Psilocybin: A Magic New Treatment for Depression?

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Anyone who has experienced depression, or knows well someone who has, knows what a scourge it is and how difficult it can be to shake. Effective management requires a multi-pronged approach, which may include pharmaceuticals. There is yet to be a perfect drug that fixes everything- and dare I say, there never will be. Nevertheless, in the continuous search for improved treatments psilocybin has received a surge of interest. It appears this component of magic mushrooms may have unique antidepressant potential. Here we have a deeper look at the evidence. 

Key points:

  1. Psilocybin is the active ingredient in magic mushrooms responsible for their psychedelic effects
  2. Psilocin is produced from psilocybin within the body. This psilocin acts upon serotonin receptors in the brain and may be responsible for mood-lifting effects
  3. Early research has suggested that psilocybin may be of value in the management of treatment-resistant depression, when used in a carefully controlled, clinically supervised program on 1-2 occasions
  4. Research is ongoing, which will hopefully provide more high-quality data on its effectiveness, its mechanisms of action, and any risks and guidelines for usage.

What is psilocybin?

Psilocybin is the active ingredient that gives magic mushrooms (more scientifically named psilocybe mushrooms) their psychedelic effects. It is thought that the changed mood, perception and thought that can be fostered with psilocybin use may have therapeutic benefits for people who suffer with depression.

There are a wide variety of mushrooms which contain psilocybin. It is not recommended- despite misrepresentations by some people/media outlets- that magic mushrooms be used in managing depression. One of the problems with taking magic mushrooms is that it can be difficult to differentiate them from poisonous varieties that can make you sick- or kill you. This toxicity can be avoided with the use of synthetic psilocybin (which comes in white crystalline powder which can be dissolved in water, or taken in tablet/capsule form.)  

However, just as the possession, sale, use and cultivation of magic mushrooms are illegal in more countries than not, psilocybin is not freely available outside limited research settings. This is because research into psilocybin for depression is at the frontier of medical science- put less flatteringly, it’s still very much in its infancy. In 2018, the Rolling Stone reported that it could be legalised within the USA for therapeutic use by 2021. This does not mean it would be freely available for prescription, but that specially-trained therapists could administer it in highly supported programs including patient preparation, debriefing and processing sessions, and supervision on the day of use. 

Why the interest in using psilocybin to treat depression?

A portion of people with depression have treatment-resistant depression: meaning they might try a number of conventional pharmaceutical or psychological treatments without significant improvement. Some people who recover may also relapse down the road. As depression can be debilitating to individuals’ lives, and society as a whole, some early indications of mood-lifting effects of psilocybin have seen interest in it as a potential treatment grow. Psilocybin indeed shows promise; but whether it is a superior alternative or preferable for those with treatment resistant depression remains to be proven. 

How does psilocybin work?

Details on this are sketchy. Research makes some fascinating suggestions… which, due to a lack of scientific rigour, can only be taken as suggestions. 

  • Psilocybin may mimic the mood-enhancing effects of serotonin

Going back to some of the chemical basics of depression: Serotonin is one of the bodies’ key “happy chemicals”: the binding of it to serotonin-receptors on neurons elicits changes within the cells. It is thought that functionally inadequate levels of serotonin contribute to depression, so many conventional antidepressants help people by increasing the serotonin available to the brain. 

Once in the body, psilocybin is converted to psilocin. Psilocin in turn binds to the very same receptors within the nervous system as serotonin, so it can have similar mood-boosting effects to conventional antidepressants. However, beyond this similarity, the action of psilocybin on the brain may differ. 

  • Psilocybin seems to have effects on the amygdala 

This is significant because: a) The amygdala is a small part deep in the brain that has an important role in emotional regulation; and b) It has been found that the amygdala of clinically depressed people is hypersensitive to negative emotional stimuli. 

In a small study of healthy, non-depressed individuals, it was found that psilocin binding to serotonin receptors in the amygdala reduces it’s activity in response to threatening visual stimuli. It is thought this reduced activity makes the visual cortex less able to process negative stimuli, thereby enhancing the processing of positive stimuli. As sensitivity to visual threats may be amplified in depression, further research among depressed people should be conducted. 

I did find one study of people with treatment-resistant depression that would seem to corroborate the findings among healthy people. It showed decreased blood flow to the amygdala with psilocybin use. Blood flow is (only) an indirect measure of activity within the area. Further, the decreased blood flow was correlated with reductions in depressive mood. 

However, another study of people with depression who received psilocybin in combination with psychological support, increased amygdala responses to emotional stimuli were found. One day after receiving psilocybin, increased amygdala activity in response to fearful versus neutral faces, and furthermore these were related to a successful clinical outcome one week later. It would be useful to assess amygdala responses after more time had passed since psilocybin use. In the context of the above mentioned response in healthy and depressed people, this increased activity may be unexpected- in addition, it is opposite to the demonstrated effect of a conventional class of antidepressants (SSRIs). The authors suggest that these drugs exert their therapeutic effects through very different mechanisms: that is, while SSRIs lessen the force of negative emotions, psilocybin helps people to confront and work through them. This hypothesis is supported by patients’ reports of being more willing to accept all emotions, whether positive or negative, after treatment, whereas they felt previous depression treatments reinforced emotional avoidance and disconnection. Assuming that emotional confrontation does become more likely with psilocybin use, the psychological support would be valuable in turning this into emotional breakthrough and resolution. 

This seems a reasonable explanation for the effects of psilocybin vs SSRIs. However, it does not resolve the contradictions between studies. The fact is, how reproducible and accurate any of these studies are is open to conjecture, being limited by small sample sizes, a lack of blinding and control groups, indirect measures, differences in research execution and the level of engagement of subject etc. Much more research is required to elucidate what effect psilocybin has on the very small, but important amygdala. 

  • Psilocybin appears to have effects on the Default Mode Network and the functional connectivity between distant brain parts. 

The Default Mode Network is a technical name for a network of brain structures that work together when we think about ourselves, others, the past and future- and certain goal-oriented tasks. 

On such matters there are more contradictions between studies. It has been suggested that psilocybin may ‘reset’ the Default Mode Network, causing structures to work together less effectively in the short-term, but re-integrating afterwards, bringing about a return to normal function. An improvement in mood was also seen with this. However, this study has many of the limitations mentioned above, so studies with larger sample sizes, controls and so forth are necessary to see if the ‘reset’ phenomenon can be replicated. 

  • Possible reduction of activity in other areas of the brain 

A 2012 paper showed that when non-depressed people took psilocybin, there was reduced blood flow several areas of the brain, indirectly indicating reduced activity. The medial prefrontal cortex is one such area that was deactivated. The medial prefrontal cortex is known to be overactive in depression, and correction has been shown with successful treatment. It is suggested that serotonin receptor stimulation leads to this reduced activity.  In addition, rigid pessimism- a common thinking style in depression- has been linked to deficient serotonin receptor stimulation, particularly in the medial prefrontal cortex.

  • Possible effects on worldview

An interesting possibility is that psilocybin, in conjunction with psychological support, may elicit a long-term (at least up to 7-12 months) increase in nature relatedness and reduced authoritarianism among people with depression.  Perhaps these changes in attitudes and belief could also impact their mental health. However, this study had several limitations, such as a very small sample size (7 patients receiving psilocybin and 7 ‘healthy’ people who did not receive psilocybin), and a lack of control for placebo effects. 

What is the evidence?

As noted, scientific interest in the use of psilocybin for treatment-resistant depression is quite a recent thing. It was preceded by studies looking at other mental health applications. For example, a 2006 study found that psilocybin, used in controlled circumstances, could be safe and lead to short term improvements in Obsessive Compulsive Disorder symptoms. in 2011 with a pilot study looking at its’ effect on anxiety (a distinct, but sometimes-related condition to depression) specifically among cancer patients. The studies were limited by small sample sizes and problems with quality-control techniques such as blinding- besides the fact the findings are not generally applicable to this topic. By 2016 a double-blinded randomised controlled trial (i.e. a better quality study) demonstrated improvements in depression and anxiety among cancer patients six-months after psilocybin use (at a dose of 22 or 30mg/70kg of body weight). A study claiming to be the first investigation of the efficacy and safety of psilocybin’s use for major depression also appeared in 2016- at last! Only 12 people with treatment-resistant depression were recruited. They received 10mg of psilocybin one day, and 25mg on another day, a week later. 

One problem confronting mental health research, is that the effects of any practice can not be as reliably or accurately measured as, say, changes in blood glucose levels among diabetes patients. The best we can do is track physical signs that can reflect mental health and/or use structured questionnaires. These questionnaires are either used by health professionals in their assessment, or self-rated, and essentially convert subjective experiences into as precise data as possible. 

Unfortunately, there has been some academic doubt over how well these questionnaires fulfil their measurement purposes. This 2016 study with 12 adults, in all thoroughness of intent, used several questionnaires to track their treatment effects, including one which was long considered the golden standard. However, in more recent years its’ validity and reliability has been called into question.  

This 2016 study reported some adverse events- primarily mild- such as anxiety at drug onset, confusion, nausea. All participants reported a decrease in depression severity one week after treatment,and seven of the twelve demonstrated benefits 3 months later- 5 assessed as being in complete remission. 

These lasting improvements among 7 of the 12 participants appear quite remarkable. However, as in any study of such humble size, the results cannot be taken as representative of how the population at large would respond. Also, everyone involved- research team and participants- knew the details of what treatment was provided, and what to expect. Participants actively sought this treatment, which may suggest high expectations. Furthermore, it is noted that psychedelics tend to make people more suggestible, which basically means there could be an extreme placebo effect.  

A 2019 article by folk known as O’Donnell, Mennenga and Bogenschutz, available online as recently as September 19, states that a number of research bodies are now in the process of developing protocols that will allow the question of psilocybin (and other psychedelics’) effect on depressive symptoms to be studied systematically. They remind us that both depressive symptoms and psychedelic experiences are highly subjective, which makes accurate measurement difficult, and also that trials to date have not necessarily met the standard expected in other areas of research practice. They also note that antidepressant trials generally have inherent safety risks and a high placebo affect. Thus, they have described an extensive list of standards that should be met in order for us to obtain reliable evidence, in areas ranging from participant selection, characteristics of the depressive episode, study interventions, safety monitoring, trial duration, outcome measures. These have not been consistently met by the studies I reviewed.

What are the risks?

In my literature review, I found little investigation into the risks of psilocybin use, particularly among depressed people. Known risks among the general population include hypertension, anxiety and paranoia. In one study, 36 healthy individuals received 30 mg of psilocybin found no sustained deleterious physiological or psychological effects.

In the face of this lack, I would say it’s prudent to err on the side of caution and assume that synthetic psilocybin could have similar risks as magic mushrooms- asides from the risk of inadvertently consuming poisonous mushrooms. The Alcohol and Drug Foundation states  there are a number of risks from consumption of magic mushrooms, including agitation, vomiting, diarrhoea, muscle weakness, panic, fear or paranoia, anxiety, hallucinations, seizures or coma. There are also possible ‘come down’ effects of headache, exhaustion, depression or anxiety. Some long-term magic mushroom users experience flash-backs of frightening moments or hallucinations up to years after they last took the drug. 

The Alcohol and Drug foundation cites material from 1998 and 2000 which indicates that people are unlikely to become physically dependent on magic mushrooms, and that beyond psychological effects or fatigue, not many withdrawal effects are known. 

People tend to develop tolerance to magic mushrooms very quickly. But since the treatment models represented by psychedelic research aims to attain improvements via a small number of profound psychological experiences- unlike standard treatments that seek to provide medications on a chronic basis- this may not be such an issue with controlled therapeutic psilocybin interventions.

More research of risks is plainly needed beforepsilocybin becomes available as a treeatment for depression.

***

If you’d like to keep up with the developing knowledge of this field, some key centres producing research are:

In some cases there are opportunities to support the work financially or apply to participate in trials (with medical referral). 

What healthy things do you find help when you're in a rough patch? Feel free to share below.  

Alcohol and Drug foundation. Psilocybin. https://adf.org.au/drug-facts/psilocybin/ Last published June 26, 2019

Bagby, R.M., Ryder, A.G., Schuller, D.R., and Marshall, M.B. (2004). The Hamilton Depression Rating Scale: Has the Gold Standard Become a Lead Weight? doi:/10.1176/appi.ajp.161.12.2163

Carhart-Harris, R.L., Bolstridge, M., Rucker, J., Day, C.M.D., Erritzoe, D., Kaelen, M., Bloomfield, M., Rickard, J.A., Forbes, B., Feilding, A., Taylor, D., Pilling, S., Curran, V.H., and Nutt, D.J. (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry, 3(7), 619-627. doi:10.1016/S2215-0366(16)30065-7

Carhart-Harris, R.L., Erritzoe, D., Williams, T., Stone, J.M., Reed, L.J., Colasanti, A.,Tyacke, R.J.,Leech, R., Malizia, A.L., Murphy, K., Hobden, P., Evans, J., Fielding, A., Wise, R.G., and Nutt, D.J. (2012) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences, 109 (6) 2138-2143; doi:10.1073/pnas.1119598109

Carhart-Harris, R.L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J.N., Wall, M.B., Tanner, M., Kaelen, M., McGonigle, J., Murphy, K., Leech, R., Curran, H.V., and Nutt, J.N. (2017). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports 7. doi:10.1038/s41598-017-13282-7

Curran, H.V., and Nutt, D.J. (2018) Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology, 235:399–408

Griffiths, R.R., Johnson, M.W., Carducci, M.A., Umbricht, A., Richards, W.A., Richards, B.A., Cosimano, M.P. and Klinedinst, M.A. (2016). 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(12) 1181–1197 doi:10.1016/j.nicl.2015.08.009

Grob, C.S., Danforth, A.L., Chopra, G.S., et al. (2011) Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer. Arch Gen Psychiatry, 68(1):71–78. doi:10.1001/archgenpsychiatry.2010.116

Hartman, S. (2018) Psilocybin Could Be Legal for Therapy by 2021:The psychoactive ingredient in magic mushrooms could soon be legal to use in a clinical setting. The Rolling Stone. https://www.rollingstone.com/culture/culture-news/psilocybin-legal-therapy-mdma-753946/

Kraehenmanna, R , Fristone, A.S.K. , Prellerb, K.H., Seifritza, E., and Vollenweiderb, F.X. (2016).  The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. NeuroImage: Clinical, 11 53–60

Lyons, T., and Carhart-Harris, R.L. (2018) . Increased nature relatedness and decreased authoritarian political views after psilocybin for treatment-resistant depression. Journal of Psychopharmacology, 32(7) 811–819

Mahapatra, A., and Gupta, R. (2017). Role of psilocybin in the treatment of depression. Therapeutic Advances in Psychopharmacology, 7(1) 54–56

Moreno, F.A., Wiegand, C.B., Taitano, E.K., and Delgado, P.L. (2006) Safety, Tolerability and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder. J Clin Psychiatry, 67. 1735-1740

O’Donnell, K.C., Mennenga, S.E., and.Bogenschutz, M.P. (2019) Psilocybin for depression: Considerations for clinical trial design. Journal of Psychedelic Studies. doi:/10.1556/2054.2019.026

Roseman, L., Demetriou, L., Wall, M., Nutt, D.J.., and Carhart-Harris, R.L. (2018). Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression. Neuropharmacology, 142, 263-269. doi:10.1016/j.neuropharm.2017.12.041

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