, including racemic ketamine, esketamine nasal spray, and intravenous ketamine, each with distinct pharmacological properties and administration routes.
At low doses, it has become a promising option for treating treatment-resistant depression, particularly in clinical settings, where ketamine hydrochloride is the form most commonly used.
What is psilocybin?
Psilocybin, found naturally in certain mushrooms and legal truffles in the Netherlands, is a classical psychedelic. It’s known for producing emotionally and spiritually rich experiences that can lead to profound personal insight and emotional release. Psilocybin treatment is currently being studied for its therapeutic potential in addressing mental health conditions such as depression.
Psilocybin trips are characterized by vivid sensory and emotional experiences, often lasting several hours and involving deep introspection. Psilocybin assisted treatment is typically conducted in a controlled, supportive environment to ensure safety and maximize therapeutic benefit.
Learn more about how we work with legal psilocybin truffles in our retreats.
For context, other classical psychedelics like lysergic acid diethylamide (LSD) also produce altered states of consciousness and are being explored for their potential therapeutic applications.
Differences in effects and experience
Ketamine: Fast, Dissociative Relief
- Alters glutamate signaling in the brain
- Induces a detached, “floaty” mental state
- Often described as calming, even neutral or non-emotional
- Popular in clinical, medicalized environments
Common adverse events during ketamine therapy include increases in blood pressure. The effects ketamine can have on mood and perception range from rapid antidepressant responses to dissociative experiences.
Psilocybin: Deep, Connected Insight
- Activates serotonin (5-HT2A) receptors
- Brings forward emotional depth and introspection
- Often visionary, symbolic, and sometimes spiritual
- Higher doses of psilocybin can intensify the subjective and mystical experiences, but do not always lead to proportionally greater therapeutic benefits
- Best experienced in a natural or therapeutic setting with guidance
Therapeutic Potential: What Each Substance Offers
When Ketamine Might Help Most: Treatment Resistant Depression
- Acute depressive episodes
- Major depression and major depressive episodes, especially when other treatments have failed
- Suicidal ideation
- When fast-acting relief is needed (ketamine is known for its rapid onset of therapeutic effects)
- Often delivered in a series of clinical sessions
When Psilocybin Might be Best
- Emotional and spiritual growth
- Processing grief, trauma, or addiction
- Gaining clarity around purpose or life direction
- Usually guided in a retreat setting, with longer-lasting outcomes
Recent systematic reviews and subgroup analysis of clinical trials have identified specific populations that may benefit most from psilocybin therapy, highlighting the importance of tailored approaches based on individual needs and characteristics.
Read more about our approach to psychedelic integration after a retreat or journey.
Research and Clinical Trials
A growing body of clinical trials has explored the efficacy and safety of ketamine and psilocybin in treating depressive symptoms, particularly in individuals with treatment-resistant depression and major depressive disorder. These studies have provided compelling evidence that both substances can lead to a significant reduction in depressive symptoms, even in cases where traditional antidepressant medications have failed.
For example, a randomized controlled trial published in the Journal of Psychopharmacology demonstrated that ketamine produced a rapid and marked improvement in depressive symptoms among participants with major depressive disorder. Similarly, research on psilocybin-assisted therapy has shown that a guided session with psilocybin can result in significant and sustained reductions in depressive symptoms for those with treatment-resistant depression.
These findings suggest that ketamine and psilocybin may offer effective alternatives for individuals who have not responded to standard treatments. While the results are promising, ongoing clinical trials and further research are essential to fully understand the therapeutic potential, long-term safety, and optimal use of these substances across different populations. As studies suggest, the future of depression treatment may increasingly include psychedelic therapy as a viable and effective option.
Safety and side effects
Both ketamine and psilocybin have strong safety profiles when used in a professional, guided setting. Studies have not observed significant withdrawal symptoms or evidence of drug abuse following supervised use. Both substances have also been studied for their potential to provide pain relief in certain conditions.
Ketamine can be habit-forming when used frequently or recreationally. Overuse has been linked to bladder issues and cognitive fog in some cases. It’s important that ketamine therapy is administered under medical supervision.
Psilocybin is non-addictive and has low toxicity. However, it can bring up intense emotional or spiritual experiences, which may be overwhelming without the right support. There’s a small risk of triggering psychosis in those with a personal or family history of schizophrenia or bipolar disorder.
Substitute for Ketamine: Why Psilocybin Is a Viable Option
For those seeking a legal, natural substitute for ketamine, psilocybin truffles offer a compelling alternative. While ketamine is available only by prescription and typically administered in clinical settings, psilocybin is legally accessible in the Netherlands and used in supportive retreat environments.
Both psilocybin and ketamine are being studied as rapid-acting agents that can be used alongside traditional oral antidepressant treatment. Some patients may transition from or combine these therapies with a new oral antidepressant or a newly initiated oral antidepressant regimen, especially in cases of treatment-resistant depression. The role of an oral antidepressant as adjunct therapy is also being explored in clinical trials to enhance long-term outcomes.
Many participants report that psilocybin offers deeper emotional insight, longer-lasting shifts, and a more holistic sense of healing. It may not have the same fast-acting dissociative effect, but for those open to emotional exploration and guided integration, it can serve as a powerful and effective alternative.
Learn more about guided psilocybin retreats
What Users Say: Comparing Experiences
Ketamine Users Often Report:
- Feeling emotionally distant but cognitively clear
- Some users report changes in cognitive functions, such as increased clarity or focus, during or after ketamine sessions
- A sense of mental “reset”
- Relief from persistent negative thoughts
- Occasional confusion or numbness without support
Psilocybin Users Often Report:
- Profound emotional breakthroughs
- Insights around relationships, purpose, or self-worth
- Connection to nature, others, and the “bigger picture”
- A sense of renewal and clarity that lasts weeks or months
Ketamine alternative
If you’re looking for a ketamine alternative that offers therapeutic benefits in a more natural and introspective format, psilocybin may be a great fit. While not identical in effect, both substances can lead to profound shifts in mood, mindset, and self-awareness.
Both ketamine and psilocybin are currently being explored as alternative treatments for bipolar depression and unipolar depression, especially in cases where traditional therapies have not been effective.
Some people explore both therapies over time. Using ketamine for stabilization during crisis phases, and psilocybin for deeper personal transformation once they feel emotionally ready.
Choosing Between Ketamine and Psilocybin: Personal Considerations
While scientific studies and clinical outcomes are important, choosing between ketamine and psilocybin is also a deeply personal decision. Both can be effective, but the context, intention, and individual needs of the user play a crucial role in determining which path is most supportive.
Decisions between ketamine and psilocybin are also informed by evidence from randomized controlled trials and randomized clinical trials. These studies use strict inclusion criteria to select participants and assess antidepressant efficacy. Researchers often define a primary endpoint to measure the success of the intervention, and trials may be designed as active controlled studies or placebo controlled studies to ensure rigorous evaluation of treatment effects.
1. Your Therapeutic Goals
If you’re seeking fast relief from acute depression or suicidal thoughts, ketamine may be the most appropriate option—particularly in a clinical, supervised environment. However, if you’re drawn to exploration, deep emotional healing, or a sense of spiritual reconnection, psilocybin may offer more resonance.
2. Your Comfort with Emotional Depth
Ketamine tends to create a detached, dissociative state that can offer relief without engaging directly with difficult emotions. Psilocybin, by contrast, often invites users to feel more deeply, which can be powerful but also challenging. Ask yourself: am I ready to face what might come up?
3. Your Environment and Support System
Ketamine is usually administered in a medical setting, while psilocybin is often experienced in retreats with therapeutic guidance and aftercare. If you value community, nature, and holistic integration, a guided psilocybin retreat may align more with your values.
4. Accessibility and Legality
In the Netherlands, psilocybin truffles are legal, offering a safe and supported option for personal exploration. Both ketamine and psilocybin are classified as controlled substances in many countries, which affects their legal status and accessibility elsewhere. Ketamine, while legal by prescription, requires a medical setting and can be cost-prohibitive for long-term treatment. Esketamine, a form of ketamine, is FDA approved for treatment-resistant depression, whereas psilocybin is still investigational and not yet FDA approved. The FDA approves certain psychedelic-based treatments under strict conditions, highlighting the evolving regulatory landscape.
Ultimately, there’s no one-size-fits-all answer. It’s about choosing the medicine and setting that best meets you where you are—and supports where you want to go.
Conclusion
Ketamine and psilocybin each offer a unique doorway into healing—one fast-acting and clinical, the other deep and transformative. Your choice doesn’t have to be about which is “better,” but rather which resonates with your current needs, intentions, and readiness.
Both have the potential to support growth, relief, and renewal when used consciously, safely, and with integration support. Ongoing research is exploring mechanisms such as brain derived neurotrophic factor, which is involved in synaptogenesis and cellular excitability, as well as alternative treatments like transcranial magnetic stimulation for treatment-resistant depression. And for those seeking a legal, guided alternative to ketamine therapy, psilocybin truffles offer a powerful, nature-based path to insight and connection.
Curious to experience the therapeutic potential of psilocybin in a safe, supportive setting? Learn more about our guided psychedelic retreats.
Frequently Asked Questions about ketamine vs psilocybin
Is psilocybin as effective as ketamine for depression?
Clinical evidence suggests both can reduce symptoms of depression. Ketamine tends to act faster, while psilocybin may produce longer-lasting effects with fewer sessions.
Can I combine both treatments?
Some people benefit from using ketamine to stabilize first, then explore psilocybin for deeper personal work. Always consult with a qualified professional.
Is psilocybin legal in the Netherlands?
Psilocybin mushrooms are illegal, but psilocybin truffles are legal and regulated. This allows legal, guided psychedelic retreats like those we offer at Essence.