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Ketamine, MDMA, DMT and Psilocybin:

A Closer Look at Four Psychedelics
Ruairi J Mackenzie

Ketamine, MDMA, DMT and psilocybin. These four psychedelic substances are making waves
in psychiatric medicine. While they are all banned or restricted in the industrialized west,
these compounds have moved past decades of stigma to become well-studied therapeutics
either approved or in trial to treat mental health conditions such as major depression and
post-traumatic stress disorder.

Hundreds of millions of people worldwide are affected by these conditions. And currently
available therapies prove ineffective for a substantial proportion of patients. There is a great
need for a new class of drug for these disorders and well over a hundred clinical trials
investigating psychedelic compounds are underway worldwide. Here, we examine these
psychedelics’ backgrounds, their properties and the conditions they could potentially treat.

Ketamine
This synthetic psychedelic was first developed in the 1960s and has, unlike the other
compounds on our list, been legally available, under restriction, as a medication ever since.
While its most common use has been as an animal tranquilizer, it has also been an FDA-
approved human anesthetic since 1970. Ketamine is thought to primarily achieve its action
by blocking signals through a type of receptor in the brain and spinal cord called the NMDA
receptor. By blocking these receptors, ketamine induces pain relief, or analgesia, in low
doses, and full sedation at higher doses.

As a recognized medication, it faces far fewer legal blocks than some of the other drugs on
our list, and it is little surprise that means there are more ongoing trials for ketamine than
for any other psychedelic drug, with over 100 appearing on the EU Clinical Trials Register
alone.

Ketamine has recently been developed as an antidepressant, as it can produce a fast-acting,

medium-term improvement in depressive symptoms. The mechanism of action that leads to
this effect is unclear – different theories suggest glutamatergic, dopaminergic or even opioid
signaling pathways are involved.

Ketamine is, chemically, a mixture of two distinct molecules that are mirror image flips
of each other. This is called a racemic mixture. The two configurations, arketamine and
esketamine, have slightly different effects on the brain and body.

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Esketamine has, so far, been the more well-studied molecule, having received FDA and
European Medicines Agency approval in 2019 for treatment-resistant depression. It is now
available in the US under the commercial name Spravato® where it is sold by Janssen
Pharmaceuticals, Inc. In this form, it is taken as a nasal spray under clinical supervision.
Unlike traditional SSRI antidepressants, esketamine’s antidepressant effects begin within
a few hours of dosing. The effects can then endure for weeks. While its high cost means
it isn’t currently widely used, it may soon be accompanied by arketamine-based options.
Arketamine has a weaker anti-NMDA action, but rodent studies suggest that it could
nonetheless produce an antidepressant response with a better side-effect profile.

MDMA
3,4-Methyl​enedioxy​methamphetamine (MDMA) isn’t a traditional hallucinogenic psychedelic.
It’s widely used recreationally as ecstasy, fueling generations of ravers and partygoers.

Despite this reputation, MDMA received Breakthrough Therapy Designation from the FDA
before ketamine. In 2017, the Multidisciplinary Association for Psychedelic Studies (MAPS)
was granted the designation, which allows for the FDA to fast-track certain elements of the
clinical trials procedure, to investigate the use of MDMA in treating post-traumatic stress
disorder (PTSD).

MDMA stimulates the release of the neurotransmitter serotonin. This is what leads to the
feeling of happiness and wellbeing so sought after by recreational users. It is also capable of
enhancing the release of another mood-boosting brain chemical, dopamine.

Earlier this year, MAPS released the results of its MDMA clinical trial for PTSD. In this
trial, MDMA was paired with rounds of psychotherapy. After three sessions of this therapy,
32% of users given a placebo no longer qualified for a PTSD diagnosis. But for those given
MDMA as well, this percentage rocketed to 67%. Lead author on the paper that documented
MAPS’s success, the University of California San Francisco’s Jennifer Mitchell, said that
the “unique ability of MDMA to raise compassion and understanding while tamping down
fear is likely what enables it to be so effective.” It appears to be most effective at helping
patients with the dissociative subtype of PTSD. This group tend to exhibit depersonalization
from the trauma that caused their PTSD. Mitchell suggests that with the right mindset and
appropriately supportive environmental setting, MDMA can help those that have mentally
distanced themselves from a trauma confront and overcome it.

Unlike ketamine, MDMA is listed as a schedule 1 drug in the US, a classification that
suggests the compound has “no medical benefit”. Trials like MAPS’s are knocking down
these walls and will hopefully make research using these compounds far easier in the
future.

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Set and Setting

Set and setting refers to the psychological and environmental parameters that play a
significant role in determining how someone will respond to psychedelics. Mindset –
the outlook, preparation and expectation of the individual undergoing the psychedelic
experience and setting – the physical and social environment in which the psychedelic
experience takes place – are thought to be essential factors in making sure a participant
undergoing psychedelic therapy has a positive outcome.

DMT
N, N-dimethyltryptamine (DMT) is a psychedelic derived from the root bark of the Mimosa
tenuiflora plant, which is found across South and Central America. This compound is the
active component of the traditional South American hallucinatory brew ayahuasca, which
is renowned for the strong out of body effects it produces. It was first synthesized in 1931,
before it was “discovered” by Western medicine in 1946. Ayahuasca has been used for
centuries by indigenous peoples in the area, with the oldest sample found estimated to be
1000 years old.

The drug was dubbed the “spirit molecule” by Rick Strassman, associate professor of
psychiatry at the University of New Mexico School of Medicine, due to the similarities
between the drug’s effects and intense religious or spiritual experiences . These similarities,
Strassman said, included “visions, voices, a seeming separation of consciousness from the
body, extreme emotional states and contact with seemingly discarnate intelligences.”

The compound is chemically similar to that of our mood-boosting neurotransmitter

serotonin (5-hydroxytryptamine). Our brain can actually endogenously produce DMT in trace
amounts. Why or how this happens remains a mystery.

DMT trips are intense, but very short, lasting just a few minutes. Unlike MDMA and ketamine,
DMT is a compound that remains poorly assessed for therapeutic benefit. Small Pharma, a
UK-based drug developer, is working with Imperial College London on the world’s first trial
of DMT in combination with therapy for depression. Like trials with MDMA, this effort will
involve taking the drug in the presence of trained therapists. Other, pre-clinical studies are
even looking at the potential of DMT to help with stroke recovery.

Psilocybin
Psilocybin is a natural psychedelic compound derived from over 200 species of fungi.

The compound is a serotonin agonist, increasing levels of this mood-boosting brain

chemical. It has been illegal in most industrialized countries for nearly half a century but
was, in 2019, decriminalized for personal use in Denver, CO.

There are a number of theories on how psilocybin produces psychedelic effects in the brain,
including alterations to thalamic gating and increases to activity in the prefrontal cortex.

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In May 2021, psilocybin was used in one of the first trials to directly compare the
antidepressant effects of a psychedelic and an antidepressant, in this case the selective
serotonin reuptake inhibitor (SSRI) escitalopram. This landmark study was organized by
researchers at Imperial College London’s Centre for Psychedelic Research.

This showed that psilocybin could match the antidepressant effects of the SSRI. The data
suggested that psilocybin may produce a deeper and faster effect, but the trial wasn’t
adequately powered to detect a significant difference.

All four of these compounds, at different stages in their progress towards being accepted
and legal treatments for mental health conditions, show the power and potential of
psychedelics.

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