Discover how psilocybin, the active compound in 'magic mushrooms,' is challenging conventional antidepressant therapies. Could this controversial substance hold the secret to healing deep-seated mental anguish?

When standard antidepressants fail, where can the estimated 100 million trapped in disabling depression turn?¹ Emerging research suggests an answer drawing scientists and psychiatrists back to prohibited fungi rather than forward to yet undiscovered pills. 

In a pioneering 19-patient trial, a single dose of psilocybin mushrooms brought nearly half into full remission for weeks—an accomplishment unmatched by even newly approved 'rapid-acting' antidepressants.² Yet guidelines still recommend escalating conventional drugs that may never provide real relief. As lead author Dr. Guy Goodwin declares: 

“We’re witnessing no less than a paradigm shift away from just daily meds towards finally holistically healing the mind itself.”³

No Quick Fixes for Treatment-Resistant Depression...Except Maybe Psychedelics  

When multiple antidepressant trials yield little lasting improvement, a patient meets the diagnosis of “treatment-resistant” —a status held by roughly 30% today.⁴ Few emerge from this dark abyss through therapy tweaks or combination meds alone.⁵ In fact, remission plummets from nearly 40% to less than 20% after a first failed antidepressant.⁶  

Perhaps no population urgently needs innovative solutions more. Hopelessness and the risk of side effects compound with each new ineffective prescription. Issues earning income or parenting often rise while motivation, concentration, and sleep suffer.⁷ No wonder treatment-resistant depression doubles suicide attempt rates.⁸

Psilocybin as Rapid-Acting Antidepressant 

Psilocybin mushrooms contain psilocybin and psilocin—serotonin-like compounds triggering vivid hallucinations and spiritual experiences by stimulating 5-HT2A receptors.⁹ Though illegal and controversial, psilocybin intrigue erupted in 2016 when UK researchers found a single dose delivered rapid antidepressant responses lasting 6 months for cancer patients.¹⁰

Another 12-patient study reported 71% remission at 5 weeks after psilocybin-assisted therapy.¹¹ Confirming results, last October researchers led by Dr. Goodwin announced a randomized 233-patient trial—the largest of its kind ever conducted.¹² Two doses of psilocybin bracketed by psychology support outperformed escitalopram (Lexapro) in treatment-resistant depression: After 3 weeks, 57% improved on psilocybin versus just 28% assigned medication.  

The psilocybin groups also enjoyed nearly 4-fold higher complete remission—a holy grail combination of nearly vanished symptoms plus restored functioning lasting months. By contrast, newly approved esketamine (Spravato)—the first antidepressant innovation in decades—demonstrated 37% response and 29% remission after 6 weeks when doubly augmented by daily oral antidepressants.¹³

Adding Psilocybin to Antidepressants 

The recent 19-patient trial led once more by Imperial College’s Dr. Goodwin breaks further new ground.¹⁴ Rather than substituting psilocybin for antidepressant withdrawal, participants added a single 25mg psilocybin dose alongside their regular SSRI like Prozac, Zoloft, or Lexapro. Remission still proved twice as frequent as the best modern comparators at 42% sustained a month out. 

Side effect frequency also proved comparable to placebo with mostly mild headaches resolving quickly. This relieves concerns combining serotonin-elevating compounds could risk serious toxicity. Beyond symptom relief, 89% rated their psilocybin session “spiritually significant” with lasting life improvements in relationships, creativity, mindfulness, and nature connectedness.

Mechanisms: A Mystical Connection 

Researchers increasingly recognize depression as a disorder of both mood and worldview—a mind besieged by negative biases that narrows options.¹⁵ Psilocybin co-founder of psychedelic therapy research Roland Griffiths proposes the compound “opens a window of awareness compared to normal waking consciousness” through which entrenched mental patterns loosen their grip.¹⁶

Brain scans reveal psilocybin hyperconnects neural regions while damping habitual fear and control circuits. Users describe emerging “unity” and “interconnectedness” with existence often lasting years.¹⁷

Lead author Dr. Michael Pollan suggests this temporary ego dissolution offers a wellspring of empathy and flexibility refreshing rigid perspectives.¹⁸ Users feel less “apart from nature” and more appreciation towards loved ones. By flexing mental muscles of holism and awe at existence’s interconnectivity, Pollan theorizes psilocybin “trips” may act as emotional anti-inflammatories cooling searing psychological pain. The more mystical the experience, research corroborates, the further depression and anxiety recede months later.¹⁹

Beyond a Chemical Cure 

Antidepressant medications are designed to address falling serotonin or norepinephrine activity. Psilocybin, within a scaffolding of psychological support before and after, can be used to purse no less than a wholesale mental renewal of the patient.²⁰ Whereas daily regimens only suppress symptoms, this soul-searching expedition seeks a wholesale reconfiguration of one's entire worldview and relationship to the spiritual domains of existence and to one's very own soul.

By inducing a temporary 'psychosis, psilocybin may facilitate relearning pathways out of stolid paralysis in a redirected brain state.²¹ Goodwin envisions adding psilocybin sessions

“to help reset rigid thoughts holding people back once conventional meds provide initial symptom relief.”²²

The Verdict: A “Paradigm Shift” in Mental Health 

More research is still needed, but depression dynamos like Goodwin and Pollan envisage an approaching reality where therapy offices offer guided psychedelic voyages. Instead of chasing chemical tweaks to cumbersome daily meds, psilocybin provides periodic mental spring cleaning—a reboot for worldviews warped by despair and isolation.²³

With replication studies underway in the UK, North America, Australia, and Europe on disorders from alcoholism to anorexia, evidence supporting psilocybin therapy mounts.24 As Pollan concludes, banned mushrooms may yet

“augur a paradigm shift in the treatment of these conditions, perhaps even replacing antidepressants and talk therapy.”²⁵

Two-thirds receiving psilocybin rate it amongst their life’s most meaningful experiences—a gateway to self-transcendence offering liberation where medications never quite reached.²⁶

To learn more about the health applications of psilocybin view our database on the subject here.

REFERENCES

1 WHO, “Mental Disorders,” 2022, https://www.who.int/news-room/fact-sheets/detail/mental-disorders.

2 Goodwin et al., “Single-Dose Psilocybin for Treatment-Resistant Depression,” New England Journal of Medicine.

3 Goodwin et al., “Psilocybin for Treatment Resistant Depression in Patients Taking a Concomitant SSRI Medication,” Neuropsychopharmacology, 1498.

4 Al-Harbi, “Treatment-Resistant Depression: Therapeutic Trends, Challenges, and Future Directions,” Patient Preference and Adherence 6 (August 3, 2012): 369–88, https://doi.org/10.2147/PPA.S29716. 

5 Rush et al., “Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report,” Focus (Madison) 10, no. 2 (Spring 2012): 128–41, https://doi.org/10.1176/appi.focus.10.2.128.

6 Rush, 128.

7 Reppermund et al., “Persistent Depressive Disorder,” Therapeutic Advances in Chronic Disease 10 (January 2019): 2040622319829430, https://doi.org/10.1177/2040622319829430.

8 Dong et al. “Research: Treatment-Resistant Depression Increases All-Cause Mortality: Systematic Review and Meta-Analysis,” Journal of Affective Disorders 320 (March 2023): 274–93, https://doi.org/10.1016/j.jad.2022.12.071.

9 Passie et al., “The Pharmacology of Psilocybin,” Addiction Biology 13, no. 4 (October 2008): 357–64, https://doi.org/10.1111/j.1369-1600.2008.00137.x.

10 Griffiths et al., “Psilocybin Produces Substantial and Sustained Decreases in Depression and Anxiety in Patients with Life-Threatening Cancer: A Randomized Double-Blind Trial,” Journal of Psychopharmacology 30, no. 12 (December 2016): 1181–97, https://doi.org/10.1177/0269881116675513.

11 Davis et al., “Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder,” JAMA Psychiatry 78, no. 5 (May 1, 2021): 481–89, https://doi.org/10.1001/jamapsychiatry.2020.3285. 

12 Goodwin et al., “Single-Dose Psilocybin for Treatment-Resistant Depression,” New England Journal of Medicine, 1646.

13 Daly et al., “Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial,” JAMA Psychiatry 75, no. 2 (February 1, 2018): 139–48, https://doi.org/10.1001/jamapsychiatry.2017.3739.

14 Goodwin et al., “Psilocybin for Treatment Resistant Depression in Patients Taking a Concomitant SSRI Medication,” Neuropsychopharmacology.  

15 Hagan et al., “Neural Correlates of Psilocybin-Induced Alterations in Consciousness and Their Modulation by Ketanserin,” NeuroImage: Clinical 31 (January 2021): 102708, https://doi.org/10.1016/j.nicl.2021.102708.

16 Sanchez and Halberstadt, “Recent Advances in the Neuropsychopharmacology of Serotonergic Hallucinogens,” Behavioural Brain Research 277 (January 1, 2015): 99–120, https://doi.org/10.1016/j.bbr.2014.07.016.  

17 Griffiths et al., “Survey of Subjective ‘God Encounter Experiences’: Comparisons among Naturally Occurring Experiences and Those Occasioned by the Classic Psychedelics Psilocybin, LSD, Ayahuasca, or DMT,” PLOS ONE 14, no. 4 (April 23, 2019): e0214377, https://doi.org/10.1371/journal.pone.0214377.

18 Pollan, How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence (New York, NY: Penguin Publishing Group, 2018).

19 Roseman et al., “Increased Nature Relatedness and Decreased Authoritarian Political Views After Psilocybin for Treatment-Resistant Depression,” Journal of Psychopharmacology 32, no. 7 (July 2018): 811–19, https://doi.org/10.1177/0269881117748902.  

20 Carhart-Harris and Goodwin, “The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future,” Neuropsychopharmacology 42, no. 11 (October 2017): 2105–13, https://doi.org/10.1038/npp.2017.84.

21 Petri et al., “Homological Scaffolds of Brain Functional Networks,” Journal of The Royal Society Interface 11, no. 101 (October 6, 2014): 20140873, https://doi.org/10.1098/rsif.2014.0873.  

22 Goodwin et al., “Psilocybin for Treatment Resistant Depression in Patients Taking a Concomitant SSRI Medication,” Neuropsychopharmacology, 1499. 

23 Goodwin, 1499.

24 “Psilocybin Therapy Clinical Trials,” COMPASS Pathways, Accessed March 1, 2023, https://compasspathways.com/research/psilocybin-therapy-clinical-trials/.

25 Pollan, How to Change Your Mind.  

26 Griffiths et al., “Survey of Subjective ‘God Encounter Experiences,’” PLOS ONE.