Inside the Challenge to DEA’s Proposed Scheduling of 5 Psychedelic Tryptamines
Last week, the DEA ditched plans to place five tryptamines on Schedule I after a small group of researchers, psychedelic startups and lawyers challenged the agency.
Psychedelic Alpha was presented with around 200 documents pertaining to the docket, including evidence that was set to have its day in court on August 22nd. We sifted through these documents, along with public comments, to parse out some key takeaways from the proceedings.
In what follows, we dip in and out of some of what we deemed to be the most salient arguments and most interesting wrinkles in the proceedings. We certainly don’t cover everything.
- The true costs of schedule I: how the bureaucratic baggage associated with the toughest schedule can make-or-break efforts to develop new therapeutics.
- Why these low-profile tryptamines are worth fighting for, according to their proponents: from their therapeutic potential to their use as building blocks for further research. And then there’s the matter of precedent.
- “Six lab rats in Texas get to determine that all psychedelics are too dangerous”: we take a look at a few of the arguments used to critique the DEA’s evidence base, which rested on decade-old analyses.
- Judge’s “frustration” as DEA appears to flout the rules: in a transcript viewed by Psychedelic Alpha, Administrative Law Judge Wallbaum called out a DEA supervisor over an apparent attempt to ignore her order came straight from the top.
Context & Background
January 14th, 2022: DEA Announces the Proposed Scheduling of Five Psychedelic Tryptamines
On Thursday 13th January, 2022, the National Institutes of Health (NIH), along with a couple of its constituent institutes, were hosting the second day of a Workshop titled, “Psychedelics as Therapeutics”.
The director of the National Institute on Drug Abuse (NIDA), Dr. Nora Volkow, memorably remarked that, “with all the attention that the psychedelic drugs have attracted, the train has left the station” and “people are going to start to use” them.
Not more than 24 hours later, the U.S. Drug Enforcement Administration (DEA) announced its intent to place five tryptamine hallucinogens in Schedule I of the Controlled Substances Act (CSA).
- 4-Hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT),
- 5-Methoxy-alphamethyltryptamine (5-MeO-AMT),
- N-Isopropyl-5-Methoxy-N-Methyltryptamine (5-MeO-MiPT),
- N,N-Diethyl-5-methoxytryptamine (5-MeO-DET), and
- N,N-Diisopropyltryptamine (DiPT).
The move came as a surprise to many. It appeared to be out-of-tune with the agency’s recent actions on psychedelics, which included raising production quotas upwards of 1,000% for some molecules.
As is customary, the agency stated that it would accept comments from the public, which were to be submitted within a month. Valentine’s Day 2022 marked the deadline. It’s broadly accepted, however, that such public comment periods are largely performative: window dressing to present the image of democratic input, if you will.
“For a country that proposes freedom and human rights this is a definite example of how bullshit that even is.”
– Anonymous Public Comment
Ultimately, the proposed rule received nearly 600 public comments. All of the comments reviewed by Psychedelic Alpha opposed the proposal, with varying degrees of professionalism and profanity.
While a motley crew (from anonymous individuals with experience using said tryptamines, right through to renowned researchers and nonprofits) were whipping up a storm on the public comments side, a smaller group of individuals and organisations were preparing formal requests for hearings to challenge the proposed rulemaking. The comments, testimonies, and submissions of these groups are what we drew upon most prominently in putting this report together.
FYI, FAA: These 5 Tryptamines are Already Illegal for Consumption
One of the most important pieces of context regarding the proposed scheduling is that human consumption of all five tryptamines under discussion is already unequivocally illegal in the United States thanks to the Federal Analogue Act (FAA).
In the mid 1980s, Reagan’s administration felt that underground chemists were exploiting the myriad potential permutations of molecular structures to evade the Controlled Substances Act (CSA). By making minor tweaks to scheduled substances, savvy chemists could identify, produce, and distribute drugs that reproduced similarly desirable effects to their scheduled predecessors without, well, the scheduled status.
Given that these so-called “designer drugs” were frequently being iterated at a pace that outstripped scheduling efforts, the Federal government sought to pre-empt the development of analogues as opposed to continuing to play an expensive game of whack-a-mole. The result was the Federal Analogue Act of 1986, which was tagged onto the CSA.
The act sought to squash the ‘designer drug’ loophole by replacing sluggish, molecule-by molecule scheduling with statute that allowed for those chemicals deemed to be “substantially similar” to any Schedule I or II substance to be dealt with as if they were Schedule I substances: but crucially, only where they are intended for human consumption.
Given that the five tryptamines are deemed to be “substantially similar” to Schedule I drugs like 5-MeO-MiPT, they fall within the remit of the Analogue Act. Consequently, the drugs become Schedule I substances as soon as they are deemed to be destined for human consumption. Those that consume them, or those that offer such drugs for sale that are not expressly providers of research chemicals, are liable for prosecution.
Importantly, the act was only intended to preclude human consumption of these ‘designer drugs’. As attorney Shane Pennington (who, alongside practising law, has a streak for researching and publishing on the history of the CSA and DEA) notes in his statement on the matter of the five tryptamines, those who drafted the act sought to make it explicit that the aim of the legislation is not to prevent research into such drugs.
In fact, then-Senator Joe Biden explained at the time that, “this legislation is not aimed at legitimate drug research that unwittingly falls within the designer drug definition.” In addition to drugs approved by the FDA, Biden explicitly noted that, “[e]arly stage, clinical research is also protected,” and that such exemptions strive to “prevent interference with legitimate research and development of new pharmaceuticals.”
One might think, then, that these five tryptamines are already adequately controlled under the Federal Analogue Act. As Pennington further noted in his statement, the DEA’s proposal to schedule these tryptamines, “is at odds with how Congress structured the CSA,” with the Analogue Act supposed to play an important role in protecting public health by restricting human consumption while maintaining access for researchers.
The Costs of Schedule I
Despite the existence of what may appear to be adequate defence against human consumption provided by the Analogue Act, the DEA moved to schedule the five tryptamines.
In light of this decision, it’s worth looking at the costs—both direct and indirect—that such a move would levy on those seeking to research and develop these molecules.
Obtaining DEA Permits: A Slow, Expensive Process
In the simplest terms: if these 5 tryptamines were added to Schedule I, every person and organisation working with them—and their chemical relatives—would have to stop, with immediate effect.
Research would only resume if and when the investigators and service providers obtain the necessary licences from the DEA. However, the acquisition of such licences often entails a lengthy application process and expensive requirements such as bringing facilities and practices up to code.
Researchers across the board have repeatedly discussed the barriers associated with handling Schedule I substances. Dr. Lynnette A. Averill, assistant professor adjunct of psychiatry at Yale School of Medicine, went so far as describing such barriers as “formidable” in her statement.
Even NIDA’s Director Dr. Volkow has discussed how she is discouraged from working with Schedule I substances due to the administrative quagmire they often force one to negotiate. That’s quite remarkable considering the remit of NIDA, the National Institute on Drug Abuse.
In real terms, those looking to handle Schedule I substances would have to obtain a permit from the DEA for each project and each facility involved. This requirement must be met irrespective of the quantities involved: even a droplet in a petri dish for the purposes of a preclinical study requires a permit.
Obtaining these permits often entails direct costs, notably those associated with bringing a facility into compliance. To convince the DEA that your location can safely store Schedule I drugs, for example, you’ll need to procure a safe weighing at least 750 pounds. You can opt for a lighter safe, but you’ll need to bolt it to the floor, or set it in cement. Whichever you choose, it’s likely that this alone will set you back a few thousand dollars.
Even if a company or research group is able to absorb the costs associated with Schedule I, is this really the best use of their funds?
The other factor is time: the DEA is notoriously slow to approve requests. Given the pace of research and development in the psychedelic space (and the pace of patenting such work, for that matter), and the accelerating nature of the mental health crisis that many organisations are seeking to address, the addition of further time delays can represent serious challenges, especially for newer entrants.
Modern, Decentralised Drug Development Increases the Red Tape Surface Area
The difficulties and costs associated with obtaining, and maintaining, DEA Schedule I licences are exacerbated by the increasingly decentralised nature of drug discovery and development, as well as the interdisciplinary nature of much of the present research into psychedelics.
As is common in many other industries, biotech companies embrace an increasingly decentralised mode of operation, whereby drug discovery and development is outsourced to third-parties that specialise in different stages of the myriad processes involved. The most common party to provide such services are contract research organisations (CROs), of which there are over 4,000 in the U.S.
However, only a small portion of these service providers are equipped to handle Schedule I substances. Given that licences are required for each site involved in the discovery and development of a drug, the scheduling of a candidate is certain to drastically reduce the number of operators available to a company. Those CROs and providers that are willing to meet Schedule I requirements can charge a premium, and are generally selective about who they partner with.
What’s more, the pain associated with such difficulties and added costs is not felt evenly. As is to be expected, larger firms may be able to absorb the cost of contracting a CRO capable of handling Schedule I substances, or even perform some or all of these functions in-house. Smaller biotechs are less likely to be able to absorb such additional costs.
Matthew Baggott, neuroscientist and MDMA researcher-cum-CEO of psychedelic pharmatech company Tactogen, explained in his comments submitted as part of a challenge to the DEA’s proposals that, “we rely on many commercial partners to run specialized assays.” According to Baggott, the majority of those partners would be “unwilling to go through the effort of setting up procedures and getting approvals for Schedule I compounds.”
It would be so difficult, in fact, that Baggott said his company would completely stop studying one of the 5 tryptamines, 5-MeO-MiPT, if it were added to Schedule I.
The CEO of preclinical psychedelic biotech Mindstate Design Labs, Dillan DiNardo, expressed similar sentiments when speaking to Psychedelic Alpha. “Biotech companies like Mindstate work, by necessity, with many contract research organisations,” he explained. DiNardo, an MBA with a consulting background, teamed up with Tom Ray ¹ to launch Mindstate, which raised $11.5m in February.
If the five tryptamines were added to Schedule I, DiNardo told us his company would be forced to reevaluate many of its CRO relationships.
More academic endeavours are not immune to this complexity, either. Jitka Nykodemová, who upped sticks from Prague to work in Jason Wallach’s lab at U Sciences, explained in a public comment that the “explorational cross-disciplinary research” that’s characteristic of many psychedelics research efforts might be hindered by the addition of further molecules to Schedule I. “Scheduling will require all potential collaborators involved […] to obtain DEA licenses,” she wrote.
¹ Ray started his academic career in tropical biology back in 1974, segued into researching “digital evolution” until the turn of the millennium, and ever since has been focused on pairing published reports of subjective experiences with molecular datasets.
Schedule I Drugs Are Especially Expensive to Obtain
Beyond reducing the pool of third party service providers that are crucial to the modern drug development process—and, by simple supply-and-demand economics, increasing their rates—scheduling also has apparent implications on the price of drugs purchased for research purposes.
Testimony provided by Jeffrey Becker, Chief Scientific Officer at Bexson Biomedical, a biotech company focused on developing subcutaneous drug delivery systems, was particularly insightful on this matter.
Becker, who is a physician psychiatrist, explains how he has witnessed the “regulatory ease or difficulty” of R&D across a variety of molecules: from unscheduled drugs like flumazenil and antibiotics through to Scheduled molecules like ketamine (III) and mescaline (I).
By his count, Becker has witnessed the development of around 25 different molecules, and uses these experiences to describe the direct and indirect costs that scheduling, and the degree of scheduling, confers on developers.
|Drug||Cost (50 grams)||Schedule|
Above: prices paid by Bexson Biomedical for 50 grams of raw API. Note that Bexson contracted Thermo Fisher Scientific for direct synthesis of a number of psychedelics, due to low quantities being available.
When combined with the aforementioned difficulties and premiums associated with identifying a willing CRO, these high-cost active pharmaceutical ingredients (APIs) can be a death knell for such programs among small biotechs.
In Bexson Biomedical’s case, the company abandoned its mescaline program after around 18 months of work and $150,000 of investment. The drug is thought to show promise in the treatment of alcoholism.
We have argued in unrelated coverage that the cost of the drug itself is often a small portion of the cost of psychedelic-assisted therapy. Even where the cost far exceeds the street price of drugs like psilocybin, it usually represents less than 10% of the overall cost of administering a psychedelic-assisted therapy, with therapist-related costs representing the vast majority².
While this is true, it’s largely irrelevant for early drug discovery and development work where the cost of acquiring the drug is better understood in proportion to a company’s confidence in its likelihood of proceeding to clinical studies.
As shown in the table above, many manufacturers will only offer ‘direct synthesis’ of Schedule I substances (i.e., they’re not always offered as ‘off the shelf’ chemicals), meaning minimum quantities can be in the region of 50 grams: a significant outlay for a drug discovery outfit that may be looking to screen a vast array of candidates.
² Of course, this will not hold for so-called ‘non-hallucinogenic psychedelics’, or other next-generation psychedelics that may in the future be taken at home (such as the ones companies like Tactogen aspire to develop).
These Costs Hit Smaller Companies Hardest; Are There Large Companies Ready to Take up the Torch?
It’s clear, then, that the costs associated with obtaining and maintaining the relevant licences to work with Schedule I substances are relatively higher for smaller companies who favour greater decentralisation (and thus greater points of licensure) and have leaner budgets.
It’s not surprising, then, that Tactogen and Mindstate’s counsel invoked the Regulatory Flexibility Act in their request for a hearing on this matter. The act compels agencies to consider the impact on small businesses (the definition of which would likely include most, if not all, psychedelics companies) of any proposed rulemaking. Should the proposed rulemaking be deemed to impact a substantial number of small businesses, regulatory alternatives should be explored. In the case of the five tryptamines, one might conclude that the Federal Analogue Act is most appropriate.
While larger drug developers may be able to shoulder such costs, there’s little sign of their entry into the psychedelics space. Aside from small investments in companies like Compass Pathways, and a development agreement between Otsuka Pharmaceuticals and Mindset Pharma, ‘big pharma’ has been absent from the psychedelic renaissance.
Some have speculated that this is due to the apparent threat that psychedelic-assisted therapy may pose to the pharmaceutical industry’s business model. If a psychedelic therapy is able to send a meaningful portion of patients with treatment-resistant depression into remission after just a handful of sessions, for example, what does this mean for the business model associated with the current standard of care, which more closely resembles a subscription model in the case of antidepressants? As a presenter representing Goldman Sachs famously pondered: “Is curing patients a sustainable business model?”
Regardless of the cause for their hesitancy (it’s just as plausible, for example, that larger companies are waiting to see how MDMA-assisted therapy fares before scooping up a psychedelics pipeline or company; all of which are tiny by their standards), the fact remains that there is little involvement from these constituents.
Drugs such as these five tryptamines that are added to Schedule I, then, risk being abandoned by smaller firms, with no larger firms willing to take up the torch.
Schedule? I. Catch? 22.
Unsurprisingly, the costs and hurdles associated with researching Schedule I substances have a drastic impact on the availability of funding for their development as therapeutics, especially in terms of grants.
Given that placement of Schedule I classifies the substance as having, ‘no currently accepted medical use,’ research on their therapeutic potential and “refutations of harms” is “severely impeded,” according to Professor David Nutt in his written statement on the matter. In this sense, he suggested a Schedule I classification is “self-fulfilling.”
Out of Step?
Proposing rulemaking that would levy costs on researchers and drug developers, and surely bring about a chilling effect on such work, was identified in many public comments as out of step with the U.S. government’s other stances and actions pertaining to psychedelic research.
While the glaring fact is that almost all psychedelics currently reside on Schedule I, the government and its agencies have made a number of moves to reduce barriers to their research.
In September 2021, citing its commitment to “evidence-based public policy”, the Biden administration recommended a change aimed at reducing existing regulatory hurdles and supporting research into Schedule I drugs. The administration proposed simplifying the registration process for researchers looking to work with Schedule I substances so that the process would mirror the slightly less arduous registration required for working with Schedule II substances.
Soon thereafter the DEA announced a revised increase to its 2022 production quotas for an array of controlled psychedelic compounds that were to be used in research. The final 2022 quota for psilocybin was set at 8,000 grams, up 2,000 from the year prior. While the quotas for LSD, mescaline, and MDA saw no increase from the year before, those for DMT and 5-MeO-DMT were increased 1,200% and 464% respectively.
The FDA, meanwhile, has recognised the potential of a number of psychedelic-assisted therapies, granting Breakthrough Therapy Designations to MDMA-assisted therapy for PTSD, and psilocybin-assisted therapy for treatment-resistant depression and major depressive disorder.
So, why this scheduling proposal, and why now? If it had passed, researchers and companies in the U.S. may have been placed at a relative disadvantage to those exploring the same drugs in jurisdictions where they have not been explicitly controlled. In the case of the 5 tryptamines, that includes Canada.
It’s clear that placing drugs in Schedule I has detrimental consequences for associated research and development efforts. But, given that psychedelics are almost universally already Schedule I in the U.S., why have many deemed the pre-emption of the same treatment of these five psychedelic drugs important?
While many readers will not recognise these tryptamines, at least three psychedelics companies are currently developing drugs that would be impacted by the scheduling proposal.
Much of what drives the investigation of these lesser-known psychedelics is a belief among a growing pool of psychedelic researchers that there’s a need to look beyond the better-characterised psychedelics, like MDMA and psilocybin. While these two drugs are both benefiting from Breakthrough Therapy Designations, and show signs of efficacy in treating a number of mental health disorders, there is good reason to look at the class of drugs in its entirety.
This is the raison d’etre of companies like Tactogen, for example, which is looking to develop alternative treatments with fewer side effects than drugs like MDMA.
“Thoughtlessly placing psychedelics into Schedule I takes potential medicines and important scientific research tools and turns them into vehicles for injustice.”
– Matthew Baggott
While data suggests that MDMA has a generally positive safety profile, it’s not without acute physiological effects, like hypertension. It has also been observed that individuals build tolerance to MDMA, meaning it’s likely, at least in the early instances of any prospective medical approval, that there will be limits on the number of doses someone can receive.
Palo Alto-based Tactogen, then, is looking to develop drugs with fewer side effects that may be appropriate for use in contexts where MDMA-assisted therapy may not be the best fit. Such drugs may be gentler, have a shorter duration of action, and at least some are envisioned as being take-home drugs. To this end, the Public Benefit Corp. is investigating 5-MeO-MiPT, as is Mindstate Design Labs.
As we reported in January, Field Trip is developing a prodrug of 4-OH-DiPT under the moniker FT-104. The company’s motivation lies in the tryptamine’s shorter duration of action relative to that of psilocybin, despite having a similar potency and pharmacology. Just last week, the company announced the first patients had been dosed with the drug in a Phase I trial.
The proposed scheduling of the company’s lead candidate came shortly after it revealed its molecular identity, leading some to speculate that the company would face increased costs and paperwork should the drug be added to Schedule I.
It shouldn’t be surprising, then, that the company’s Chief Scientific Officer, Nathan Bryson, made a submission to the DEA during the public comment period.
What might be surprising, however, was Bryson’s decision to recommend that all of the tryptamines be added to Schedule I, except for 4-OH-DiPT: the subject of the company’s development efforts. The letter reads, “Field Trip Discovery appreciates DEA’s ongoing efforts to prevent the diversion and abuse of controlled substances and concurs with the DEA’s proposal to place into Schedule I of the CSA the latter four (4) compounds.”
The heavily-redacted letter ³ explains that, “the barriers to research imposed by Schedule I regulation are formidable,” adding that the company, “believes it is imperative to avoid such barriers to the ongoing R&D of FT-104.”
Curiously, shortly after the DEA withdrew its proposal to add 4-OH-DiPT to Schedule I the company’s CEO, Ronan Levy, tweeted ⁴ that the repercussions of such an action would have been “nothing that wasn’t manageable.”
It’s clear that a handful of psychedelics companies have identified therapeutic potential in these tryptamines. It’s no surprise, then, that they exercised their right to request a hearing to challenge the proposed rulemaking.
³ In documents seen by Psychedelic Alpha, counsel for Mindstate and Tactogen argued that, given the level of redaction in Field Trip CSO Nathan Bryson’s letter, it would not be possible to adequately cross-examine or otherwise consider it in the course of the proceedings. Instead, they considered a subpoena of Bryson, or exclusion of the comment from evidence. Counsel for Field Trip struck back, stating that the company would “vociferously object” to any effort to exclude the submissions, and would “quash any subpoena.”
⁴ The tweet has since been deleted.
How the Scheduling of 5 Tryptamines Could Affect Up to 90 Compounds
The addition of these 5 tryptamines to Schedule I would apply also to their positional isomers. These are, generally, molecules that possess the same chemical formula (the same carbon chain) as the five tryptamines described above, but where the location of the functional group differs.
Matthew Baggott told Psychedelic Alpha that he counts as many as 89 potential positional isomers, of which 2 are already scheduled. Some such molecules are yet to be characterised, meaning any potential therapeutic utility is unknown.
Despite their similarities, a positional isomer of one of the 5 tryptamines may not even be psychedelic, or psychoactive at all for that matter. Tactogen cites the example of 6-MeO-MiPT, which is a positional isomer of one of the five tryptamines: 5-MeO-MiPT.
While researchers don’t know much about the potentially useful properties that we might expect the molecule to contain ⁵, we do know it’s non-hallucinogenic. “If the proposed changes are made, we may never know,” reads a blog post on Tactogen’s website.
Tryptamines as Research Tools
Beyond potential therapeutic applications of the tryptamines themselves, they may also be used as tools on the path to uncovering the potential of psychedelics as a broader class of drugs.
Perhaps the most obvious of the 5 tryptamines here is DiPT, the scheduling of which was of such concern to psychedelic researchers Hamilton Morris and Jason Wallach that they made it the sole subject of their request for a hearing and prehearing statement, and Morris’ testimony focused only on DiPT with no reference to the four other tryptamines.
While it may have potential therapeutic effects in and of itself, researchers are excited about what it may teach us about neurobiological mechanisms, especially those pertaining to auditory hallucinations in schizophrenia, for example.
One of Wallach and Morris’ collaborators, Jitka Nykodemová, submitted a public comment that counted DiPT as “an example of a unique and indispensable scientific tool for studying neurobiological mechanisms of auditory perception.”
Nicholas Denomme, a PhD student at University of Michigan Medical School, said in a public comment that “research on the mechanism of action of DiPT may provide better treatments for those suffering from the debilitating auditory hallucinations that are often featured in the clinical presentation of Schizophrenia.”
Aside from DiPT, 5-MeO-MiPT is also being harnessed as a springboard for psychedelic drug development and insights into neurobiology.
Tactogen’s Baggott told Psychedelic Alpha that 5-MeO-MiPT is one of very few classical psychedelics that produces MDMA-like social and emotional effects at lower doses, without relying on serotonin release. “It may therefore provide clues to the mechanisms of how MDMA and entactogens work,” he went on to explain.
Given its MDMA-like effects, Tactogen is employing 5-MeO-MiPT as a positive control: i.e., a drug with a well-characterised effect that’s of interest to researchers. This could prove especially helpful in the development of psychedelics, where suitable controls are notoriously hard to come by.
Mindstate, too, is looking to use 5-MeO-MiPT as a building block. DiNardo explained in his comments that Mindstate has chosen to progress the tryptamine to human studies, “specifically because of its uniquely unremarkable effects as compared to other hallucinogens,” adding that this has led to the drug being dubbed (along with others, it should be noted) “psychedelic tofu.” The company is, presumably, looking to use the tryptamine as a base molecule from which to explore more fine-tuned receptor targeting via the employment of derivatives and analogs, or the coadministration of other substances.
Regardless of the potential utility of the five tryptamines, those who opposed DEA’s proposed Scheduling of them were often driven by a broader goal: catalysing a more fulsome review of the scheduling decisions of the DEA, particularly with regard to psychedelics. If the DEA were encouraged to back away from the proposed scheduling of these five tryptamines in order to review updated evidence, it may set a precedent for future matters.
Just as it’s easier to challenge a patent before it’s issued than after the fact, it’s equally prudent to attempt to prevent a drug being scheduled than it is to attempt to have a scheduled drug de- or rescheduled.
This reality is partially due to where the burden of proof lies in each case. Where a drug is not yet scheduled, the burden of proof for any scheduling action lies firmly with the DEA, who should demonstrate (among other things) that the drug has significant abuse potential and no accepted medical use in order to add a drug to Schedule I, for instance.
However, in any attempt to have a drug descheduled or rescheduled, the burden of proof would fall on the petitioners.
It should also be noted just how few precedents there are for successes on either side of this coin.
The DEA is entitled under federal law to re-cast the scheduling net to include additional substances. To do so, the agency must first publish notice of the proposed rulemaking, then accept public comments for a period of time.
As alluded to earlier, many people (including those well versed in the matter) did not expect these public comments to hold sway. Writing in January, attorney Griffen Thorne wrote on his firm’s blog that:
“Given our experience with the DEA, we think it’s highly unlikely that comments will go anywhere, and that the agency will move forward with finalizing the rule once comments are in.”
“If this rule passes – and you can rest assured that it will – these drugs will be banned.”
Unperturbed, a small group of petitioners prepared to challenge the proposed scheduling and request hearings.
The challenge took place on a number of fronts, with three entities formally challenging the proposed addition of the five tryptamines to Schedule I by requesting hearings.
Matt Zorn (Yetter Coleman), no stranger to litigating against DEA, and Graham Pechenik (Calyx Law) represented petitioners Mindstate Design Labs and Tactogen Inc: both of which stated that they are “currently investigating one or more of the Five Tryptamines” in preclinical research and as part of a program to develop new medicines, respectively.
Panacea Plant Sciences also requested a hearing via its CEO, David Heldreth, who represented himself.
The above petitioners requested a hearing to challenge the proposed addition to schedule I of all five tryptamines, with Zorn and Pechenik questioning whether the analysis on which the proposal rests may be deemed to be, “arbitrary, capricious, contrary to law, or lack[ing] substantial evidence.”
The other party that requested a hearing consisted of researchers Hamilton Morris and Jason Wallach, represented by John T. Hunter. As mentioned elsewhere, Morris and Wallach only requested a hearing to challenge one of these tryptamines, DiPT.
Of course, many other individuals and organisations were involved in this challenge*. These include public submissions from the likes of psychedelic researcher and Field Trip advisor (among other companies) Matthew W. Johnson, who argued that 4-OH-DiPT should not be scheduled; as well as testimony from the likes of David Nutt and Lynnette A. Averill.
* A fourth party, independent healthcare policy advocate Amy Rising, also requested a hearing and was involved until the government successfully argued that despite her previous meetings with a Senate DEA liaison and Senate Judiciary Committee counsel to discuss drug scheduling, and her general interest in reducing barriers to research and providing “life-saving healthcare to US patients”, she does not “seek to advance any interest that is within the ‘zone of interests’ protected or regulated by the scheduling provisions of the CSA” and thus was not an “interested person” with standing to participate in the proceedings. A team at MINDCURE also committed to involvement and contributed initially, until the company wound down operations as part of a strategic review.
The Foundation of the DEA’s Proposal: A 2012 HHS Review
Perhaps testament to the sluggish and somewhat mercurial nature of the Drug Enforcement Administration and its adjacent agencies, the evaluation of these tryptamines was originally commissioned by the DEA fourteen years ago, in 2008.
In 2012, the United States Department of Health and Human Services (HHS) delivered their opinion that there were sufficient grounds for scheduling the substances, recommending this course of action.
However, the DEA sat on the 2012 analysis until a decade later, leading many to ask: why now?
The official line from the DEA is that it began investigating the five tryptamines “[i]n response to reports of abuse and trafficking.”
One might also wonder if perhaps the dramatic uptick in interest around psychedelics, epitomised by companies such as Field Trip prominently announcing their work with a prodrug of one such tryptamine, also prompted the agency to dig HHS’ analysis out from the filing cabinet and move to schedule these drugs?
In making their cases, petitioners (and those who submitted public comments) generally argued that these five tryptamines don’t exhibit significant levels of actual or potential abuse, and that scheduling them would impeded promising research into their potential as therapeutics; or tools that may be harnessed on the way to discovering them.
As is to be expected, those that made formal challenges via requests for hearings produced a greater proportion of technical arguments that point out methodological shortcomings in the DEA and HHS analyses, with testimony challenging the animal models used to imply abuse potential, for example.
When referring to the agency’s analysis, it’s generally that which is reproduced in its “Eight Factor Analysis,” the schema through which the DEA assesses the scheduling of drugs.
Here, we explore a few lines of argument that appeared to be salient: though, it is worth remembering that these arguments never had their day in court.
Low Abuse Potential
In recommending that this quintet of tryptamines be added to Schedule I, HHS were suggesting that they have a high potential for abuse.
However, the agency struggled to demonstrate the dangers of these drugs, with just one death cited. Even then, the evaluation notes that “it is not clear from this report whether 5-MeO-AMT had a direct role in causing this death,” with alcohol and bupropion also involved.
What’s more, the analysis frequently relied on unverified reports on websites like Erowid.
All five of these tryptamines entered the literature by the mid-80s, but none appear to have become a significant public health issue in the nearly four decades since.
In the case of 4-OH-DiPT, for example, psychedelics researcher Matthew W. Johnson commented, “it could not reasonably be concluded in 2012—and it certainly cannot be concluded ten years later in 2022—that 4-OH-DiPT is readily available to be abused or actually being illicitly diverted or abused.”
Aside from these more public health-focused arguments, petitioners took specific issue with claims that pertain to hallucinogens as a broader class (insofar as such a category can be agreed to exist) such as, “hallucinogen abusers may develop psychological dependence,” which is unfounded in the literature with animal models suggesting the contrary.
Animal Models as an Unreliable Predictor of Abuse Liability
A more fundamental argument forwarded by a number of petitioners and their witnesses takes aim at the fundamental inadequacies of using animal drug discrimination studies to determine the abuse liability of a drug.
In a drug discrimination model, researchers observe the behaviour of animals (such as rats) in response to a dose of a particular drug as compared to another, or to a saline control (“vehicle”), for example. The purpose of this behavioural test is to get an early read on the potential subjective effects of a drug.
Agencies like the DEA employ these models to decide whether a drug is likely to elicit behavioural responses similar to those seen in scheduled substances, and then extrapolate abuse liability from such findings.
“For years, DEA has used a biased process where six lab rats in Texas get to determine that all psychedelics are too dangerous for any human use.”
– Matthew Baggott
However, a number of researchers Psychedelic Alpha consulted explained that such models are especially inappropriate for evaluating the subjective effects of psychedelics like tryptamines, let alone their abuse liability.
What’s more, yhe tryptamines were only administered to rodents alongside other Schedule I and II substances. Comparing them instead to substances that lack abuse liability but are known to affect brain functioning, such as antidepressants, may be more appropriate.
Baggott explains it via an analogy:
“This is analogous to asking how similar milk is to different types of alcoholic beverage. One will invariably conclude that milk is at least a little similar to alcoholic beverages and this might even suggest to some that society should reconsider our regulation of milk. Yet this apparent similarity does not mean that milk is not also similar to nonalcoholic beverages such as fruit juices. In fact, milk is arguably more similar to fruit juices in that both provide nutrition and neither causes inebriation. Comparing milk only to alcoholic beverages only provides evidence in one direction and leads to an interpretive bias. The same type of selective comparison creates bias in the case of the Five Tryptamines.”
There’s a more fundamental point to be made, though (which Baggott invokes, to be sure): drug discrimination data in rats is, at best, an indirect measure of a drug’s abuse potential; for we cannot understand why these animals are determining two drugs to be similar. As such, drug discrimination data is a signal that a deeper dive into the abuse liability of a drug should be taken (see Heal et al., 2018, for more).
And, this deeper dive will surely have to take place in humans: how might we be expected to differentiate a state of oceanic boundlessness from contact with ‘Machine Elves’ in a rat? Two drugs that appear chemically similar, and substitute for one another in drug discrimination studies, may be chalk and cheese in humans.
“With many drug families, the results of animal model studies (steps 2 and 3) can allow prediction of new drug structures (step 1). However, with research in hallucinogenic drugs (where the desired pharmacological activity can only be demonstrated in humans), the confirmation of activity must occur by necessity in humans.”
– Jacob and Shulgin (1984)
Structurally Related, Subjectively and Pharmacologically Disparate?
Another critique of the DEA’s analysis questions the inference that the fact that the tryptamines are structurally related to Schedule I substances means that they will be subjectively and pharmacologically similar.
To this tune, Zorn and Pechenik identify an unsound syllogism. Effectively, DEA argues:
- “5-MeO-MiPT is a synthetic analog of tryptamine”
- It is “is structurally related to other tryptamines, such as DMT”
- Therefore, “the effects and pharmacological action of 5-MeO-MiPT are […] similar to that of other Schedule I hallucinogens, such as DMT or LSD”.
The petition points out that melatonin, an over-the-counter sleep aid used by more than 2% of American adults, and the prescription migraine and cluster headache drug sumatriptan (“Imitrex”), are both analogues of tryptamine.
Reminding the DEA of Its Discretion in Such Matters
Those who sought to challenge the proposed scheduling reminded the DEA of its discretion in such matters. Shane Pennington’s statement recounts a number of examples of the agency exercising such discretion, such as in the case of nutmeg.
Nutmeg has been widely used since the 12th century for its euphoric and hallucinogenic qualities, yet eluded scheduling when the CSA was enacted. That’s probably a common-sense decision, given that nutmeg is mostly used as a culinary enhancer.
Enter a TikTok trend that took off two years ago: the ‘nutmeg challenge.’ The trend saw (primarily young) people consume ground nutmeg in order to experience its hallucinogenic effects. Some would make the case that this represents abuse at a much higher rate than the 5 tryptamines, but nutmeg was never scheduled ⁶.
The curious case of nutmeg aside, citizens might expect the DEA to exercise its discretion in order to align scheduling decisions with advances in research and science.
A Memorandum (obtained from the Richard Nixon Presidential Library and Museum by a witness in preparation for the hearing) addressed to the Attorney General dated March 1969 sought to clarify that the Controlled Substances Act, which at the time was undergoing debate, would allow for scientific advances to inform scheduling decisions:
“The bill proposes initially to identify the drugs in each Schedule. Recognizing however that scientific advances may develop new drugs or new insights into old drugs, the bill authorizes the Attorney General, with the advice of a scientific board, to add drugs to the Schedules, switch drugs from one Schedule to another or to drop a drug from control.”
It is logical, then, that such discretion would extend to decisions to not schedule a drug at all.
While such decisions are rarely borne out in public, the case of kratom represents a rare precedent. HHS recommended that mitragynine and 7-OH-mitragynine, the active constituents in kratom, be placed in Schedule I in October 2017.
A short while thereafter, in 2018, HHS changed tack entirely and recommended they not be controlled at that time, basing the decision on factors including new data and lack of evidence. Newer research had found that kratom-related deaths were usually the result of polysubstance abuse, or were confounded by pre-existing medical conditions. The DEA ultimately U-turned on its intent to schedule kratom.
After reviewing the analyses, Brett Giroir, who served as 16th Assistant Secretary for Health during the Trump administration said in a declaration that, “the case for revisiting the medical and scientific findings in [the case of the tryptamines] is much more compelling than the case of kratom,” pointing to the fact that much of the research “has developed over the past decade.”
⁶ Note that in the UK, sales of nutmeg to anyone under the age of 18 are prohibited under the country’s Intoxicating Substances (Supply) Act 1985.
An Outdated Evidence Base
The most glaring issue with the DEA’s case for adding these five tryptamines to Schedule I, however, is the fact that its evidence base is a decade old.
This is particularly relevant in the case of psychedelics, where the pace of research has accelerated enormously in the past decade, including a significant amount of studies and trials in humans.
Above: Psychedelic research publications over time. Blue represents literature published prior to the 2012 HHS review on which the DEA based its proposal. Red shows research published since.
Nuance has entered the field, too. Researchers and policymakers alike are moving away from identifying hallucinogens as a homogeneous class of drugs with high abuse potential and no medical uses, as might have been the case just two decades ago.
Some of this research has been funded by federal agencies, and has fundamentally questioned assumptions about these drugs’ abuse potential.
These facts, among others, led researchers including Yale’s Dr. Lynnette A. Averill to conclude that, “from a scientific and medical perspective, relying on an evaluation of the evidence that is a decade old (2012) is highly troubling in any case and especially so in an area with such rapidly advancing and expanding evidence.”
Administrative Law Judge Orders Rare Public Hearing
In early July the DEA made the surprising announcement that it would hold a hearing on August 22nd, for which those who might be “adversely affected or aggrieved” by the proposed scheduling could make a bid to testify.
The hearing was mandated by Administrative Law Judge Teresa Wallbaum, who was presumably convinced by the petitioners’ claims that they would be particularly impacted by the proposed rulemaking.
Individuals do not have a right to a hearing in these cases, and nor is the DEA required to adhere to the judge’s recommendation. In fact, there is precedent for the DEA ignoring and overruling them, perhaps most famously in the case of Francis L. Young’s 1988 ruling against the classification of marijuana. It’s also a matter that MAPS are all-too-familiar with.
Administrative Law Judge Expresses “Frustration” with DEA’s Apparent Defiance of Her Orders
A transcript of a ‘Status Conference’ shared with Psychedelic Alpha reveals that an Administrative Law Judge was concerned that the head of the DEA (the Administrator, Anne Milgram) was instructing her office to ignore orders from the Judge. If this were true, the Judge explained that it could compromise her ability to provide a fair hearing on this matter.
The Administrative Law Judge assigned to the matter, Teresa A. Wallbaum, convened a Status Conference held virtually on July 11th to air her concerns.
A trio of DEA attorneys were present on behalf of the Government, including one ‘Paul Dean’ who was in attendance at the specific request of Judge Wallbaum who had asked a DEA supervisor to appear.
Wallbaum makes it immediately clear that she is frustrated with the DEA’s “failure to follow two of my orders,” and that she had aired these frustrations off the record, but now wished to do so on the record. The two orders related to the disclosure of materials and the publication of the hearing date.
“I wanted to reiterate my frustration that the government has failed to comply with two of my orders so far,” she began.
Wallbaum explained that she “made it very clear” that documents should be prepared, adding that the DEA “had four months” to do so from a “a finite universe of documents.”
The Judge notes that, after making it clear that she “was not inclined to grant extensions” to the “generous amount of time” she had given the DEA, the agency’s lead counsel (who left the agency during the course of the proceedings) offered to negotiate an extension through an email exchange with the interested parties. “I had expressly told him I would not grant that,” Wallbaum contended.
Wallbaum makes her frustrations on this first matter known swiftly, before moving onto the second order that the Administrative Law Judge says was not complied with by the DEA; one that she feels is “more pressing.” Essentially, the DEA failed to publish any Notice of Hearing for over 6 weeks, leading to the Judge to issue an order directing the government to publish a notice. However, the DEA’s former lead counsel on the matter claimed to have been directed by the DEA’s Administrator Anne Milgram to disregard the order, and instead publish a notice ordered earlier in proceedings.
“You were complying, it sounds like, to a different order, a different directive,” Wallbaum noted. The DEA supervisor, Mr. Dean, insisted that they believed Wallbaum’s latest order had been substantially complied with.
Judge Wallbaum describes the fact that no one from the DEA communicated their intent to publish language agreed upon in a prior order, but not the ultimate order delivered by her, as “unacceptable,” and the reason for her convening the status conference.
“You don’t get to do an ex parte communication with the Administrator about a pending order, and I don’t know how to go forward from that if you can’t tell me, if you can’t give me any more information,” said Wallbaum, evidently frustrated by the DEA supervisor’s invocation of attorney-client privilege in denying to provide the name of the individual who directed the order to be ignored. Counsel for both parties questioned this privilege later in the conference.
In an attempt to prevent a similar matter arising in future, Wallbaum asks the DEA supervisor to agree that if anyone from the agency’s “front office” gives instructions to “do something differently” than what she has offered, that he will make it known so that the interested parties can be informed. Mr. Dean responds, “I think I can”.
Judge Wallbaum snapped back: “I need more than I think I can Mr. Dean”.
“I’m going to hold you to that,” she replied when the DEA representative agreed, and later said that she would “consider the appropriate sanctions” should the government fail to do so.
The Judge then notes that the Notice of Hearing that was published in the Federal Register contains “two errors”: one of which was an incorrect phone number. It should have been one associated with the Office of Administrative Law Judges. Instead, Wallbaum explains, it is the number of “an employee of the DEA who has nothing to do with us or with you.”
“So you might want to sort that out,” she suggested.
The second was the location for the hearing, which the Judge was yet to have set.
While these concerns may seem purely administrative and procedural, it’s clear that the Administrative Law Judge assigned to the matter is frustrated by the possibility that the DEA’s Administrator might be making decisions unilaterally.
On Friday 22nd July, it became apparent that the DEA was withdrawing its proposed rule, and the hearings. The withdrawal was first noted in a response to a motion forwarded by Panacea Plant Sciences ⁷, and shortly thereafter reflected in the Federal Register.
For now, the DEA has withdrawn its intention to place these five tryptamines on schedule I, and denied the petitioners their day in court.
Responding to the news, Tactogen’s Matthew Baggott said, “it is to their credit that they decided to hit the brakes on the planned hearing and go back to square one.”
Similarly, Matt Zorn told Psychedelic Alpha that, “Administrator Milgram and DEA made the right decision, and that should be recognized. After each side put in our witness statements and exchanged evidence, the record did not provide adequate support to justify a Schedule I placement.”
“Arguably this is an example of the process working well,” Andrew Chadeayne, CEO of psychedelic drug discovery company CaaMTech, told Psychedelic Alpha. “I liked that the DEA listened to the experts in the field, took the advice provided, and then arrived at an ‘unprecedented’ result that exceeded everyone’s expectations.”
“This is an unprecedented and unheard of win—and that’s part of the problem,” said Graham Pechenik. “The outcome is correct and certainly worth celebrating, but the fact that enormous energy and effort from experts across the field was necessary to show why psychedelics are inappropriate for Schedule I underscores just how fundamentally flawed DEA’s approach to regulating drugs is generally.”
“This is an unprecedented and unheard of win—and that’s part of the problem. The outcome is correct and certainly worth celebrating, but the fact that enormous energy and effort from experts across the field was necessary to show why psychedelics are inappropriate for Schedule I underscores just how fundamentally flawed DEA’s approach to regulating drugs is generally.”
– Graham Pechenik
In its withdrawal notice the agency explained that, “[u]pon further consideration, DEA has determined that it is appropriate to submit a new request to the [HSS] for an updated scientific and medical evaluation and scheduling recommendation for these substances.”
As such, this should be viewed as a success, but also as a temporary stay. Matt Zorn told Psychedelic Alpha that, “[i]f a contemporary assessment of these factors and policy considerations justifies scheduling, DEA may move forward in the future.”
But, there’s also hope that the assessment will come to the opposite conclusion: that the current evidence suggests these five tryptamines are adequately controlled under the Federal Analogue Act, for example.
Pechenik would go further: “This case was a start, but DEA should broadly recognize that evidence of the actual harms and benefits of drugs demonstrates the current scheduling system is neither sensible nor effective, and can no longer be supported.”
⁷ Panacea’s motion sought to realise an injunction that would delay the proceedings of the hearing and potential scheduling for three years. The DEA noted that such a motion was now “moot as these proceedings will be terminated imminently.” Regardless of the fact that Panacea’s motion was now moot, DEA was sure to argue that the motion was “meritless,” citing “misstatements of the record” and “selective quotation,” and intimating that Heldreth did not act in accordance with “judicial standards of practice and ethics.” In response to a similar motion to stay made subsequently by Panacea in the DOI and DOC case, a different ALJ (Paul Soeffing) granted Panacea’s request and ordered all deadlines in that case extended by 45 days.
Supporting This Work
A number of organisations are looking to continue pressing the DEA to make evidence-based scheduling decisions, especially when it comes to psychedelics.
Drug Science, founded in 2010 by Professor David Nutt, is an independent, science-led drugs charity with a mission of providing up to date, unbiased, and honest information about drugs, to create a foundation for rational and evidence-based drug laws. Drug Science’s “one single minded message—to tell the truth about drugs” was delivered to great effect here, as Prof. Nutt submitted an expert statement that may have played a critical role in the victory.
Prof. Nutt’s expert statement—covering the history of research with psychedelics, their safety and lack of abuse potential, and the importance of continued research—also was provided pro bono. Those that wish to show gratitude for Prof. Nutt’s time and effort, and the immense impact Drug Science makes by providing a scientific evidence base for sensible drug policy reform, can support their work here.
Reason for Hope
Reason for Hope is a non-profit that, among other initiatives, is working with the Biden Administration to establish a Federal Task Force within HHS focused on the development of the regulatory infrastructure for emerging substances such as psychedelics (see recent coverage in The Intercept).
Those interested in contributing to these policy initiatives to advance research, streamline development of the regulatory infrastructure, and provide a pathway for emergency access to psychedelic-assisted therapy for those who have exhausted all other treatment options, can do so at this link.