Depression, despite affecting millions worldwide, is still a condition that we don’t fully understand.

In fact, we understand it so poorly that typical pharmaceutical treatments indiscriminately target whole neurochemical systems, resulting in unstable effectiveness and a host of side-effects.

Up to 44% of people suffering from depression have not found relief from typical antidepressant therapies. Even patients who find some form of relief from the usual prescribed antidepressants need frequent doses, sometimes causing unpleasant side-effects, and these drugs often lose their effectiveness after several years of treatment.

But where pharmaceuticals are failing, psychedelics could be a new hope.

Psilocybin Mushrooms and Depression

Recent large studies, using psychedelics such as psilocybin mushrooms, have shown that a single moderate dose of these substances can significantly reduce depression scores in patients with treatment-resistant depression. The antidepressant effect of psychedelics also last much longer than typical treatments, with reduced depression scores maintained for several months after treatment.

A big part of the reason that psychedelics appear to be so effective at treating depression is due to their ability to induce a ‘mystical’ experience. Participants who describe a highly spiritual or personally meaningful experience with psilocybin were more likely to have reductions in depression scores, according to one study – and the strength of the mystical experience has also been directly linked to psychedelics’ anti-addiction effects.

It appears that there’s something special about having a transcendental encounter during treatment. Linking this powerful effect of psychedelics to their mechanisms of action in the brain is helping scientists start to piece together the way that depression works, and potentially the best ways of treating it.

A recent review, from psychedelic icons Dr Robin Carhart-Harris and Professor David Nutt, presents a new, all-encompassing model of depression, that explains how both typical antidepressants and psychedelic therapies could help treat depression in different way.

Psychedelics and Stress

Their ‘bipartite’ model of serotonin signalling proposes that depression can be most effectively treated through two receptor systems – the 5-HT1A and the 5-HT2A receptors.


The authors’ theory is that the 5-HT1A system of the brain is generally in charge of regulating anxiety during normal consciousness. This is the receptor system that typical SSRI medications work through – reducing levels of anxiety directly.

This is the system that deals with “passive coping.”

However, when people start to experience abnormally high levels of stress (such as in cases of severe depression), the brain’s 5-HT2A system takes over, and starts to change the receptivity of the brain. In other words, it makes the brain more flexible to change, and makes us more sensitive to the environment.

This is the system that deals with “active coping.”

This is the receptor system that psychedelics activate – and it explains a lot about their effects.

The activation of the 5-HT2A system can backfire – if we’re in a highly dangerous or stressful environment, while also suffering the stress-inducing effects of severe depression, the activation of the 5-HT2A system can amplify our anxiety and make things worse. This explains why people can have traumatic psychedelic experiences if they’re not in the right setting, or receiving the proper guidance.

However, activation of 5-HT2A receptors can also produce the most significant changes in people’s cognition, helping them address serious problems in their life in a unique form of self-therapy. This has been observed in participants of clinical trials into the effectiveness of psychedelic therapy, who report the most significant benefits after experiencing major personality changes.

The overall theory, state the authors of the review, is that the brain has two mechanisms in reacting to depression. Firstly, the brain’s 5-HT1A system tries to address feelings of anxiety. When this becomes too much, and the brain faces too much stress, the 5-HT2A system takes over, and tries to change the way the brain responds to the world in a more dramatic way.

Therefore, the ideal therapy for depression could be a combination of 5-HT1A activation (to help people cope with anxiety as a first defence), followed by 5-HT2A activation (to help people adapt and heal).


It’s important to know that this is still just a theory. The authors acknowledge that this is an oversimplification of one of the most complicated neurotransmitter systems in the brain, and that the evidence isn’t yet complete. But this is arguably the most coherent model of depression that has been put forward so far.

So what does this mean for our use of psychedelics?

Although this ‘bipartite’ theory of depression highlights how typical antidepressants may work, it also shows that the most important treatment of depression lies through the 5-HT2A receptor system. And psychedelics activate this receptor system with inscrutable precision.

However, the review also highlights the immense importance of environment and context during a psychedelic experience. Because psychedelics increase cognitive flexibility, and make us more sensitive to external stimuli, their therapeutic benefit relies heavily on the way in which they’re administered.

So before people dive in and take a big dose of shrooms to self-treat their depression, they should consider why they’re doing so, and whether they’re doing it in an optimal environment. People should never take psychedelics in vulnerable situations, unfamiliar locations, or without sober people they trust to guide and look after them.

Ideally, psychedelic therapy will always be administered by professionals. However, until an accessible and affordable framework for psychedelic therapy is created, people should educate themselves about responsible use. Resources like those provided by The Third Wave help people learn about safe and effective psychedelic journeying; including an extensive microdosing course for those not ready to jump into the deep end of psychedelic healing.

The Future of Psychedelics

We’re living in a special time… science is starting to provide us with evidence that an holistic approach to mental health is within our grasp. We’re starting to understand the power of mystical and transformative personal experiences – and scientific advancements will help us marry the worlds of transpersonal psychology and modern psychiatry.

Psychedelics could be the catalyst for a theory of depression that treats patients as minds rather than objects; as people rather than malfunctioning machines.

Here’s to a humane, holistic, psychedelic future.