How Does Ketamine Compare to Psilocybin, Ibogaine & Ayahuasca?

Legality: Access and Regulation

One of the most significant distinctions between ketamine and plant-based psychedelics is its legal status. Currently, ketamine is the only legally available substance among them, classified as a Schedule III drug under the Controlled Substances Act. This designation means it has an accepted medical use in the U.S. and a moderate to low potential for physical and psychological dependence. Other Schedule III substances include anabolic steroids and certain codeine-containing medications.

• Ketamine is FDA-approved for anesthesia and has an established off-label use for treatment-resistant depression, PTSD, and chronic pain. It is legally available in medical clinics throughout the U.S. Notably, esketamine, a derivative of ketamine marketed under the brand name SPRAVATO, is FDA-approved as a monotherapy for major depressive disorder. Previously, its use was limited to treatment-resistant depression (TRD), requiring patients to have failed trials of antidepressants and to take an oral antidepressant alongside esketamine.
• Psilocybin remains federally illegal in the U.S., classified as a Schedule I substance. However, Oregon and Colorado have decriminalized its use in supervised settings, and research trials are underway for FDA approval.
• Ibogaine is also Schedule I in the U.S., though it is legal or semi-legal in countries like Mexico and Canada. It has gained attention for its potential in treating opioid addiction.
• Ayahuasca contains DMT, a Schedule I substance, and is illegal in the U.S. outside of certain religious exemptions. It is widely used in South America in traditional healing ceremonies.

Ibogaine has recently gained significant attention, especially following its discussion on Joe Rogan’s podcast, featuring former Texas Governor Rick Perry and W. Bryan Hubbard, former Chairman of the Kentucky Opioid Commission. Their conversation highlighted ibogaine’s potential in addressing addiction and mental health challenges, further fueling public interest in this powerful plant medicine.

‍

Mechanism of Action: How Do They Work?

Each of these substances has a distinct pharmacological profile. Ketamine, best known for its dissociative effects due to its anesthetic properties, operates primarily as an NMDA receptor antagonist. In contrast, psilocybin, ibogaine, and ayahuasca induce hallucinatory experiences that are more aligned with classic psychedelic effects, largely mediated by their interaction with serotonin receptors—particularly the 5-HT2A receptor. These plant-based psychedelics often produce intense, immersive experiences that can be profoundly therapeutic but also highly challenging, depending on dosage and set and setting.

• Ketamine works primarily as an NMDA receptor antagonist, increasing glutamate release and promoting neuroplasticity. It also has effects on opioid and dopamine receptors, which contribute to pain relief and mood stabilization.
• Psilocybin is a serotonergic psychedelic that activates 5-HT2A receptors, leading to altered perception, emotional breakthroughs, and mystical experiences.
• Ibogaine acts on multiple systems, including NMDA, opioid, and serotonin receptors. It is thought to reset neural pathways associated with addiction.
• Ayahuasca contains DMT and harmala alkaloids that inhibit MAO enzymes, leading to an extended psychedelic experience involving intense visions and emotional processing.

What is Ibogaine?

Ibogaine, a naturally occurring psychoactive substance derived from the root bark of the Tabernanthe iboga plant, is primarily used for treating opioid addiction and other substance dependencies. It is known for its profound psychoactive effects and its ability to reset neurochemical pathways associated with addiction.

High-dose (flood dosing) administration of ibogaine induces a powerful, long-lasting psychedelic experience lasting 12–24 hours, with aftereffects that can persist for days or even weeks. This introspective, dreamlike state may aid in processing trauma and disrupting compulsive behaviors. Additionally, flood dosing rapidly alleviates withdrawal symptoms from opioids, stimulants, and alcohol, often eliminating cravings within 24–48 hours.

Important Safety Consideration for Ibogaine

Ibogaine carries serious cardiac risks, including QT interval prolongation, which increases the potential for fatal arrhythmias. Medical screening (ECG, liver function tests) is essential before treatment to ensure safety.

Setting of Use: Medical vs. Traditional and Underground Practices

While ketamine is typically used under medical supervision, plant-based psychedelics are often utilized in spiritual, ritualistic, or underground therapy settings. The setting in which these substances are used varies greatly. Ketamine is administered in clinical environments, often with medical monitoring and integration therapy.

Psilocybin is used in research settings, psychedelic therapy sessions, and underground ceremonies led by facilitators. Ibogaine is typically administered in specialized clinics, primarily in Mexico or other countries where it is legal. Ayahuasca is traditionally consumed in ceremonial settings, often led by shamans in the Amazon or at retreat centers worldwide.

Route of Administration & Duration of Effects

• Ketamine: Administered via IV infusion, IM injection, sublingual lozenges, or intranasal spray (e.g., Spravato). Effects last approximately 40 minutes when given intravenously.
• Psilocybin: Consumed orally as dried mushrooms or brewed into tea. Effects typically last 4 to 6 hours.
• Ibogaine: Taken orally in capsule or extract form. Effects can persist for 12 to 24 hours.
• Ayahuasca: Brewed into a tea and consumed in a ceremonial setting. Effects generally last 4 to 8 hours.

Ketamine has the shortest active duration, making it more practical for structured therapy sessions compared to longer psychedelic experiences that can last an entire day.

Indications: What Are They Used For?

Ketamine is widely recognized for its effectiveness in treating treatment-resistant depression, PTSD, chronic pain, anxiety, and suicidal ideation, with extensive clinical research supporting its rapid symptom relief. Psilocybin has shown significant promise in the treatment of depression, anxiety, PTSD, existential distress, and addiction.

Ibogaine is primarily explored for opioid addiction treatment and substance use disorders, with reports suggesting it may help reduce withdrawal symptoms and cravings, though concerns about potential cardiac risks have limited its widespread use. Ayahuasca, is used for trauma healing, depression, addiction, and spiritual exploration.

While all of these substances hold therapeutic promise, ketamine remains the most widely used and extensively researched in medical settings, with well-established protocols and increasing integration into mainstream psychiatric and pain management care.

Health Concerns and Side Effects: What Are the Risks?

• Ketamine: Dissociation, nausea, increased blood pressure, bladder issues with chronic ketamine abuse.
• Psilocybin: Anxiety, paranoia, nausea, risk of exacerbating psychotic disorders
• Ibogaine: Serious cardiac risks, including arrhythmias, nausea, long duration, potential neurotoxicity
• Ayahuasca: Intense vomiting, emotional distress, interactions with medications (e.g., SSRIs), risk of serotonin syndrome

Efficacy: How Well Do They Work?

Ketamine has been shown to provide rapid relief for depression and suicidal ideation, often within hours of administration. Research indicates that 70-85% of patients with treatment-resistant depression experience significant symptom improvement after a series of IV ketamine infusions, with effects lasting from several weeks to months, depending on individual response and treatment protocol.

Psilocybin, on the other hand, has demonstrated long-lasting antidepressant effects in clinical trials, often after just one or two high-dose sessions. Studies suggest that a single psilocybin session can alleviate depressive symptoms for up to six months in some individuals, often demonstrating efficacy comparable to traditional oral antidepressants like selective serotonin reuptake inhibitors (SSRIs).

Ibogaine has shown promise in addiction treatment, particularly for opioid dependence, with reports of significant withdrawal symptom relief and reduced cravings after a single session. However, further research is needed due to safety concerns, including potential cardiac risks.

Ayahuasca has garnered anecdotal and preliminary research support for PTSD, addiction, and depression, with some studies suggesting improvements in emotional processing and reduced symptoms. However, its effectiveness varies widely, influenced by factors such as set, setting, and individual physiology.

Conclusion: Which One Is Right for You?

Ketamine, psilocybin, ibogaine, and ayahuasca each offer unique benefits and challenges. While plant-based psychedelics are deeply rooted in traditional and underground practices, ketamine stands apart as a legally accessible, medically supervised treatment with rapid and well-documented effects. If you are considering a psychedelic-assisted therapy, working with a trusted medical provider can help determine the safest and most effective option for your needs.

At Innerbloom Ketamine Therapy, we specialize in ketamine treatments for depression, PTSD, and chronic pain. If you're curious about how ketamine might help you, contact us today to learn more.

‍

About the Author

Dr. Ray Rivas, a former general and trauma surgeon with over a decade of experience utilizing ketamine, became a ketamine therapy specialist to treat mental health and pain after witnessing its profound impact on his hospital trauma patients and his own mental health. As the founder and medical director of Innerbloom Ketamine Therapy in San Luis Obispo, California, Dr. Rivas applies his extensive medical expertise to provide safe, evidence-based ketamine treatments for mood disorders, including depression, anxiety, PTSD, and chronic pain. His passion lies in helping patients find relief and rediscover hope through personalized, compassionate care.

‍

References:

Carhart-Harris, Robin L., et al. "Psilocybin with Psychological Support for Treatment-Resistant Depression: An Open-Label Feasibility Study." The Lancet Psychiatry, vol. 3, no. 7, 2016, pp. 619-627, doi.org/10.1016/S2215-0366(16)30065-7.

Drug Enforcement Administration (DEA). "Drug Scheduling." DEA, U.S. Department of Justice, www.dea.gov/drug-information/drug-scheduling.

Food and Drug Administration (FDA). "FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic." FDA, U.S. Food and Drug Administration, 5 Mar. 2019, https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified.

Gukasyan, Natalie et al. “Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up.” Journal of psychopharmacology (Oxford, England) vol. 36,2 (2022): 151-158. doi:10.1177/02698811211073759

Johns Hopkins Center for Psychedelic and Consciousness Research. "Psychedelics Research and Psilocybin Therapy." Johns Hopkins Medicine, 2024, https://www.hopkinsmedicine.org/psychiatry/research/psychedelics-research

Maciulaitis, R et al. “Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review.” Human & experimental toxicology vol. 27,3 (2008): 181-94. doi:10.1177/0960327107087802

Multidisciplinary Association for Psychedelic Studies (MAPS). "Ibogaine." MAPS, 2025, maps.org/research/ibogaine.

National Institute on Drug Abuse (NIDA). "Psilocybin (Magic Mushrooms)" NIDA, National Institutes of Health, 2024, https://nida.nih.gov/research-topics/psilocybin-magic-mushrooms

Palhano-Fontes, Fernanda et al. “Ayahuasca for the Treatment of Depression.” Current topics in behavioral neurosciences vol. 56 (2022): 113-124. doi:10.1007/7854_2021_277

Psychedelic Alpha. "Psychedelic Laws & Regulations: A Global Overview." Psychedelic Alpha, 2024, psychedelicalpha.com/data/psychedelic-laws.