Medicine For the Mind: Psychedelics For Depression & Mental Illness

How a new era of psychedelic medicine is challenging the conventional model of depression (for the better). 🍄🌈

Tripsitter

and

Justin Cooke 🍄

Sep 24, 2024

The current model for treating depression is broken.

Depression levels continue to rise despite decades of antidepressant drug development. They reached an all-time high in 2021, and today, the WHO estimates around 5% of the global population suffers from depression.

New research in the field of psychedelic medicine suggests we’re looking at it all wrong — that depression isn’t merely a ‘dysfunction’ of the brain but something else buried deep within the psyche.

Here, we’ll explore what makes psychedelics so powerful for treating depression and how they’re changing our fundamental understanding of what causes this debilitating condition.

I initially wrote this post in 2021, but this area of research has evolved significantly over the past 3 years. This post has been updated to reflect these recent discoveries.

7 Ways Psychedelics May Help Treat Depression

Psychedelics themselves don’t cure depression. The real cure comes from the deep, personal insights gained during the experience.

These insights change our unconscious thought patterns, which permeate into higher cognitive centers and alter our brain chemistry.

This explains why psychedelics are so effective at treating depression after just a single session — compared to the weeks, months, or years needed with chemical antidepressants.

Treating depression requires a fundamental shift in ontology rather than a simulated emotional buttress administered through antidepressant drugs.

Here are seven leading theories and their associated research about how psychedelics work for depression. We’ll explore both internal (chemical) and external (metaphysical) mechanisms.

1. Neurochemical Changes & Neuroplasticity

Neuroplasticity is a measurement of a neuron’s capacity to grow and form new connections. It’s relevant in the discussion of depression because a disruption in neuroplasticity is believed to be a key factor in the underlying mechanisms of depressive disorders.

Many of the factors that contribute to the pathophysiology of depression also disrupt neuroplasticity — such as traumatic events, brain damage, sleep deficiency, neurodegenerative disorders, and chronic stress.

Depression is also believed to be either caused by or exacerbated by a maladaptive neuroplastic response. Psychedelics are believed to facilitate a corrective response to neuroplasticity deficits.

Classical psychedelics like LSD, magic mushrooms, and DMT have all been shown to increase neuroplasticity in the brain. These effects work through a variety of pathways, including the sigma-1 receptors, 5HT2A receptors, AMPA receptors, TrkB receptors, and BDNF.

With drugs like ketamine, the NMDA receptors and mTOR are considered critical components of the neuroplastic response.

Enhancing neuroplastic responses creates the conditions for the neural circuits to be remapped and repaired.

Even conventional SSRI antidepressant medications were recently suggested to work by enhancing neuroplasticity in the brain rather than relying solely on increasing synaptic serotonin levels, as previously thought.

2. The Default Mode Network (DMN)

The default mode network (DMN) is one of seven large-scale brain networks responsible for regulating higher cognitive functions.

Other examples include the visual network (responsible for processing visual information), the limbic network (regulates emotions and memory), the salience network (helps us prioritize important stimuli), and the ventral attention network (detects unexpected stimuli).

The default mode network is the ringleader of the group and is tasked with keeping the rest in line. It’s also responsible for controlling our abstract thoughts, rumination, theory of mind, remembering the past, projecting the future, and defining our understanding of the “self.”

The latter point has led many people to view the DMN as the “physical location of the ego.”

The actions of the DMN provide us with a key advantage over other animals. It allows us to carry out complex tasks and apply abstract concepts, such as reflecting on past events and anticipating future outcomes.

With that said excessive DMN activity can also lead to cognitive rigidity — which is now considered one of the primary causes of depression.

Too much rigidity in our thought processes can lead to a closed and biased perspective of the world. We're less able to move beyond our fixed assumptions and beliefs to adapt to new experiences or perspectives. Rumination, learned helplessness, thought loops, and confirmation cognitive bias are direct byproducts of this.

An online survey from 2021 examined how psychedelics alter thought patterns and what impact these changes had on depression, anxiety, and stress. Researchers noted a significant decrease in rumination patterns and an increase in self-reflection and compassion following the psychedelic experience.

I feel it's important to make a distinction between rumination and self-reflection:

Rumination refers to negative and repetitive self-focus motivated by the perception of threats, self-harm, and injustice. Self-rumination has a high correlation with depression.
Self-reflection refers to the process of observing and evaluating one’s internal emotional, behavioral, and cognitive processes. Self-reflection has a high correlation with contentment and well-being.

People who spend more time self-ruminating over past events, perceived inadequacies, or unrealistic desires experience a snowball effect, which can lead to a lack of sleep, social isolation, missed opportunities, poor diet, and lifestyle habits, or the development of an obsession, fixation, or addiction as a source of distraction.

Likewise, if we spend more time in self-reflection, the snowball rolls in the other direction — leading to higher energy levels, increased sociability, maintenance of healthy habits, and a greater sense of happiness and contention.

Classical psychedelics (LSD, DMT, or psilocybin) temporarily suppress the default mode network. Research suggests that after the effects of psychedelics wear off and the DMN comes back online, it behaves differently than it did prior to taking psychedelics. Physical changes in blood flow and functional connectivity are well documented following treatments with both LSD and psilocybin.

Psychedelics appear to facilitate a hard reset of our default mode network — ultimately relinquishing some of its control over the other brain networks and allowing more flexibility in our thoughts.

Comparing Neural Connectivity With Placebo (A) vs. Psilocybin (B). **Source:** Petri et al., 2014

3. The Mystical Experience & Ontological Shock

Mystical or “peak” experiences are characterized by feelings of deep spiritual, existential, transformative, and transpersonal awareness.

These experiences yield new insights that foster a shift in one’s ontological position of the world (how one perceives existence).

Studies have shown that up to 86% of people who have used psychedelics in a therapeutic setting claim the experience to be within the top five most meaningful experiences of their lifetime.

Common themes of mystical experiences include:

Encounters with “supernatural” beings
Comprehension of spacial and temporal vastness
Experiences of an “ultimate reality”
A sense that all things are connected (unitive experience, non-dual states)

The nature of mystical experiences is hard to define because they’re inherently ineffable — meaning they’re far too abstract to put into words.

Mystical experiences often lead people to discover some sort of deep truth about themselves and the mental blocks or conditioning that put pressure on their ability to feel happy.

These insights are often overlooked by researchers because they’re nearly impossible to quantify — yet they remain one of, if not THE most powerful catalysts for initiating lasting change from within.

When we talk about the importance of integration and reflection after taking psychedelics — much of what we’re referring to is a gradual deconstruction, organization, and processing of these profound insights.

4. Spotting Unconscious Influences (The Shadow)

Psychedelics are a valuable tool for uncovering traits we deem “undesirable” about ourselves — and how our attempts to suppress them only make their influence stronger.

This is the fundamental principle behind a form of therapy called shadow work — which seeks to reintegrate ‘negative’ traits such as grief or fear that reside in our unconscious mind. This includes traits we either don’t like about ourselves or believe others in society won’t like. Other examples include lust, rage, sexual orientation, or jealousy.

The idea is that the more we deny and suppress these traits (all of which are completely natural and out of our control), the stronger they become.

When talking about depression, grief is one of the main traits to consider. Grief is an emotional, physical, and philosophical response to loss. It’s not something that can be suppressed for long.

When we try to suppress grief, we force it deeper into our unconscious mind. Since we can't get rid of grief, it simply remains out of sight in the unconscious parts of our minds. The problem is that when emotions are relegated to our unconscious, we lose the ability to recognize and understand how it manifests itself in our conscious thoughts and actions.

Acknowledging grief and other aspects of the shadow means accepting them for what they are, inviting them into the conscious sphere of awareness, and leveraging them as a strength rather than a weakness.

Here are some of the changes that can happen when we learn to integrate our shadow:

Grief facilitates connection with the self & others
Fear becomes a source of courage
Aggression becomes a source of passion
Pain becomes a lesson in perseverance & grit
Selfishness becomes a source of empathy
Lust facilitates passion, connection, & love

5. Psychedelics Temporarily Increase Suggestibility

When used in therapeutic settings, psychedelics can be useful for increasing suggestibility. They make us more receptive and engaged with the guidance a skilled therapist has to offer. This action is invaluable for breaking down the barriers that stand in the way of healing.

This phenomenon has also been reported in group sessions — a tactic often used in traditional psychedelic rituals such as those employed in a typical ayahuasca ceremony.

Of course, the ability to induce a state of heightened suggestibility is also one of the key sources of problems within the psychedelic sphere. It provides a tool for exploitation and manipulation. It’s one of the key reasons why proper vetting of facilitators and ethical safeguards is so important.

6. Changes in Cerebral Blood Flow

One of the older theories that’s been partially debunked in the last couple of years is the idea that psychedelics work by increasing blood flow to the brain.

We now know that simply increasing blood flow to the brain is not sufficient to explain their effects on depression. Instead, alterations in blood flow, as seen on fMRI scans, indicate a modulation or disruption of activity within specific brain regions.

Recent studies involving fMRI machines have proven that while some areas of the brain may experience increased blood flow after taking psychedelics, other regions demonstrate the opposite.

For example, psilocybin causes a decrease in blood flow to the amygdala and temporal cortex. The amygdala is associated with the fear response, and hyperactivity in this region is directly correlated with the development of depression. A reduction of blood flow to this region of the brain implies a suppressive action from psychedelics.

Likewise, a reduction in blood flow to the temporal cortex is thought to be directly correlated with psilocybin’s ability to suppress the default mode network — which is one of the other leading theories for how psychedelics treat depression.

7. Psychedelics Change Our Metaphysical Position

Most people hold distinct metaphysical positions even if they aren’t aware of it. These positions affect every aspect of one’s existence, including mental health, motivation, and decision-making.

Some of these belief systems limit our capacity to find meaning in life and understand the purpose and pain of existence.

Of particular importance are the positions of physicalism (materialism), idealism, and dualism:

Physicalism (materialism) — the belief that the nature of reality is purely physical, and there is nothing beyond the physical realm.
Idealism — the belief that all physical properties are derived from a non-physical (mental) reality.
Dualism — the belief that the nature of reality consists of both physical and mental influence.

A recent study found that after taking psilocybin, participants displayed a shift away from hard materialism (survey) towards more dualistic beliefs. Researchers also observed a positive correlation between non-physicalistic beliefs and a greater sense of well-being.

This was verified in another clinical trial that compared the effects of psilocybin against conventional antidepressant therapy (a 6-week course of escitalopram). The study examined the capacity of each treatment to induce positive metaphysical position changes.

In this trial, only the psilocybin group resulted in significant changes in worldview. These changes were not reported with conventional depression therapy.

Research Roundup: Psychedelics & Depression

The concept of using psychedelics for treating mental health diseases isn’t new — humans have been using these substances for thousands of years for ceremonial, spiritual, and medicinal purposes.

Unfortunately, in 1968, right when psychedelic research was reaching its peak, governments all over the world imposed sweeping bans on this research. These bans lasted 32 years before being revoked (gradually).

Today, research has picked up where researchers from decades earlier left off — and the results are forcing us to rethink everything we believed to be true about depression.

Psilocybin/Psilocin/Magic Mushrooms

So far, the results we’re seeing from psilocybin research blow everything else out of the water — with the possible exception of ketamine.

The success rates from just one session of psilocybin (when used in the proper context and with the right guidance) result in a more significant reduction of depressive symptoms than conventional antidepressant medications taken over several weeks or months.

Key Studies: Psilocybin & Psilocin For Depression

Raison et al., 2023 (RCT) — A 25 mg dose of psilocybin with therapeutic support produced a rapid and sustained antidepressant effect compared with an active placebo.
Davis et al., 2021 (RCT) — 71% of patients had a reduction in depression scores by over 50% at the 4-week follow-up. 54% were in complete remission.
Carhart-Harris et al., 2017 (Case-Control) — Decreased depressive symptoms were observed in all 19 patients.
Carhart-Harris et al., 2016 (Open-Label) — Persistent decrease in depressive symptoms and sustained improvements in anhedonia
Griffiths et al., 2016 (RCT) — Significant reduction in depression and anxiety scores after 6 months in 80% of study participants

DMT/Ayahuasca

Both ayahuasca and its active ingredient, DMT, have demonstrated similar chemical changes in the brain, and both have been successful in treatment-resistant depression.

Ayahuasca brings additional facets to the table that make it especially useful for the purposes of treating mental health thanks to the ritual associated with it (increased openness and benefits of groups) and additional ingredients (namely the harmala alkaloids).

Key Studies: DMT & Ayahuasca For Depression

Van Oorsouw K et al., 2022 (RCT) — Depression scores significantly reduced after a single ayahuasca ceremony. 71% reportedly in remission at 1-year follow-up.
Sarris J et al., 2021 (Survey) — 94% reported that their depression had improved either ‘a bit’ (15%), ‘very much’ (46%), or was ‘completely resolved’ (32%) after drinking ayahuasca.
Palhano-Fontes et al., 2019 (Meta-Analysis) — Evidence of rapid antidepressant effect after a single dosing session with ayahuasca when compared with placebo.
Davis et al., 2019 (Survey) — 80% of participants who self-reported a history of depression reported clear improvements in depression symptoms following 5-MeO-DMT use.
Palhano-Fontes et al., 2019 (RCT) — Significant reduction in depression scores in the ayahuasca group compared to the control.
Sanches et al., 2016 (Open-Label) — Significant decreases in HAM-D, MADRS, and anxious-depression BPRS subscale scores were observed from days 1–21 following treatment.
Osório et al., 2015 (Open-Label) — Reductions in depression scores up to 82% following the treatment.

Ketamine

Ketamine has been demonstrated through multiple clinical trials to produce a rapid and reliable antidepressant action. Just one 40-minute IV therapy has an average success rate of around 60%.

The only problem is that these effects tend to wear off after 7–14 days. Users need an average of around six sessions for longer-lasting results, and many still need to come back to ketamine therapy a month or two later.

It also appears that ketamine doesn't just work for depression with no other therapeutic modalities in place. A study from earlier in 2024 found ketamine had no significant impact on depression when used as surgical anesthesia.

Key Studies: Ketamine For Depression

Glue et al., 2024 (RCT) — Extended-release ketamine (R-107) significantly reduced depression scores at 180 mg compared to placebo in a phase 2 trial.
Anand et al., 2023 (RCT) — Ketamine showed a higher response rate (55.4%) than electroconvulsive therapy (ECT) (41.2%) for depression, with ECT causing more memory issues.
Lally et al., 2014 (RCT) — Rapid and significant reduction in anhedonia after a single ketamine infusion lasting up to 14 days.
Szymkowicz et al., 2013 (Open-Label) — Rapid and significant reduction in depression scores after 5 treatments.
Murrough et al., 2013 (RCT) — Rapid and significant reduction in depression scores following a single treatment (64%).
Ibrahim et al., 2012 (Open-Label) — Significant reduction in depression symptoms in 62% of participants lasting up to 4 weeks.

Key Takeaways: Can Psychedelics Help With Depression?

So far, the research backing the use of psychedelics for treating depression is promising, to say the least. There have already been several clinical studies proving these substances offer clear therapeutic benefits in ways we’re only just beginning to understand.

What makes psychedelics so useful for treating mental health disorders is their capacity to treat beyond the physical components of the brain (neurons, neurotransmitters, blood flow, etc.) and address underlying dysfunctions residing in the mind.

While the research has been promising — strong enough for the FDA to declare compounds like psilocybin a “breakthrough therapy” — we still have a long way to go, and there’s plenty we still don’t understand.

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