Psychedelic Hallucinogens as Antidepressants

Hallucinogens (also known as Psychedelics) have been part of spiritual and healing practices for centuries. Still, the controversy surrounding their potential medical benefits led to their disuse by the mid-20th century, mainly without evidence of harm or toxicity despite data suggesting therapeutic uses. Social and political considerations were blamed for the criminalization of hallucinogens despite the plethora of scientific research, with the social unrest of the ’60s playing a pivotal role.

Why Do People Use Psychedelics for Depression

Classical antidepressants can take weeks to take effect with only 30-40% effectiveness, while hallucinogens may have immediate results that are sustainable over time, as evidenced by six-month follow-ups post-treatment that show continued antidepressant benefits for many psychedelics. Plus, traditional antidepressants do not offer the life-changing experiences that the psychedelic “high” often brings. Hallucinogens may be faster, safer, and more effective than classical antidepressants. Hallucinogens and psychedelics are considered the same entity.

Overview of the Neurobiology of Depression

Not to shortchange this critical component of work by condensing the theories of the neurobiology of depression into a few paragraphs, but a cursory review can be beneficial in understanding how hallucinogens and psychedelics affect depression.

Neurotransmitters in Depression

While the origin of depression is far more complex than just the role that neurotransmitters play, they do constitute a key role in its beginning and progression. Neurotransmitters such as dopamine, norepinephrine, glutamate, and serotonin are chemical messengers that carry information across the brain by communicating through neuronal synapses or chemical channels between neurons.

How Do Neurotransmitters Work?

Classical antidepressants work by regulating these monoamine (neurotransmitters) chemicals and increasing their levels. Research has shown that those with a major depressive disorder or MDD have a higher level of an enzyme that clears neurotransmitters from the brain called monoamine oxidase. While monoamine oxidase inhibitors are rarely used anymore as antidepressants due to their side effects, classical antidepressants work by other metabolic channels to increase serotonin, norepinephrine, dopamine, or a combination thereof.

Often, they work by preventing the reuptake of these neurotransmitters, causing them to stay active in the brain’s communication system for a more extended time. Some of the commonly prescribed antidepressants are called reuptake inhibitors. Reuptake inhibitors have been shown to increase brain-derived neurotrophic factor (BDNF) involved in plasticity.

Many hallucinogens work by increasing the activity at serotonin (5-HT) receptors. While this is a common trend for hallucinogens, this is not their only mechanism of action. Ketamine works differently by decreasing activity at the N-methyl-d-aspartate (NMDA) receptor level, decreasing amounts of the neurotransmitter glutamate.

The Role of Plasticity in Depression

Plasticity is the ability of the brain to rewire itself, to form new connections in the way messages are transferred by neurotransmitters. Without this ability, the brain would not develop properly or recover from trauma experienced from birth to adulthood. This role is true for animals as well as humans.

The establishment of healthy transmission of information in the brain depends on the plasticity of neural networks. Neuroplasticity is a general term that “encompasses molecular, cellular, electrophysiological, structural, functional, and psychological alterations occurring in the brain. “

According to Artin et al. in a 2021 research study, neurotrophic factors play an important role in neuroplasticity. Neurotrophic factors are molecules that support the growth, survival, differentiation, and synaptic plasticity of neurons. Brain-derived neurotrophic factor (BDNF) is the primary messenger molecule involved in most forms of neuronal plasticity.

What Affects Plasticity in the Brain?

This same research further states that atrophy and synapse loss, and loss of volume in brain structures affect plasticity and are present in MDD. Other changes include an increase in the level of the stress hormone cortisone, anti-inflammatory cytokines, and impaired communication between different structures in the brain. The role of the hippocampus and amygdala are essential, as is the communication between the other organ structures of the brain.

The maladaptive nature of the hypofunction of some organs and hyperfunction of others are present in depression and impair neuroplasticity.

In their 2021 research, Artin et al. state that hallucinogenics may result in rapid brain plasticity. Ketamine, for example, has long been shown to increase cortical excitability, which promotes vivid mental imagery. The cerebral cortex is the outer shell of the brain structure.

Despite this explanation, the monoamine theory and plasticity theory are still only attempts at explaining the mechanisms involved in depression. These theories are an ongoing area of research.

Psychologists and psychiatrists are key clinicians in this research agenda and are pushing for change in the laws and expansion of hallucinogenic research. Without these clinicians, the research would stall, and users would continue to experiment on their own, leading to potential side effects and possible loss of effectiveness. The use of hallucinogens can precipitate psychotic episodes, and clinicians must take care to choose the appropriate patients for this type of therapy, something psychologists and psychiatrists are closely involved in selecting.

 The Psychedelic Experience

Not too many clinicians document this in the research. Still, the mystical experiences that people have in their psychedelic, life-changing experiences while on hallucinogens cause a long-lasting shift in perception and behavior as a result. Psychedelics open people up to suggestibility or new ways of thinking and feeling.

Activation at the serotonin receptor seems to influence “existential concepts of self, including moral values, self-identity, and purpose.” It brightens the mood and makes people more receptive to change.

How Do Hallucinogens Affect Depression?

Depending on the individual taking the drug, the setting with which the drug is administered, the expectations associated with the experience, and the drug dose, the user may feel any number of perception-altering states. Any of the following mechanisms may bring on these experiences:

The Fear Center

We know from research that psilocybin exerts its effects by increasing activity in the amygdala, the brain area that processes fear, and the “fight or flight” syndrome. This activation decreases the tendency of the depressed individual to ruminate over negative thoughts again and again. It breaks the cycle of negative communication, which may explain some of the therapeutic potentials of this drug. Increased activity in the amygdala allows people to work through difficult emotions cutting the negative thought pattern loop and increasing activity in the emotional regions.

Neurotransmitter Activity

Just about all of the hallucinogens operate by increasing the activity at the serotonin receptors. DMT is a neurotransmitter of its own accord. Disorders in glutamate transmission occur in depression and can be corrected by hallucinogens. Depression is a disorder of communication in the brain, and neurotransmitters are chemical messengers. Hallucinogens change the action of these neurotransmitters at the receptor level, causing an increase or decrease in targeted messenger molecules.

What Hallucinogens Are Used to Treat Depression?

An advantage to using hallucinogens instead of antidepressants to treat depression is that the onset to the relief of symptoms is hours instead of weeks. The sustainability of the treatment is high, with many users reporting life-changing events in their psychedelic experiences that have changed them forever. Some of the hallucinogenic drugs used to treat depression include the following:

Psilocybin

High doses of psilocybin (22/30 mg/70 kg in two dose sessions) given to depressed patients with a life-threatening disease showed that it produced large and significant decreases in scores related to depression. The study group showed sustained scores at a six-month follow-up proving the long-term usefulness of psilocybin therapy.

A clinical trial in 2021 showed no difference in effectiveness for the treatment of depression with psilocybin vs. Escitalopram for relief of depression. The other side of the coin is psilocybin is as effective as classical antidepressants, with psilocybin being favored over Escitalopram for secondary outcomes.

Another 2021 randomized clinical trial found psilocybin to produce rapid and sustainable relief of MDD (major depressive disorder), proposing that psilocybin has a broader audience for use than just for those with a life-threatening illness.

Ketamine

There are two forms of ketamine, the kind used in IVs for release into the bloodstream called racemic ketamine and the kind used for nasal inhalants called Esketamine. So far, most of the research has been done on the IV form.

Mechanism of Action for Ketamine

One mechanism of action proposed for ketamine is blockage of the NMDA receptors involved in glutamate transmission and activation of other receptors that allow the brain to communicate better. More recent research suggests that the mechanism is not solely the NMDA receptors but rather ketamine’s action on the brain’s plasticity. Although the mechanism is only partially understood, it is thought that ketamine induces transient structural plasticity induced by a glutamate burst.

Approval of Esketamine for Depression

On March 5, 2019, FDA approved the drug Esketamine for nasal inhalant treatment of MDD. The spray is administered in the clinician’s office and cannot be taken home. Stravato, the brand name for Esketamine, showed significant reductions in MDD, and this effect was noticed within two days of administration of the drug. Esketamine is legal in the UK.

Ketamine Clinics

Today, ketamine clinics exist throughout the United States. Infusions are given for MDD and other medical conditions. People usually respond to it in one to three infusions.

A UK clinic opened its first ketamine-assisted psychotherapy clinic for depression in March of 2021 in Bristol. This clinic will use a dose of 100 mg ketamine to treat patients’ depression in conjunction with psychotherapy. Ketamine has been trialed since 2011 by psychotherapists in the UK to treat MDD and other depressive disorders, but not necessarily in conjunction with psychotherapy.

MDMA

Only one rodent and one volunteer study identify MDMA as a treatment for unipolar depression. Long-term use of MDMA can cause depression, so its use in its treatment is not a common occurrence.

MDMA Mechanism of Action

MDMA can operate as a rapid-onset antidepressant via its effect on the 5-HT system and its release of norepinephrine and dopamine. It also improves communication between the hippocampus and amygdala. This effect wears off quickly, with a reversal of the impact within weeks.

MDMA in Treatment of Depression

In a small study of MDMA-assisted psychotherapy, a decrease in measures of depression was found in the treatment group. Still, outliers confounded the results, and the conclusion was that a trial with a larger sample size was needed to tease out the effects of therapy.

MDMA is currently being used in Switzerland to treat depression with the same results as in similar studies with research subjects with regards to remission of depression.

LSD

The 1950s-1970s saw a surge in LSD research on the remission of psychiatric symptoms of various disorders. Effects on the serotonin, norepinephrine and dopamine systems have been observed. LSD was outlawed in 1968 despite promising research.

2020 review of LSD studies found that the research was fraught with methodological errors that made it difficult to come to valid conclusions despite the plethora of research. Dosages ranged from 20-800 mg in the studies reviewed. In one such review, a significant increase in health parameters was observed in subjects. In another study, significant improvements were noted in symptoms of depression and feelings of “self-actualization” with the use of LSD. But, methodological errors clouded the perceptions of the findings.

Studies from the 1960s indicated that LSD made dying patients more responsive to their families and enhanced their everyday life.

Researchers in a University Hospital in Switzerland are attempting to explore the effects of LSD on depression, with results anticipated in 2023. Downsides to LSD include the long time that patients under the influence of the drug need to be monitored, usually 6-16 hours, for side effects including perceptual disturbances, anxiety, and even depression.

DMT

DMT is found in many plants and is a neurotransmitter produced by the pineal gland in the brain of humans and animals. It is also one of the active ingredients in ayahuasca, a bitter drink taken in shamanistic rituals in North America and elsewhere. DMT is available as a street drug in the UK and the US. It is fondly called “the spirit molecule” due to its ability to produce “near-death” experiences.

DMT is scheduled to be trialed in the UK in 2021 to treat depression in conjunction with psychotherapy. The trial will run with 36 patients who have clinical depression. The patients will undergo a “setting” session, during which time the therapist instructs the patient to open their mind to the drug. Once the psychedelic experience ends, they immediately take part in psychotherapy.

In another study, Ly et al. demonstrated that LSD and DMT both stimulated neuronal and synapse growth in the brain, enhancing neural plasticity and proving their usefulness in treating depressive symptoms. Although these studies were carried out in vertebrates and invertebrates, the results are expected to extend to humans.

In a survey of 362 people who used DMT, 80% reported an improvement in depressive symptoms. These effects were attributed to a profound mystical experience while on the drug, giving users an increased sense of spiritual significance and personal worth. DMT can enhance awareness and facilitate the release from negative memories, similar to effects seen with LSD.

Conclusions

Hallucinogens have a long history of being used for healing and in spiritual rituals. The act of criminalizing hallucinogens was hasty and poorly thought out. It interrupted necessary research into the use of some crucial chemicals in the health and well-being of our population, particularly the depressed. Unadulterated psychedelics are mostly physiologically safe and do not generally lead to dependence or addiction. To ignore the benefits of hallucinogens in the treatment of depression negates the healing power of the psychedelic experience, something classical antidepressants cannot duplicate.