- Trial of Psilocybin versus Escitalopram for Depression | NEJM
- Trial Design
- Adverse Events
- Statistical Analysis
- Mushrooms for Depression? The Pros & Cons Revealed
- Effective for Treatment-Resistant Depression
- Lasting Results
- Emotional Connection
- Limited Options
- Unsettling Experiences
- Legal Risks
- TMS Therapy As an Alternative Option
- Need Help for Your Depression?
Trial of Psilocybin versus Escitalopram for Depression | NEJM
A Schedule 1 drug license from the U.K. Home Office was obtained by the investigators, and the trial was approved by the Brent Research Ethics Committee, the U.K.
Medicines and Healthcare Products Regulatory Agency, the Health Research Authority, the Imperial College London Joint Research Compliance and General Data Protection Regulation Offices, and the risk assessment and trial management review board at the trial site (the National Institute for Health Research [NIHR] Imperial Clinical Research Facility [CRF]). Psilocybin was provided by COMPASS Pathways, and escitalopram and placebo were provided by the Pharmacy Manufacturing Unit at Guy’s and St. Thomas’s Hospital.
This was an investigator-initiated, university-sponsored trial. All medicinal products under investigation were stored and dispensed by Invicro. Trial visits occurred at the NIHR CRF from January 2019 through March 2020.
The first author designed the trial and wrote the first draft of the manuscript with assistance from the second author. The second through seventh authors performed the trial and collected the data, and the eighth author analyzed the data.
Clinical oversight of the trial was provided by the third, penultimate, and last authors, and the overall trial was overseen by the last author. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol (available with the full text of this article at NEJM.
org). There was no industry involvement in the collection or analysis of the data, and no agreements were in place between the authors and any commercial entity.
Men and women between the ages of 18 and 80 years were recruited formally through trial networks, informally through social media, and through other sources, which directed patients to a recruitment website.
The main exclusion criteria were an immediate family or personal history of psychosis, medically significant health conditions that make a person unsuitable to participate in the trial (as assessed by a physician), a history of serious suicide attempts, a positive pregnancy test, contraindications to taking selective serotonin-reuptake inhibitors or undergoing magnetic resonance imaging (MRI), previous use of escitalopram (although previous use of psilocybin was allowed), or suspected or known presence of a preexisting psychiatric condition (e.g., borderline personality disorder) that could jeopardize rapport between the patient and their two mental health caregivers within the trial. Additional details about the trial exclusion criteria are provided in the protocol.
Information about the trial, including inclusion and exclusion criteria, was made available online at the Centre for Psychedelic Research website (www.imperial.ac.uk/psychedelic-research-centre), the ClinicalTrials.gov website, the MQ mental health research recruitment platform (www.mqmentalhealth.org/home/), and the ISRCTN Registry website.
Volunteers initiated contact by emailing the recruitment coordinator after hearing about the trial. Most of the recruited patients referred themselves. Candidates were sent a patient information sheet and invited to a telephone screening.
Assessments with the 17-item Hamilton Depression Scale (HAM-D-17) were performed by means of a video call; a score of at least 17 (indicating moderate-to-severe major depressive disorder) on a scale that ranges from 0 to 52, with higher scores indicating greater depression, was required for trial enrollment.
Confirmation of a diagnosis of depression and medical history were obtained from the patient’s general physician. Eligible patients then underwent face-to-face physical and mental health assessments with a trial psychiatrist, which was followed by their first psychological support session (see the protocol).
The patients discontinued any use of a psychiatric medication before starting the trial, with full discontinuation occurring at least 2 weeks before starting a trial medication; any use of psychotherapy was stopped at least 3 weeks before starting a trial medication.
After the telephone screening, each patient was assigned to two supervising mental health professionals. The role of these mental health professionals was to build a therapeutic alliance with the patient before, during, and after each day of dosing. (Additional details are provided in Section S2.
8 of the Supplementary Appendix, available at NEJM.org.) One of the pair was a clinical psychologist, psychotherapist, or psychiatrist, and the other could be an equivalent grade clinician or trainee. The mental health professionals were present for all trial visits.
Baseline assessments were completed 7 to 10 days before trial visit 1.
Randomization (performed with the use of a random-number generator) was implemented by staff members who were not part of the research team. (Details regarding the randomization process are provided in Section S2.6.
) All the patients provided written informed consent and, after screening, were required to attend six visits over a 6-week trial period.
Procedures for the ingestion of psychotherapeutic agents and size- and color-matched placebo capsules were consistent between the trial groups.
At visit 1 (baseline), all the patients underwent functional MRI, completed a battery of cognitive and affective processing tasks (data not yet analyzed), and attended a preparatory therapeutic session.
At visit 2, which occurred 1 day after visit 1, the patients in the psilocybin group received 25 mg of psilocybin, and those in the escitalopram group received 1 mg of psilocybin, which was presumed to have negligible activity (dosing-day 1).
To standardize expectations, all the patients were informed that they would receive psilocybin, but the dose was not disclosed to them. The medications and placebos were prepackaged with nondisclosing labels, and all the investigators and medication administering staff were unaware of the trial-group assignments.
The dosing days for each patient were supervised by the two mental health professionals who had been assigned to the patient.
Supervision consisted of caring for the physical and psychological well-being of the patient and responding to signs of patient discomfort during and immediately after the administration of a trial medication.15 (Additional details regarding psychological support are provided in Section S2.8.) A trial psychiatrist assessed eligibility for discharge when the functional status of a patient had returned to the baseline level.
Before the patients left the CRF after visit 2, they received a screw-top bottle of capsules and were instructed to take one capsule each morning until their next scheduled day of psilocybin dosing.
The capsules contained either microcrystalline cellulose (placebo), which were given to the patients who had received the 25-mg dose of psilocybin on dosing-day 1, or 10 mg of escitalopram, which were given to the patients who had received the 1-mg dose of psilocybin on dosing-day 1.
Visit 3 occurred 1 day after dosing-day 1 and included a psychological debriefing. An additional debriefing by telephone or video call occurred 1 week later.
At visit 4, which occurred 3 weeks after dosing-day 1, the patients received their second dose of psilocybin or placebo (dosing-day 2), and at visit 5 (the next day), a psychological integration session involving open, attentive listening was held. After dosing-day 2, the patients were asked to take two capsules each morning (either placebo in the psilocybin group or an increased dose of 20 mg of escitalopram in the escitalopram group) for the next 3 weeks.
Three weeks after visit 5, the patients returned for their final trial visit (visit 6) for the assessment of the primary outcome.
The structure of this visit was similar to that of visit 1 and involved the performance of functional MRI (6 weeks after the first), cognitive and affective processing tasks, final clinician-rated assessments, and psychological debriefing.
After these assessments, the patient and the trial staff were informed of the trial-group assignment, and a trial psychiatrist discussed future treatment options. In the escitalopram group, discontinuation of the trial drug was managed by the patients and their general physicians.
After week 6, the patients were followed for 6 months by the investigators, but these data have not yet been fully collected.
The initial trial design included a placebo group that was to receive 1 mg of psilocybin and placebo, but this group was not included in the final protocol because it was determined that a trial involving three groups would be too complex and expensive to conduct and power adequately, given the resources that were available at the time. The data obtained from an imaging group in the trial, in which functional MRI was used to predict responses to the trial drugs, have not been analyzed.
The primary clinical outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at 6 weeks.
Secondary outcomes included response at 6 weeks according to the QIDS-SR-16 (defined as a decrease in score of ≥50% from baseline); remission at 6 weeks according to the QIDS-SR-16 (defined as a score of 0 to 5); change in the score on the 14-item QIDS-SR (QIDS-SR-14) from the day before to the day after dosing-day 1; and the changes from baseline to week 6 in the scores on the Beck Depression Inventory 1A (BDI-1A), the 17-item Hamilton Depression Rating Scale (HAM-D-17), and the Montgomery and Asberg Depression Rating Scale (MADRS). Other secondary outcomes were the changes from baseline to 6 weeks in the scores on the Flourishing Scale (FS), the Spielberger’s Trait Anxiety Inventory (STAI), the Brief Experiential Avoidance Questionnaire (BEAQ),16 the Work and Social Adjustment Scale (WSAS), the Snaith Hamilton Anhedonia Pleasure Scale (SHAPS), the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS), and the Suicidal Ideation Attributes Scale (SIDAS), as well as the scores at 6 weeks on the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ), the Laukes Emotional Intensity Scale (LEIS),17 and the Emotional Breakthrough Inventory,18 which assessed acute subjective experiences after each dosing day (Fig. S4 and Table S5). An investigator-constructed patient-rated scale (the Post-Treatment Changes Scale [PTCS]) was used as a safety outcome measure for assessing post-treatment side effects and other phenomena that previous work has associated with psychedelic compounds or selective serotonin-reuptake inhibitors (Section S2.11 and Table S2). Additional details of these outcomes are provided in the protocol.
Adverse events were recorded at every visit and telephone call from dosing-day 1 through week 6. Adverse events were assessed by asking “how have you been since your last visit?” or on the basis of events that were observed at the trial site.
Additional details of the criteria used for the reporting of adverse events are provided in the protocol.
All adverse events that occurred or worsened between dosing-day 1 and week 6 were recorded and coded with the use of the Medical Dictionary for Regulatory Activities, version 23.0.
The clinical component of the trial was powered on the basis of data from previous trials10,14 and on an assumption of equal variance for both trial drugs with respect to the primary outcome and the ability to detect a difference between the groups at a two-sided level of P
Mushrooms for Depression? The Pros & Cons Revealed
Magic mushrooms are a natural type of psychedelic drug that people use for recreational or spiritual purposes.
In the U.S., magic mushrooms are illegal. They contain the Schedule controlled substances psilocybin and psilocin. This drug classification means magic mushrooms have no accepted medical value and a high potential for abuse.
But scientific reports show that magic mushrooms can treat depression. The Food and Drug Administration (FDA) approved the ingredient psilocybin for use in a drug trial for treatment-resistant depression.
What are the pros and cons of using mushrooms for depression? And how does this treatment compare to other options?
Effective for Treatment-Resistant Depression
Studies show that patients with treatment-resistant depression respond well to psilocybin. Results suggest psilocybin ‘reset’ the brains of these patients. Dr. Robin Carhart-Harris led one of the psilocybin studies and says “similar brain effects” occur “with electroconvulsivetherapy.”
“Psilocybin may be giving these individuals the temporary ‘kick start’ they need to break their depressive states…”
Treatment-resistant depression is when depressive symptoms aren’t relieved by any tried therapies, including:
- – Various medications
- – Various talk therapies
- – Lifestyle changes
- – Alternative therapies
Research demonstrates that relief lasted up to five weeks after two doses of psilocybin. Separate studies show that a single dose of psilocybin can lift anxiety and depression in cancer patients.
In contrast, many depressed patients need to take antidepressants every day and/or attend therapy every week to get similar benefits. These forms of treatment can also continue for years.
According to Professor David Nutt of Imperial College London, “Our study has shown psilocybin is safe and fast acting so may, if administered carefully, have value for these patients.”. In one study on magic mushrooms, all the depressed patients showed improvements after one week.
The fast-acting nature of psilocybin mushrooms for depression is attractive since antidepressant medication and/or therapy can take weeks before patients feel benefits. This can prove problematic if your depressive symptoms are severe. Self-harming behavior or suicidal thoughts call for immediate treatment.
Researchers state that magic mushrooms help depressed patients reconnect with their emotions. They contrast this effect with antidepressants, which relieve depression by dulling your emotions. Many patients who use antidepressants say they help reduce low mood, but they blunt positive mood as well. This can leave you feeling numb or flat.
Psilocybin seems to offer patients benefits by increasing emotional processing. After the psilocybin experiment, patients said they were more willing to accept emotions. They felt that previous treatments encouraged them to “reinforce emotional avoidance and disconnection.”
The nature of psilocybin’s effects and its short-term use means there are few side effects. Magic mushrooms lack the side effects of various antidepressant medications, which often include:
- – Increased appetite and weight gain
- – Loss of sexual desire or other sexual problems (erectile dysfunction, decreased orgasm, etc.)
- – Fatigue and drowsiness
- – Dry mouth
- – Blurred vision
- – Insomnia
- – Dizziness
- – Indigestion and stomach aches
- – Diarrhea or constipation
Magic mushrooms are illegal in the U.S., including for clinical use, so patients with depression can’t receive the treatment outlined in the studies above unless they enroll in new experiments.
Magic mushrooms are legal in some countries, and you can even find ‘magic mushroom retreats’ in the Netherlands and Jamaica. These retreats don’t cater to people with depression, even though some people attend them for that reason. They’re also not controlled or structured in the same way psilocybin studies are. And there may not be psychotherapists guiding the sessions.
Researchers warn against people using magic mushrooms as a form of self-medication. This is because it involves some risks that you may not be able to cope with on your own. These include:
- – Paranoia
- – Confusion
- – Frightening hallucinations, both auditory or visual in nature
- – Derealization (the feeling that your surroundings aren’t real)
- – Depersonalization (a state in which your thoughts and feelings seem unreal)
- – Distressing thoughts
When you don’t have a trained mental health professional to guide you through a difficult experience or process it after, it could be unsettling in the long-term.
If you decide to use magic mushrooms for depression in the U.S., you are committing a crime. Most patients don’t want to have to break the law to treat their mental health condition. Also, knowing you have a controlled substance may increase your unpleasant emotions, paranoia, during an experience with magic mushrooms.
TMS Therapy As an Alternative Option
While many people are hopeful that using magic mushrooms for depression will be a legal therapy in the future, it’s hard to say if that will ever be a reality.
But you don’t have to hold your breath for fast-acting, med-free treatment!
Evidence shows that transcranial magnetic stimulation (TMS) is an effective treatment for depression.
In fact, TMS therapy is more effective than meds and it’s covered by insurance and Medicare.
The sessions are quick and provide long-lasting relief even from treatment-resistant depression. When combined with a healthy lifestyle for maintenance.
TMS can help lift your fog of depression when nothing else seems to work.
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