There has been a lot of interest in psilocybin as a treatment for several mental disorders, but the evidence is only emerging. In this blog we cover a recent study looking at psilocybin as a treatment for depression (Davis et al, 2020) and discuss what the implications for patient treatment might be.

What is psilocybin?

Psilocybin is one of the active psychoactive substance in a group of mushrooms called Psilocybin mushrooms. These are commonly called ‘magic mushrooms’ or ‘shrooms’.

Psilocybin mushrooms contain a mixture of Psilocybin and Psilocin. When ingested, Psilocybin is metabolised to psilocin, which is responsible for the psychedelic properties of these mushrooms.

The effects include hallucinations (visual and auditory) as well as changes in emotional state. Some people experience an altered sense of time and space. Colours are typically enhanced, and sounds may be more intense. A fusion of senses (synaesthesia) can occur where sounds may trigger colours, or vice versa.

The study

The first author of the study was Dr Alan Davis and the study was done at the Center for Psychedelic and Consciousness Research, in Baltimore, USA.[1]

What kind of study was it?

It was a randomised, controlled trial comparing psilocybin-assisted therapy with a waiting list control. This means that those in the control group had no active intervention and were simply on a waiting list for treatment.

The study took place over 8 weeks and those in the active intervention group had to attend at least 18 in-person visits.

Interventions

The study randomised participants to have immediate treatment, or to start treatment after 8 weeks (waiting list control).

The intervention group had two treatment sessions with psilocybin (given orally), alongside approximately 11 hours of supportive psychotherapy.

How many people were involved?

Interestingly, 870 people were assessed for eligibility, and 800 were excluded. The most common reasons included: currently on antidepressant medication (N=157); and living too far away to attend (N=161).

Twenty-seven participants were eventually randomised, with 15 in the immediate treatment group (Group 1) and 12 in the delayed treatment group (Group 2). Two participants dropped out in Group 1 and one participant dropped out in Group 2.

What were the main outcome measures?

All participants were screened using structured assessments, including personality assessments. The primary outcome was the GRID-HAMD,[2] which is a structured interview for the 17-item Hamilton Depression Rating Scale that separates out the frequency of symptom from its severity and improves reliability by incorporating consensus definitions for the ratings.

The GRID-HAMD was completed over the telephone by raters who were blinded to the group that the participant was in. Ratings were done at baseline, and at weeks 5 and 8.

Secondary outcomes included scores on the Beck Depression Inventory (BDI-II),[3] the 9-item PHQ-9,[4] the Columbia Suicide Severity Rating Scale,[5] the Hamilton Anxiety Rating Scale,[6] and the State-Trait Anxiety Index (STAI).[7]

Demographics of the participants

The mean age of participants was 39.8 ± 12.2 years. They had a total duration of depression of 21.5 ± 12.2 years, with the current depressive episode lasting 24.4 ± 22.0 months.

Around two-thirds (67%) of participants were female. Just under two-thirds (58%) had a bachelor’s degree and around one-in-six (17%) had a master’s degree. Two participants (8%) had an advanced degree. Most people being treated in secondary care in the UK do not look like this.

About half (46%) were married and 63% were in full-time education, with 17% in part-time education. Only 21% were unemployed. This is probably rather different to the kinds of patients seen by psychiatrists in secondary care mental health services where unemployment is much more common.

One of the exclusion criteria was a history of a “medically significant suicide attempt.” Whilst this is not defined, it is likely that anyone who has required medical treatment for an overdose or attempted suicide would have been excluded. Such a history is common in patients being seen in the UK by mental health services.

How unwell were the participants?

The baseline HAM-D score for the group was 22.8 ± 3.9. This puts them in the category of ‘moderate depression’ according to commonly-used conventions.[8]

Results

The table below shows outcomes on the primary outcome measure, the GRID-HAMD.

Group	HAMD (Baseline)	HAMD (5 weeks)	HAMD (8 weeks)
Immediate treatment	22.9 ± 3.6	8.0 ± 7.1	8.5 ± 5.7
Delayed treatment	22.5 ± 4.4	23.8 ± 5.4	23.5 ± 6.0

The authors reported that similar reductions were seen on other measures of depression and anxiety, and the tables in the supplementary content show minimal/ no change in the delayed treatment group and marked reductions in the immediate treatment group.

The authors report effect sizes of 2.2 at 5 weeks and 2.6 at 8 weeks for intermediate vs delayed treatment. These are very large effect sizes. For comparison, the effect size of antidepressants is typically around 0.3,9, [10] and the effect size of high quality CBT in high-quality studies is around 0.22.[11]

Discussion

Does this demonstrate that psilocybin is effective for treatment-resistant depression?

Not necessarily. There are a number of factors that we need to take into account.

What are the limitations of this study?

The population of patients is not that similar to the kinds of people seen in psychiatric clinics. Most were in employment, and many had high levels of further education.

The size of the effects seen are large. They are larger than almost all other interventions in medicine.[12] It is a commonly-observed phenomenon that effects in initial studies are not matched by subsequent studies; particularly when the intervention is used in less selected populations.

The total number of participants was small. Only 13 participants in the immediate treatment group completed the study, and in the delayed treatment group only 11 participants completed. It is usual to be wary of very large effects in very small groups.

Effects were only measured up to 8 weeks. For those with longstanding depression (most of the patients in the study had chronic depression, i.e. lasting ≥ 2 years), it is long-term outcomes that are more relevant.

Other confounders

Psilocybin was used alongside supportive psychotherapy. Although the total amount of therapy was relatively small (around 11 sessions), it is not possible to know if it is the therapy that generated the effects rather than the psilocybin. In order to test this, you would need to have each group receive the same amount of therapy, but only one group receives the drug. Better, the other group would receive an ‘active placebo’ to control for the fact that most people will know they have received the placebo if they do not get any psychoactive effects.

Will we see this being used in the UK?

Probably not. They had to screen around 800 people in order to identify 27 participants. Many were excluded because they were on medication or had a family history of significant psychiatric illness.

The study was conducted in people who were not taking antidepressants. This would be uncommon in the kinds of patients where specialist treatments might be used. It is unlikely that we will see GPs providing psilocybin in primary care.

Does a waiting list affect outcomes?

It is widely believed that inactive control groups favour the intervention in psychotherapy research, and there is some evidence that waiting list control groups may act as a ‘nocebo’ condition.[13] A nocebo is when a patient’s negative expectations cause an apparently inert treatment to have a more negative effect. It can occur in drug trials when someone is receiving a placebo, and it can probably occur when people do not get allocated to the active intervention group in psychotherapy trials.

Findings from other research

This is not the first study exploring the use of psilocybin for treating depression.

There are a number of small studies using a single dose of Ayahuasca, an Amazonian hallucinogenic drink. In small, non-randomised, and uncontrolled studies large improvements in depressive symptoms have been reported up to three weeks after a single dose.[14, 15]

Open-label studies of Psilocybin in treatment-resistant depression have also been reported.[16] In most cases, psilocybin has been used alongside some form of therapy.

In a systematic review conducted in 2016, the authors concluded that:

“Whilst all of the included studies have methodological shortcomings, of 423 individuals in 19 studies, 335 (79.2%) showed clinician-judged improvement after treatment with psychedelics…The evidence overall strongly suggests that psychedelics should be re-examined in modern clinical trials for their use in unipolar mood disorders and other non-psychotic mental health conditions.” [17]

Implications for treatment

Whilst the findings from this research are interesting, there are still many questions that remain unanswered in connection with whether psychedelic treatments might be helpful for depression.

It is also relevant that Psilocybin is a Schedule 1 drug under the Misuse of Drugs Act 1971 in the UK, despite it appearing generally safe. This presents major barriers to its use in routine clinical care. There are compelling arguments that some of these classifications are rather antiquated; particularly when it comes to the use of novel psychoactive substances for research and therapeutic use.[18]

References

1. DAVIS AK, BARRETT FS, MAY DG, COSIMANO MP, SEPEDA ND, JOHNSON MW, FINAN PH, GRIFFITHS RR. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial [In Press]. JAMA Psychiatry. 2020. https://doi.org/10.1001/jamapsychiatry.2020.3285

2. WILLIAMS JB, KOBAK KA, BECH P, ENGELHARDT N, EVANS K, LIPSITZ J, OLIN J, PEARSON J, KALALI A. The GRID-HAMD: standardization of the Hamilton Depression Rating Scale. International Clinical Psychopharmacology. 2008; 23(3): 120-129. http://dx.doi.org/10.1097/YIC.0b013e3282f948f5

3. BECK AT, STEER RA, BROWN GK. BDI-II Manual. San Antonio, TX: Pearson; 1996.

4. KROENKE K, SPITZER RL, WILLIAMS JB. The PHQ-9: validity of a brief depression severity measure. Journal of General Internal Medicine. 2001; 16(9): 606-613. https://doi.org/10.1046/j.1525-1497.2001.016009606.x

5. POSNER K, BROWN GK, STANLEY B, BRENT DA, YERSHOVA KV, OQUENDO MA, CURRIER GW, MELVIN GA, GREENHILL L, SHEN S, MANN JJ. The Columbia-Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings From Three Multisite Studies With Adolescents and Adults. American Journal of Psychiatry. 2011; 168(12): 1266-1277. http://dx.doi.org/10.1176/appi.ajp.2011.10111704

6. HAMILTON M. The assessment of anxiety states by rating. British Journal of Medical Psychology. 1959; 32: 50-55. https://doi.org/10.1111/j.2044-8341.1959.tb00467.x

7. SPIELBERGER CD. State-Trait Anxiety Inventory (Form Y) Manual. Redwood City, CA: Mind Garden; 1983.

8. ZIMMERMAN M, MARTINEZ JH, YOUNG D, CHELMINSKI I, DALRYMPLE K. Severity classification on the Hamilton Depression Rating Scale. Journal of Affective Disorders. 2013; 150(2): 384-388. http://dx.doi.org/10.1016/j.jad.2013.04.028

9. FOUNTOULAKIS KN, MÖLLER H-J. Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data. International Journal of Neuropsychopharmacology. 2011; 14(3): 405-412. http://dx.doi.org/10.1017/S1461145710000957

10. KIRSCH I, DEACON BJ, HUEDO-MEDINA TB, SCOBORIA A, MOORE TJ, JOHNSON BT. Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Medicine. 2008; 5(2): e45. http://dx.doi.org/10.1371/journal.pmed.0050045

11. CUIJPERS P, VAN STRATEN A, BOHLMEIJER E, HOLLON SD, ANDERSSON G. The effects of psychotherapy for adult depression are overestimated: a meta-analysis of study quality and effect size. Psychological Medicine. 2010; 40(2): 211-223. http://dx.doi.org/10.1017/S0033291709006114

12. LEUCHT S, HIERL S, KISSLING W, DOLD M, DAVIS JM. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. British Journal of Psychiatry. 2012; 200(2): 97-106. http://dx.doi.org/10.1192/bjp.bp.111.096594

13. FURUKAWA TA, NOMA H, CALDWELL DM, HONYASHIKI M, SHINOHARA K, IMAI H, CHEN P, HUNOT V, CHURCHILL R. Waiting list may be a nocebo condition in psychotherapy trials: a contribution from network meta-analysis. Acta Psychiatrica Scandinavica. 2014; 130(3): 181-192. https://doi.org/10.1111/acps.12275

14. DE L. OSORIO F, SANCHES RF, MACEDO LR, SANTOS RG, MAIA-DE-OLIVEIRA JP, WICHERT-ANA L, ARAUJO DB, RIBA J, CRIPPA JA, HALLAK JE. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Revista Brasileira de Psiquiatria. 2015; 37(1): 13-20. http://dx.doi.org/10.1590/1516-4446-2014-1496

15. SANCHES RF, DE LIMA OSORIO F, DOS SANTOS RG, MACEDO LR, MAIA-DE-OLIVEIRA JP, WICHERT-ANA L, DE ARAUJO DB, RIBA J, CRIPPA JA, HALLAK JE. Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study. Journal of Clinical Psychopharmacology. 2016; 36(1): 77-81. http://dx.doi.org/10.1097/JCP.0000000000000436

16. CARHART-HARRIS RL, BOLSTRIDGE M, RUCKER J, DAY CMJ, ERRITZOE D, KAELEN M, BLOOMFIELD M, RICKARD JA, FORBES B, FEILDING A, TAYLOR D, PILLING S, CURRAN VH, NUTT DJ. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016; 3(7): 619-627. http://dx.doi.org/10.1016/S2215-0366(16)30065-7

17. RUCKER JJ, JELEN LA, FLYNN S, FROWDE KD, YOUNG AH. Psychedelics in the treatment of unipolar mood disorders: a systematic review. Journal of Psychopharmacology. 2016; 30(12): 1220-1229. http://doi.org/10.1177/0269881116679368

18. RUCKER J, SCHNALL J, D’HOTMAN D, KING D, DAVIS T, NEILL J. Medicinal Use of Psilocybin: Reducing restrictions on research and treatment London: Adam Smith Research Trust. https://www.adamsmith.org/research/medicinal-use-of-psilocybin