DMT Phase I Update; DEA Allows Psilocybin Cultivation; FDA promotes Spravato; Michigan's Decrim Measure

Feb 25, 2022

It felt strange to write this newsletter yesterday as Russia invaded Ukraine and the world watched. The violence and suffering the people of Ukraine are experiencing are gut-wrenching. The images and accounts coming from the invasion are painful to witness. Despite the good we hope psychedelics can bring about, today, it feels insignificant by comparison.

Hoping for a peaceful outcome. 🇺🇦

Today, we’re exploring:

Small Pharma’s Phase I trial of DMT in healthy volunteers
DEA greenlights Mycrodose’s cultivation plans
The FDA’s warning about generic ketamine and promotion of Spravato
Psychedelic Policy update from Michigan

Let’s jump in.

🧝DMT Phase I Update

The renewed attention on psychedelics is a sight to behold.

Among the many plot lines, narratives, and forthcoming developments, the prospect of using DMT in modern mental health practices is one of the most captivating.

The intensity of the experience, the otherworldliness, and commonly reported entity encounters (more on this below), would make its introduction into clinical practice a true spectacle.

This week, Small Pharma, which is taking intravenous DMT through the drug approval process, announced a preliminary update of its phase I trial in healthy volunteers.

Positive takeaways include:

No serious adverse events
No statistically significant negative effects on anxiety and well-being during the three-month follow-up
The dose-escalating study showed a clear correlation between dose level and the ‘richness of the psychedelic experience’
IV administration of DMT enabled a dosing session to last a mere 30 minutes

Because of its shorter duration, DMT is an attractive candidate for psychedelic medicine.

However, an odd feature of the DMT experience is remarkably consistent: entity encounters.

Terrence Mckenna dubbed these beings DMT Elves or Machine Elves.

A paper from Johns Hopkins titled Survey of entity encounter experiences occasioned by inhaled N, N-dimethyltryptamine: Phenomenology, interpretation, and enduring effects noted:

“Among the most vivid, intriguing, memorable, and sometimes disconcerting experiences that people report after taking a high dose of inhaled or intravenous DMT are those of encountering seemingly autonomous entities or beings… Strassman (2008) estimated that at least half of the participants in his studies of high doses of intravenous DMT reported experiences of journeys to invisible or alternative worlds, and that contact with alien beings or entities were a variant of this category.”

More recently, a study of naturalistic DMT use found that 94% of participants reported encounters with ‘other beings.’

The Phase I update did not include reported entity encounters, but a full readout is forthcoming in a peer-review journal.

In addition to such encounters, DMT has been shown to catalyze religious conversation. The Johns Hopkins team found that:

“More than half of those who identified as atheist before the experience no longer identified as atheist afterward.”

Psychedelic Informed Consent

How do these aspects of the DMT experience in particular, and psychedelics more broadly, related to the ethical mandates of informed consent?

Most commentary on ‘wraparound’ care and infrastructure has been concerned with preparation, supportive therapy, and post-treatment integration.

Less common in the discourse has been informed consent.

A paper from the Journal of Medical Ethics explored the unique properties of psilocybin that demand tailored informed consent processes:

“we believe that three components of the therapeutic process, mechanism and side effect profile of psilocybin will be novel and potentially unexpected for patients. These are shifts in values and personality, rare mental health side effects and the possible use of therapeutic touch during therapy. They thus require special attention in enhanced consent.”

In considering DMT, we can add the potential for alien encounters and the possibility of becoming religious to the list.

We’ll be keen to see the full data readout from Small Pharma and, more interestingly, the phase II results on Major Depressive Disorder.

For now, it appears machine elves are one step closer to the clinic.

🍄 DEA to Mycrodose: Grow Your Own

According to a company press release this week, the DEA has given Mycrodose the greenlight to cultivate psilocybin-containing mushrooms at their California facility:

“…the US Drug Enforcement Agency (DEA) and the US Food and Drug Administration (FDA) have approved the company to cultivate Psilocybe cubensis and synthesize five (5) Schedule I compounds under their Schedule I Research License.

This appears to be a first:

“As far as we’ve seen, this is the first time a company has ever been approved by the DEA and FDA to cultivate and grow these mushrooms in the United States,” says Chad Conner, Chief Executive Officer of Mycrodose Therapeutics.”

Most small-molecule drugs approved by the FDA are synthetic, even those that originate from naturally occurring compounds with medicinal properties are ultimately synthetically created in a lab.

For example, of the four cannabinoid-related prescription drugs, only one (Epidiolex) is derived from cannabis plants, the other three are synthetic cannabinoids.

Despite the natural origins of psilocybin and other compounds, most psychedelic drug development projects also use synthetic manufacturing.

The long history of these compounds, their public domain status, and their natural origins will make for various strategies when it comes to developing pharmaceutical-grade products and quality-controlled natural products for the anticipated regulated markets.

While not explicitly mentioned, one such strategy is the development of Botanicals, a drug category that the FDA defines as “products that include plant materials, algae, macroscopic fungi, and combinations thereof.”

In the early days of this newsletter, I covered the concept in Botanical Pharmaceutical Co. Enters Psychedelic Space:

Botanicals are products manufactured from naturally occurring starting materials without a single active ingredient but rather a mixture of collectively active compounds and have a horrendous track record of gaining FDA approval.

Botanicals have a poor FDA approval rate—only two botanical applications have been approved out of over eight hundred applications.

But there is reason to believe this could change.

From Natural products in drug discovery: advances and opportunities:

“In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances—are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized…”

Another reason this could change is that most botanicals have been naturally heterogeneous mixtures that lack distinct active ingredients. Their effect is contingent upon the synergy of several compounds. The lack of a known active constituent is a problem for regulators. A botanical with a known amount of active constituents, such as psilocybin, could change this.

So as increasingly sophisticated tools of natural product development come online, naturally derived psychedelic pharmaceuticals could launch a renaissance in botanical drug development.

👮‍♂️ FDA: Ketamine Bad, Spravato Good

Last week the FDA warned about possible risks of nasally administered racemic ketamine:

“FDA is aware that some pharmacies compound nasal spray formulations of ketamine either alone or in combination with other ingredients, and there have been a concerning number of case reports of adverse events in recent years.”

The statement went on to explain the details of their findings:

“FDA searched the FDA Adverse Event Reporting System (FAERS) database and the medical literature from April 2011 through January 2022 and identified five cases, reported between 2016-2021, associated with psychiatric events such as delusion, dissociation, visual hallucination, and panic attack as well as abuse and misuse[b] following the use of compounded ketamine nasal spray.”

The statement then highlighted Spravato, the FDA approved nasally administered ketamine enantiomer, as the preferred alternative:

“The benefit and risk profile for Spravato (esketamine) has been established, as described in the FDA-approved labeling and the approved Spravato REMS program, with elements to assure safe use. However, the benefit and risk profile for compounded ketamine nasal spray has not been evaluated.”

Despite the FDA’s claim that the Spravato has an established risk/benefit ratio and should be the preferred treatment, researchers have questioned that assertion since its 2019 approval.

For further reading on the safety and efficacy of Spravato:

Esketamine Failed in Five of its Six Efficacy Trials

This power struggle isn’t going anywhere—it will be interesting to see how the FDA advises healthcare providers in response to increasing psychedelic use in decriminalized and legalized settings.

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Policy News

Decrim Ballot Initiative Approved for Circulation in Michigan

“At the core of the Initiative is the addition of a section to Michigan’s Public Health Code that explicitly decriminalizes “the possession, use, cultivation, production, creation, analysis, giving away, and delivery by or between natural persons eighteen (18) years of age or older of psilocybin, psilocyn, ibogaine, mescaline, Peyote, and dimethyltryptamine” which the Initiative refers to as “natural plants and mushrooms.”

And interestingly (emphasis added):

“A major caveat found in the Initiative, however, is that in order to comply with the law, a business intending to provide such services would have to be designated by a qualifying hospital or psychiatric hospital for that purpose.”

The Trip Report by Beckley Waves

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