Psychedelic therapy for depression

Psychedelic therapy may be our best treatment for depression. So must we lose our minds to come to our senses?
03 April 2019


The academic interest in psychedelic drugs, in particular psilocybin (found in many species of mushrooms), has markedly increased over the last decade... 

The increase has been fuelled in no small part by the publication of a number of small studies investigating the therapeutic potential of psychedelic drugs. In the United States, the Food and Drug Administration (FDA) has granted Compass Pathways, a company conducting research into the clinical potential of psilocybin therapy for treatment resistant depression, the ‘breakthrough therapy’ designation. This means the FDA believes psilocybin therapy may be substantially better than other available therapies for treatment-resistant depression, and will try to help expedite clinical research with psilocybin.


Psilocybe semilanceata, commonly known as the liberty cap, is a psilocybin or "magic" mushroom that contains the psychoactive compounds psilocybin which the body breaks down to psilocin, and the alkaloid baeocystin.

Two of the more rigorously-controlled clinical trials supporting this designation examined the effect of supervised psilocybin experiences on individuals with depression and anxiety secondary to life-threatening cancer diagnoses.  Headed by Roland Griffiths at Johns Hopkins University, and Stephen Ross at New York University, these studies report rapid and sustained reductions in depression and anxiety. The subjects enrolled were randomly assigned to different conditions: psilocybin or placebo. Placebo conditions consisted of a low dose of psilocybin or niacin, which produces flushing. Both studies blinded the supervisors and the subjects: neither were sure what dose of psilocybin had been given, if any. Both groups found that for 60-80% of subjects, six months after a high dose experience, there had been a 50% or greater reduction in symptoms. Over 60% of these individuals met criteria for the remission of their depression.

Nevertheless, we have a poor understanding of what psilocybin, and psychedelics more generally, do to the brain to produce these effects. The word psychedelic is derived from the ancient Greek words psyche (meaning mind or soul) and dêlos (to reveal or make manifest), but the same drugs are also referred to as psychotomimetics (mimicking psychosis) and hallucinogens (generating hallucinations). These terms reflect different truths about this class of chemicals, which this year has been described in yet another way: as ‘psychoplastogens’ (making the mind malleable).

Psychedelics promote the growth of neural connections

This new term was introduced by Calvin Ly and David Olson at the Centre for Neuroscience at the University of California, Davis (UCSD), and it heralds a step forward in our understanding of the effect of drugs like psilocybin on the brain. These scientists bathed cultured rat neurons in a range of psychedelic chemicals including one called dimethyltryptamine (or DMT). This molecule is structurally similar to psilocybin, and is itself the psychedelic ingredient in the Amazonian brew ayahuasca, a word meaning ‘vine of the soul’ or ‘vine of the dead’. Both psilocybin and DMT are serotonergic psychedelics, which (like lysergic acid diethylamide, or LSD) exert their psychological effects through the serotonin 2A receptor.

After being bathed in DMT, the cultured cells in the experiment showed an increase in the number of nerve cell branches (dendrites), and connections (synapses) with other cells. The same was observed in neurons in the prefrontal cortex (PFC) of rats given either DMT or the anaesthetic ketamine. Lower numbers of dendrites and synapses in the prefrontal cortex are a hallmark of depression. Low doses of ketamine have also recently been shown to rapidly alleviate severe depression for up to two weeks. In fact, the authors were able to show that both drugs exert their effects through similar cellular signalling pathways. The effect of either drug on cell growth could be eliminated by blocking the action of brain-derived neurotrophic factor (BDNF), or another signalling protein called mTOR which is part of the same pathway but downstream of BDNF. Together these results suggest that the psychedelic drugs exert their these effects by upregulating BDNF signals in relevant parts of the brain.


Skeletal formulae showing the conformations of the (R)- and (S)-enantiomers of the ketamine molecule, C13H16ClNO

While this sounds promising, the authors do caution that there are drawbacks to the clinical use of both ketamine and psilocybin. Ketamine is known to be addictive, and while this cannot be said of serotonergic psychedelics, their psychological effects are confronting and sometimes disturbing.  For example, Christopher Timmermann, Robin Carhart-Harris and their colleagues at Imperial College in London found that intense psychedelic experiences bear striking resemblance to 'near-death experiences'. People reporting the former score highly on the same questionnaire used to measure the latter. The scientists at UCSD suggest that safer, structurally similar chemicals, with the same long-lasting antidepressant effects, might be developed in future.

Clinical effects of the psychedelic experience

Curiously, the psilocybin-assisted psychotherapy conducted with cancer-patients, along with open-label clinical research into its application for treatment-resistant depression and smoking cessation, seems to have cast doubt on this hope. These studies all report clinical effects that are dependent on the nature of the psychedelic experience reported. High doses have been shown to reliably produce ‘mystical-type experiences’ in a controlled environment. This is quantified using the reports of participants in a questionnaire that is based on historically recurring themes in such experiences. These themes are feelings of unity with the universe, a sense of sacredness and positive mood, a sense of transcending time and space, a sense of encountering fundamental reality and a feeling that the experience cannot be expressed in words (ineffability).

On the other hand, Roland Griffiths and his colleagues found that, five weeks after receiving a high dose of psilocybin, participants scoring higher on this questionnaire also scored lower on the hospital anxiety and depression scale (HADS), regardless of the self-rated intensity of the experience (responses on the hallucinogen rating scale, or HRS). The same pattern was found in the cancer study at NYU using both the HADS, and other measures of depression and anxiety. These findings are also consistent with two other small ‘open-label’ trials; those in which the participants know when they are to be given the psilocybin. A first trial into the effectiveness of this therapy for treatment-resistant depression found that participants describing their experiences more in terms of ‘Oceanic Boundlessness’ had greater symptom reductions five weeks later. In another trial for smoking-cessation, smokers scoring highly on the mystical experience questionnaire were more likely to remain abstinent six months after a high dose session, with abstinence being verified biologically.

The importance of a cultural container

These preliminary studies are small, they involve self-selected and highly-screened participants, they are conducted by only a few research groups and those with an open-label design cannot rigorously distinguish between the effect of psilocybin and participant expectation. In spite of its limitations, the research so far suggests the psychedelic experience may not be separable from its clinical effects. If this is the case, it highlights the care with which any effort to integrate it into society must proceed. The psychedelic experience is still considered a model for psychosis, and not without reason. The networks of cells in the brain supporting internally and externally directed attention tend not to operate simultaneously. In people under the influence of psilocybin or suffering from psychosis, these networks operate more synchronously. This would seem to parallel the subjective reports in the clinical trials of feeling unity with the universe. Indeed, “altered ego boundaries” are a common feature of early psychosis.  Additionally, the intense psychedelic experiences reported in the scientific literature are sometimes described in terms of 'ego dissolution' instead of mystical language.  For fear of provoking psychosis in those predisposed to it, current clinical research screens out at-risk populations: people with schizophrenia and bipolar disorder, and their first-degree relatives, for instance. This elimination of ego boundaries also appears to produce personality change in adults lasting at least a year. Specifically, it appears to increase subjects’ scores on the personality trait of ‘openness to experience’. An epidemiological analysis of 654 Australian secondary school students found that this trait is associated with persecutory ideas (i.e. paranoia) and magical thinking. Having said that, it is also associated with aesthetic appreciation, imagination and creativity. In short, psychedelic drugs appear to open the mind to good and bad ideas.


According to the World Health Organisation there are over 300 million people with depression globally. If the clinical effects of psilocybin therapy are replicated in larger clinical trials, meeting the increased demand responsibly may be a challenge. For instance, psychedelic use in supervised groups the way ayahuasca is used in Colombia and Peru may be more practical than providing individual therapy sessions. However, this would necessarily reduce the amount of attention paid and care provided to each person. The ayahuasca tourism industry specifically highlights the dangers posed by insufficient regulation. For example, without proper screening and supervision, psychedelic experiences can precipitate psychotic episodes with tragic consequences. Unais Gomes allegedly became homicidal after drinking ayahuasca and was killed by his friend Joshua Stevens in self-defence at a retreat in Peru in 2015.


Shamanic art

Psychedelic drugs also make people suggestible and vulnerable to abuse.  While researching shamanism in the Amazon, Harvard Divinity School student Lily Ross was repeatedly raped by a shaman who kept her under the influence ofcontaining scopolamine. If the psychedelic experience becomes part of the psychiatric toolkit, the right kind of screening, supervision, support and guidance will be necessary in order to maximise the benefits of their administration and minimise the risks. Clinical research involving psilocybin has so far involved monitors (often clinical psychologists) being present while subjects are under the influence of psilocybin to provide support. These monitors are also usually present before and after the experience to prepare subjects and then help them make sense of it. The care demonstrated in this research is reassuring. However, larger rigorous clinical trials into the safety and efficacy of psychedelic therapy are needed to clarify under what circumstances, if any, it is an appropriate intervention. 

In summary, it appears that serotonergic psychedelics could help people overcome end-of-life anxiety, depression and addictions. The blurring of conceptual boundaries, particularly between self and other, may be an important factor predicting positive clinical outcomes. That said, we owe our sanity, morality and humanity to conceptual boundaries as well.  It seems prudent to begin thinking about how the promising field of psychedelic medicine might ultimately be integrated into modern secular societies. I for one will continue to watch this space with interest and apprehension...



In this work it's vitally important that we not be reductionist in our approach. We are more than our neurons (brains) and until we start taking this "more than" seriously, we are participating in the same unhelpful reductionism that got us into the mess we're in now. Here's an article that brings together a few different perspectives (neurobiology, psychology, spirituality) to paint a more complete understanding of how and why these substances help us in our deep healing. What you'll read is that uncomfortable, challenging, and even scary experiences are a necessary part of the healing process...not something to be avoided by the development of "safer medicines."

Remember that brains are wonderful, almost inconceivably complex organs and they are teaching us new things about ourselves every year!  I hasten to add that understanding ourselves in terms of brain structure and function gives us more reasons to feel connected to each other and the world.

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