Insights

A brief history of DMT

DMT, short for N, N-Dimethyltryptamine, is a naturally-occurring, fast-acting psychoactive molecule.

Also described as the ‘Spirit molecule’, ‘Fantasia‘, and ‘more real than reality,’  DMT and its history is full of intriguing labels and stories.

Only more recently has it begun creating stirs in the mainstream and attracting serious scientific interest as a treatment for depression, which the World Health Organisation recognises as a leading cause of disability worldwide.

Psychedelic therapies to treat mental health disorders

Clinical trials are supporting both the safety and efficacy of psychedelic medicines as possible therapies to treat a number of mental health conditions, with the likes of ketaminepsilocybin (magic mushrooms) and LSD firmly on people’s radar. Yet DMT remains lesser known.

So why does Small Pharma believe in its revolutionary potential as a treatment for depression – one of the most underserved mental health needs of our time?

The history of DMT forms part of its relevance to the clinical trials of today, and why we’re optimistic that the decision to explore DMT-assisted psychotherapy as a treatment for patients with major depressive disorder holds such ground-breaking potential.

Leading researchers have been investigating DMT for more than 80 years. In doing so, they’ve laid the foundations to help us further progress this promising molecule in combination with psychotherapy.

What is DMT?

A little on the science behind it all. Chemically speaking, DMT (N,N-Dimethyltryptamine) is part of the tryptamine family.

Amongst the family of tryptamine structures is serotonin, the key hormone that stabilises our mood, feelings of well-being, happiness, and sleep. Other so-called  “classical” psychedelic drugs, such as psilocybin and 5-MEO-DMT, also have tryptamine derived chemical structures.

How DMT works in the body

DMT works by binding itself to a range of receptors in the brain, notably the 5-HT2A serotonin receptor.

Through its binding with serotonin receptors, and potentially also influenced by its binding activity at other brain receptor targets, DMT can have the effect of altering visual perception, interoception (the way the mind processes what is happening in the body) and the way that the person under its influence experiences reality for the duration of the drug’s effect. These effects are typically very short lasting; around 20-30 minutes in the case of Small Pharma’s DMT compound, SPL026, when administered as an intravenous infusion in the company’s Phase I clinical trial.

Where does DMT come from?

The DMT molecule is present naturally in a wide variety of plants and animals (including humans) and it can also be synthesised in a lab, like the variations developed for Small Pharma’s drug development programmes.

Does DMT come from ayahuasca?
ayahuasca tree with sunlight in the background

Ayahuasca (pronounced ‘eye-ah-WAH-ska’) is a plant-based psychoactive brew, used both socially and as a ceremonial spiritual medicine among the indigenous peoples of the Amazon basin. These ceremonial rites go back centuries.

DMT is often associated with ayahuasca because it is the brew’s main psychoactive ingredient. Besides DMT, the ayahuasca brew contains additional compounds including harmines and harmalines that have potential therapeutic properties of their own and stop the body from metabolising DMT as fast as it normally would, making ayahuasca possible to ingest orally, unlike DMT.

Unlike the short psychoactive experience of DMT (lasting < 30 minutes), the ayahuasca experience lasts far longer (i.e. hours) and is typically reported to have strong side effects.

A timeline of DMT history

A 1000-year-old Shamanic Pouch
Amazon rain forest

Ancient shamans in what is now southwestern Bolivia may not have known the molecule DMT but they were certainly aware of the hallucinogenic effects of ayahuasca.

José Capriles, an anthropologist at Penn State University, published a paper on the discovery of a 1000 year old shamanic pouch discovered in 2010, made from three fox snouts neatly sewn together. The author states that the pouch may contain the world’s earliest archaeological evidence for the consumption of ayahuasca.

1931: DMT is Synthesized in a Lab

Skipping forward a few centuries, we come to when DMT was first synthesised chemically in a lab. This happened in 1931 by a German-Canadian chemist, Dr. Richard Manske, although he never studied its potential pharmacological effects in humans.

1956: Discovery of DMT’s Psychoactive Properties

In 1956, DMT’s psychoactive properties and short duration of action in humans were first scientifically evaluated when Hungarian chemist and clinical psychiatrist, Dr. Stephen Szára administered synthetic DMT to 20 healthy volunteers via intramuscular injection – an administration route that is being further investigated  in one of Small Pharma’s anticipated upcoming clinical trials.

Although exploration into the potential effects of DMT in humans began to take root here, there were major setbacks along the way.

Dr. Stephen Szara
Dr. Stephen Szara
1971: Convention on Psychotropic Substances

On 21st February 1971, the international community signed a UN treaty to issue a control system on psychoactive drugs, restricting imports, exports, and limiting the use to scientific and medical purposes. Many psychedelic drugs were scheduled as having no medical benefit despite evidence to suggest possible health benefits. In the history of DMT, 1971 essentially marked a decades-long halt into DMT clinical research and other psychedelics.

1990 – Present: The Psychedelic Renaissance

1990- 1995: Rick Strassman, The Spirit Molecule

The significant progress from the early work on DMT and other psychedelics in the past 30 years has been informative to Small Pharma’s decision to investigate the therapeutic potential of DMT based treatments for mental health conditions in robust regulatory approved clinical trials.

The change first started in the 1990s when Dr. Rick Strassman, a clinical psychologist and author of “DMT: The Spirit Molecule” (where DMT derives its other name), revived this research by conducting the first US federally approved psychedelic study since the ban in the 1970s.

Arguably, Strassman put DMT and psychedelics back on the map. He published research that characterised the biological and subjective psychological dose related effects of DMT on healthy subjects and, through his book, offered rich insights into the nature of the DMT experience as reported following his assessments with the participants during his studies.

DMT The Spirit Molecule
Rick Strassman - The Spirit Molecule

Strassman’s decision to use DMT in his trials was made for two key reasons:

  1. Limiting bias: DMT was relatively unknown and did not have the reputation that other ‘classical’ psychedelic drugs (e.g. LSD, psilocybin) carried. Strassman felt this provided an advantage of reducing the susceptibility bias implicit in psychedelic studies whereby DMT’s unfamiliar nature meant its effects may be less anticipated by study participants than other psychedelic compounds.
  2. Practicality: DMT’s short duration of action when administered intravenously meant that the study’s protocol was less practically demanding.

It may have taken him two years to resolve the regulatory hurdles imposed by the 1970s ban but in doing so, Strassman opened the gateway to DMT and its potential as a treatment once more.

2015 – 2018: Early Clinical Evidence of DMT’s Potential Antidepressant Effects from Ayahuasca Studies

From 2015 to 2018, a number of ayahuasca research studies were published, such as Osaria et al. (2015)and Palhano-Fontes et al. (2018). Each of these studies explored the antidepressant potential of ayahuasca with promising results.

In the first controlled study using ayahuasca by Palhano-Fontes et al., significant antidepressant effects of ayahuasca were observed when compared to placebo when administered to 20 patients with treatment resistant depression. In the ayahuasca group compared to placebo, the mean depression scores were statistically significantly lower at all time points (Day 1, 2, and 7)  and the percentage of patients who met the response criteria, defined as a reduction of 50% or more in  baseline depression score, was significantly greater at Day 7 (64% vs 27%, p=0.04).

2019: Timmerman et al, Similarities in DMT and Psilocybin Effects in the Brain
Chris Timmerman Breaking Convention
Dr Chris Timmerman

The work published from Imperial’s Centre for Psychedelic Research has helped to investigate the mechanistic effects of DMT in the brain. In 2018, Timmerman et al. conducted a placebo controlled study investigating the correlation between levels of DMT in the blood, brain activity and subjective experiential effects. The findings highlighted certain changes in brain wave patterns, including a marked drop off in alpha waves – the human brain’s dominant electrical rhythm when we are awake,  during the peak DMT experience that were similarly shown in EEG studies conducted on participants who were administered psilocybin.

Interestingly, additional short-lived increases in short-lived brain wave activity were seen at the peak of the DMT experience and not seen in psilocybin and LSD EEG data. These changes, namely theta waves, correlated with participant reports of  complex visionary phenomena and are otherwise classically associated with REM sleep.

Timmerman commented: “From the altered brainwaves and participants’ reports, it’s clear these people are completely immersed in their experience – it’s like daydreaming only far more vivid and immersive, it’s like dreaming but with your eyes open.”

Timmerman et al. also noted that such results may shed light on the mechanisms underpinning the antidepressant potential of DMT, given that the opposing patterns of brain wave activity have been noted in EEG studies of populations of depressed individuals.

These mechanistic studies provide reason to believe that DMT based therapies could deliver similar therapeutic potential to other psychedelics.

2021: Small Pharma starts first clinical trials for DMT-assisted psychotherapy to treat major depressive disorder

In February 2021, Small Pharma initiated a Phase I/ IIa clinical trial to evaluate the combination of DMT and psychotherapy to treat patients with Major Depressive Disorder (MDD). As of today, this trial is the most advanced of its kind in commercial development.

In addition, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) awarded Small Pharma an Innovation Passport for its SPL026 development programme, providing it with earlier access to specialist advice throughout the drug development process. This has the potential to allow the NHS to adopt potential treatments faster and ultimately enable quicker patient access to this potential treatment.

This also represents a transformational shift from the ban in the 1970s to where regulation sits today. It’s an encouraging response in the means to progress the development of Small Pharma’s DMT-assisted psychotherapy towards an approved clinical treatment.

2022 and beyond

In the overall history of DMT, the recent psychedelic renaissance provided the necessary step to DMT’s potentially bright future as a viable and accessible clinical treatment. Many regulatory, economic and political questions remain, but significant scientific research is progressing to guide the answers, demonstrating a positive path forward.

Small Pharma sets out to demonstrate the potential impact that DMT-assisted psychotherapy could have in treating one of the most underserved mental health conditions of our time. As we continue to progress our pipeline of psychedelic treatments, our mission is to work towards a world where everyone can access effective mental health treatment.

Small Pharma Team

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About Small Pharma

We’re a mental health drug development company that’s accelerating the development of fast acting antidepressant treatments using DMT based therapies. We’re dedicated to making a difference.

With a focus on innovative approaches and committed to challenging the status quo, we’re targeting the root causes of depression and hoping to unlock the minds of millions.

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