Ketamine vs. Psilocybin: Which Psychedelic Therapy Fits You?

You've tried the antidepressants. Maybe two, maybe five, maybe more. You're not alone: about 30% of people with depression don't respond adequately to conventional treatments. Now you're researching psychedelic therapy and finding yourself caught between two options: ketamine and psilocybin. Both show promise for depression, anxiety, PTSD, and other conditions. Both work differently than anything you've tried before. But which one makes sense for your situation?

The short answer: For most people in the U.S. today, ketamine is the practical choice. As a Schedule III medication, it can be prescribed nationwide under medical supervision, produces effects within hours, and is accessible through at-home programs with insurance coverage in some states.

Psilocybin shows genuine promise, particularly for longer-lasting effects and certain conditions like end-of-life anxiety. But it remains federally illegal and investigational. Regulated services currently operate only in Oregon and Colorado, typically cost $1,000–3,000+ per session with no insurance coverage, and require 4–6 hours of supervised time in a licensed facility.

For people with resources and specific conditions where psilocybin shows particular promise, traveling for treatment may be reasonable. For most Americans, ketamine is the accessible path forward.

How Ketamine and Psilocybin Work

Both promote neuroplasticity, your brain's ability to form new connections. This can help loosen entrenched thought patterns that keep depression, anxiety, and trauma responses stuck.

Ketamine acts primarily as an NMDA receptor antagonist. It triggers glutamate release and downstream BDNF-related signaling, which underlie its rapid antidepressant effects. Relief can emerge within hours. For a deeper dive, explore the science behind ketamine therapy.

Psilocybin activates serotonin 5-HT2A receptors. This temporarily reduces activity in the brain's "default mode network," the region strongly associated with self-referential thinking and rumination in depression. The experience is longer and often described as more psychologically transformative per session.

This article focuses on full-dose therapeutic sessions. Microdosing (sub-perceptual doses) is a separate approach with a different evidence base and isn't covered here.

What Conditions Does Each Treat?

Both ketamine and psilocybin are being studied across multiple mental health conditions, but the evidence base differs significantly.

Ketamine has the strongest evidence for treatment-resistant depression and acute suicidal ideation, with the most robust data supporting these uses. Growing but more limited evidence supports its use for anxiety disorders, PTSD, and chronic pain with comorbid depression.

Psilocybin shows particular promise for treatment-resistant depression in smaller but compelling trials, end-of-life anxiety and existential distress in terminal illness, and alcohol and tobacco use disorders. Emerging evidence suggests longer-lasting effects per dose compared to ketamine.

The key difference: ketamine's evidence comes from large-scale trials and years of clinical use. Psilocybin's evidence is promising but earlier-stage, with smaller sample sizes.

How Do They Compare?

What Is Their Clinical Effectiveness?

A 2024 comparative review reported that available trials support rapid antidepressant effects for both ketamine and psilocybin compared with placebo in treatment-resistant depression.

Ketamine: Response rates in controlled trials fall in the 40–60% range, with some real-world cohorts reporting higher. The evidence base is robust. Benefits are often strongest in the first 1–2 weeks, which is why maintenance sessions are part of most protocols.

Psilocybin: Published trials show response rates in the 50–70% range depending on study design, with benefits observed for several weeks to months. Some studies suggest longer durability per dose compared to ketamine, though this needs replication.

What We Still Don't Know

Both treatments have gaps in the evidence.

Most studies follow patients for weeks to months, not years, so long-term safety data remains limited. Optimal protocols are unsettled: how often, how much, and for how long are questions researchers are still working to answer. We can't reliably predict who will respond to which treatment, and why psilocybin effects seem to last longer per dose isn't fully understood.

These gaps don't mean these treatments don't work. They mean the field is young.

What Do the Treatments Feel Like?

Ketamine sessions last 45–60 minutes. The experience is typically dissociative and internally observational. Many people describe ketamine treatment as watching their thoughts from a distance, with altered time perception and floating sensations. The tone is often introspective and contemplative.

Nausea is possible but typically mild. Blood pressure may temporarily increase, which is why monitoring matters. With at-home treatment, you're in your own space with telehealth monitoring and, in most programs, a trusted support person present.

Psilocybin sessions last 4–6 hours. The experience is typically more immersive and emotionally intense, sometimes described as spiritual or relational. Visual changes are common. Some people experience ego dissolution, a temporary loss of the sense of self that can feel profound or frightening depending on preparation.

Nausea is common during onset. "Challenging experiences" occur in a significant minority of sessions but aren't necessarily harmful when properly supported. Sessions must happen in state-licensed facilities where psilocybin is legal.

Who Should Avoid Psychedelic Therapy?

Both treatments are generally avoided or require careful evaluation in people with a personal or family history of psychotic disorders, active mania or unstable bipolar disorder, uncontrolled cardiovascular disease, or pregnancy.

Ketamine carries additional cautions for people with uncontrolled hypertension, history of substance use disorder, severe liver disease, or interstitial cystitis.

Psilocybin requires extra consideration for people currently taking SSRIs (which may alter or reduce effects, though findings are mixed), those unable to commit to 4–6 hour sessions, or those with a history of severe anxiety without adequate preparation.

If neither treatment is appropriate, other options exist, including TMS, ECT, and intensive psychotherapy.

What Are the Side Effects and Risks?

Ketamine

Common side effects include dissociation, dizziness, nausea, increased blood pressure, and drowsiness. With proper supervision, serious risks are rare. Dependence can develop with frequent use, and bladder damage has been documented with chronic high-dose use in recreational settings, though not in structured treatment. Supervised programs incorporate monitoring and limits on dosing frequency to mitigate these risks.

Cleveland Clinic notes that "ketamine therapy is safe when given under medical supervision."

Psilocybin

Common side effects include nausea, anxiety during the session, headache afterward, and temporary cardiovascular changes. With proper screening, serious complications are rare. These may include prolonged psychological distress, persistent perceptual changes, or triggering of latent psychotic conditions.

Warning about unregulated use: Using unregulated mushrooms outside clinical settings carries serious risks: uncertain dosing, no screening, and no support during difficult experiences. Regulated psilocybin services in Oregon and Colorado require screening and facilitator presence for good reason.

Integration: What Happens After

Both treatments work best with therapeutic support, but the demands differ.

Ketamine integration involves sessions between doses, focusing on intention-setting before and processing insights after. Because sessions are shorter and more frequent, integration fits into regular therapy. Learn more about ketamine integration.

Psilocybin integration is more intensive. Most protocols include multiple preparation and processing sessions, which adds to total time and cost.

The medication opens a door; therapy helps you walk through it.

Which Is Right for You?

Your situation determines which path makes sense.

Ketamine may be the better fit if you live anywhere in the U.S. and need relief soon (days, not months). It works well for people who want shorter sessions that fit around work and life, prefer at-home treatment over clinic visits, want potential insurance coverage, or have treatment-resistant depression, anxiety, PTSD, or chronic pain.

Psilocybin may be worth exploring if you live in Oregon or Colorado (or can travel there), can afford $1,000–3,000+ per session out of pocket, and are drawn to fewer, longer sessions rather than ongoing maintenance. It may also suit people with conditions where psilocybin shows particular promise, such as end-of-life anxiety or alcohol use disorder, and those who can commit to extensive preparation and integration time.

For most Americans, ketamine is the accessible option. If you've been struggling with depression, anxiety, or trauma that hasn't responded to traditional treatments, you don't have to wait for psilocybin to become more accessible.

How Innerwell's At-Home Ketamine Therapy Works

If ketamine fits your situation, Innerwell addresses the factors that matter most in the comparison above: cost, access, and integration support.

This isn't ketamine dropped off with minimal supervision. Innerwell's clinicians are Master's and Doctoral level licensed therapists trained in ketamine-assisted psychotherapy, not unlicensed guides. Treatment happens at home with telehealth monitoring, eliminating clinic visits while maintaining clinical oversight.

The process:

1. Evaluation: A virtual psychiatric assessment determines if ketamine is appropriate and builds a personalized protocol.
2. Delivery: Sublingual tablets ship to your door with blood pressure monitoring equipment, dosing instructions, and direct clinician access.
3. Preparation and integration: Licensed therapists help you set intentions before treatment and process insights afterward through integration exercises.
4. Ongoing monitoring: The clinical team tracks progress and adjusts protocols as needed.

Clinical outcomes: 69% reduction in depression symptoms and 60% reduction in anxiety after 10 weeks. 87% see improvement within four weeks. Average patient rating: 4.7/5.

Pricing: $54–75 per session with insurance in California and New York. $83–125 self-pay.

Take the free assessment to see if at-home ketamine therapy is right for you.

Frequently Asked Questions

Which is better for depression: ketamine or psilocybin?

Both show strong results for treatment-resistant depression in clinical trials. Ketamine response rates fall in the 40–60% range with effects in hours. Psilocybin shows roughly 50–70% response rates with benefits lasting weeks to months. The practical difference: ketamine can be prescribed now in all 50 states under medical supervision. Psilocybin remains investigational and available only in Oregon and Colorado.

How long do effects last?

Ketamine's benefits last around 1–2 weeks after a single course, which is why maintenance matters. Psilocybin research suggests benefits can persist for several weeks to months, with some studies showing effects at six months.

Is ketamine addictive?

Ketamine has dependence potential and requires medical supervision. Serious issues are documented with chronic recreational misuse, not structured treatment at therapeutic doses. If you have a history of substance use disorder, discuss this during evaluation.

Can I use ketamine or psilocybin while taking SSRIs?

Ketamine can typically be used alongside SSRIs under medical supervision; your prescriber should review all medications. Psilocybin's effects may be altered by SSRIs (though evidence is mixed), and many clinical trials require tapering off antidepressants first. Tapering should only happen under medical supervision. Discuss medication interactions with your provider.

How do I choose between ketamine, psilocybin, TMS, and other options?

Start with what's legally accessible and covered by your insurance. Ketamine can be prescribed nationwide under medical supervision, with insurance options through some providers. TMS is FDA-approved and often covered for treatment-resistant depression. Psilocybin requires traveling to Oregon or Colorado and paying out of pocket. MDMA-assisted therapy remains investigational. A comprehensive psychiatric evaluation can help determine which approach fits your situation.

What if antidepressants haven't worked for me?

These are the populations where psychedelic therapies have shown particular promise. Both work through different mechanisms than SSRIs. If conventional medications haven't worked, ketamine therapy is the accessible option available now.