Psychedelic therapy to treat depression

Early clinical trials show that psychedelic compounds treat depression up to 4 times more effectively than the usual antidepressants. The data is preliminary, but the research is being done qualitatively and is receiving more and more attention from doctors and scientists. Not to mention, the effectiveness of psychedelics suggests that more than 50 years of depression treatment has been based on false assumptions. LSD, Psilocybin, or DMT do not directly affect serotonin levels in the brain.

Due to their molecular similarity to serotonin, these substances bind to its receptors, causing severely altered states of consciousness, which are sometimes not quite accurately referred to as hallucinations. SSRi antidepressants work differently: they trap serotonin molecules in the synaptic clefts, and thus stimulate neuronal activity. One feature of antidepressant action has always contradicted the hypothesis of chemical imbalance: antidepressants do not reduce the symptoms of depression immediately, improvement is delayed for several months. If depression is really caused only by a lack of serotonin, thanks to SSRi, changes in well-being should be felt immediately. According to clinical trials, psychedelics cause positive changes in psychological parameters immediately after the end of their acute hallucinogenic effects.

What does this say about the origins of depression and the effects of these related but very different compounds? Recent studies suggest that depression is a more neurological disease associated with monoamine neurotransmitters, hypothalamic-pituitary-adrenal axis, epigenetic factors, neuroplasticity, and inflammation. In other words, the idea that depression is caused by a lack of serotonin was an overly simplistic approach. This also explains the limited efficacy of modern antidepressants, which causes controversy in the scientific community. Changing attitudes to the causes of depression may also offer new, much more effective treatments for depression.

Causes of depression

Impairment of neural plasticity

Neuroplasticity is a relatively young field of neurology because it has long been thought that no new neurons grow in the adult brain. Neuroplasticity is the ability of the brain to change, it is divided into functional: the ability of neurons to make interconnections, and structural: the growth of new neurons. It has only recently been suggested that depression may be associated with impaired neuroplasticity.

Probably the most important feature revealed in psychedelics is the very strong promotion of functional and structural neuroplasticity. Psychedelic research has reinforced the idea that it is the promotion of structural neuroplasticity that also underlies the positive effects of conventional antidepressants. This explains why the improvement is delayed. Classical psychedelic compounds, by attaching to serotonin receptors, disrupt normal neuronal communication, suppressing and disconnecting the brain’s default mode network, while causing a storm of activity at other sites in the brain.

In a normally functioning brain, independent neural networks perform distinct specific tasks such as vision, movement, hearing, and focus. LSD breaks down barriers between these neural networks and the brain becomes more integrated, unified.

In childhood, our brains are particularly plastic, but over the years they become less chaotic and more inert. LSD can temporarily bring back our infancy. Classical psychedelics dramatically increase brain plasticity and facilitate the construction of new neural networks. One of the best-known rules of neuroplasticity: neurons that fire together, wire together.

According to recent research, depression may be a sign of impaired neuroplasticity.

Epigenetic causes

Epigenetics explains the influence of the environment on gene expression. The researchers were very surprised to find out that our DNA consists of only about 20,000 genes encoded by proteins. Fly’s DNA has about 15,000 genes! Such news should make us, an advance species of mammal, feel a little more humble. A whole new field of science is arguing that DNA code expression can be affected by external factors as well, not just heredity.

How do psychedelics interact with epigenetics? Imagine that your genetic code, which is responsible for the development of the body, is an instruction for the production of proteins stored on a hard drive. The software code reads, modifies, and interprets that instruction according to environmental factors. Thus, different life events and environmental influences can change the way an organism interprets genetic information.

There are researchers who believe that epigenetic changes can be passed onto offspring. Such hypotheses are based on experiments with mice. A study by Brian G. Dias and Kerry J. Ressler showed that mice, frightened by a specific odor that predicted electric shocks, transmitted this fear to their children as well. Do you believe in reincarnation?

The Effects of hallucinogens on gene expression states that the sudden activation of the 5-HT2A receptor in psychedelics also affects gene expression, which affects synaptic neuroplasty and facilitates long-term brain neurochemical changes that allow therapeutic benefits to be achieved after a single big dose of psychedelics.

Recent scientific findings suggest that depression may be related to epigenetics. Traumatic life experiences affect the expression of our genome.

Inflammatory processes

Inflammation is considered to be a protective mechanism of the body against biological or physical irritation. Inflammation destroys foreign bodies and facilitates healing. This occurs when immune cells arrive at the affected sites and trigger the release of a defensive protein called a cytokine.

Researchers have found that inflammation plays an important role in depression. Experiments have shown that inflammatory cytokines in healthy animals provoke patterns of behavior close to social isolation, which is typical for depression.

Psychedelic-stimulated 5-HT2A receptor is thought to modulate inflammatory processes, leading to long-term relief of depressive symptoms.

Depression has been shown to be associated with inflammation in the brain or even the gut. Even in our stomach, there are many neuronal cells that communicate with the brain. We should consider what we put into it.


The part of the brain called the hypothalamic-pituitary-adrenal axis ensures a person’s adaptation to a new situation or stress, and at the same time keeps the body in a state of equilibrium. Its disorder leads to an inability to cope with stress and the resulting negative psychophysical consequences.

Hyperactivity and inflammation of the hypothalamic-pituitary-adrenal (HPA) axis may play an important role in depression.

Compounds that act on hormones associated with this part of the brain have shown in studies to have a positive effect in reducing the symptoms of depression.

Elevated release of the HPA axis-related stress hormone cortisol is a hallmark of major depression disorder, but there are increasing studies showing that too low levels of cortisol cause depressive symptoms such as malaise, weakness, low blood pressure, muscle weakness, and gastrointestinal problems. .

Even brief HPA axis irritation through stressful experiences can have long-term negative consequences. The neurotransmitter cortisol regulates different physiological, cognitive, and emotional networks. Studies show that regulating its levels is an important part of treating depression.

Neurotransmitter imbalance

The most well-known monoamine neurotransmitters in the human brain are: norepinephrine, dopamine, and serotonin. They are involved in teaching processes and emotion management in one way or another. There are many more neurotransmitters, and their imbalance can cause pathologies.

In contrast to antidepressants, classical psychedelics do not directly alter serotonin levels between neurons, but due to their similarity to it, bind very efficiently to the serotonin 2A receptor.

Although the effects of DMT, LSD, and Psilocybin are similar, there are slight differences between them: for example, LSD increases dopamine levels among neurons, making this compound slightly more similar in effect to MDMA and may cause greater euphoria.

An article was published in the Journal of Neuropsychopharmacology stating that psychedelic-induced changes in the levels of the neurotransmitter glutamate in the brain provoke so-called Ego dissolution associated with disconnection of the neural network in the default mode of the brain.

Research with the Functional Magnetic Resonance Imaging (fMRI) at Imperial College London have found that this network is only temporarily disconnected from other parts of the brain, and becomes more integrated with other parts of the brain, when acute effect psychedelics ends.

The brain default mode network is responsible for their activities when we are alert, but do nothing that requires concentration. It broadcasts random images of the past, familiar faces, shapes the self-perception of the personality.

In depression, this part of the brain causes a flow of negative thoughts called rumination. The potential therapeutic effect of psychedelics is related to the reprogramming of the default mode network.


The human brain functions constantly, updating the pre-formed model of reality with the help of the sensory input. This is called bottom-up information flow. The Top: are the most abstract patterns of reality in our consciousness and subconscious, for which the most recently developed parts of the brain are responsible. The bottom is the limbic system, the senses, whose information is processed at the lowest level of the hierarchy by the oldest parts of the brain.

In a depressed state, the renewal of the reality model is disrupted, and even positive stimuli do not replace it. The brain, guided by an abstract, non-renewable, erroneous subconscious model of reality, uses the network of background activity of the brain to transmit to the consciousness negative thoughts that affect behavior. A vicious circle emerges where information traveling from the bottom up is filtered so that the positives do not update the false pattern of reality, but the negatives reinforce it. Then negative and destructive imperatives begin to travel downward, ultimately negatively affecting our behavior.

Psychedelics with their multiple modes of action disrupt the negative thought patterns and help to renew the reality model of our brains.

Current status of psychedelics in the depression treatment


Psychedelic therapy is a much more comprehensive treatment package than current approaches. It entails a small number of psychologically supported dosing sessions, flanked by assessment, preparation, and psychological integration. There are ongoing Phase II-III double-blind clinical trials in depression treatment with psilocybin. The pilot studies show very high efficacy in treating treatment-resistant depression.

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