Fixing The Analogue Act
A Win-Win for Research and DEA
DEA has been active on the scheduling base paths in recent months.
In December 2021, with little fanfare, DEA announced it would place MXE (methoxetamine) on the schedules. Methoxetamine is an arylcyclohexylamine like PCP and Ketamine. It has no accepted medical use. DEA received notice in 2017 that MXE had been scheduled internationally, obligating it to investigate. That investigation produced at least 677 case reports over 10 years and evidence that MXE resulted in fatalities.
In January 2022, with far more fanfare, DEA announced it would place five tryptamines on Schedule I. I’m currently involved in challenging this action. As an advocate in those proceedings, I cannot comment too much about the details of the proceeding. Importantly, this scheduling action is based (1) on a 2012 evaluation by HHS and (2) relatively isolated reports of abuse (in the case of one tryptamines, just 4 reports since 2009).1
Last month, with medium fanfare (so far), DEA announced it would put 2,5-dimethoxy-4-iodoamphetamine (DOI) onto Schedule I as well as DOC. DOI is an extremely valuable unscheduled analogue frequently used in research.
The scheduling of MXE appears justifiable on its face. But as I explain below, these scheduling actions will set back pharmacological and medical research significantly, especially when there isn’t much evidence of abuse. All of the above substances are already controlled by the Federal Analog Act, which invites the question of why DEA is putting these drugs on schedule I. What gives?
Reintroducing the Federal Analogue Act
In my very first post on this newsletter on Delta 8, I discussed a bit about the Federal Analog Act.
In brief, the need for the Federal Analog Act arose out of the “designer drug” era in the 1980s and the discovery of a legal loophole in the CSA: clandestine chemistry. Famously, in 1982, two lawyers played amateur chemist: they attempted to synthesize a then-legal synthetic version of heroin called 1-methyl4-propionoxy-4-phenylpyridine (MPPP) in their basement. But they botched the synthesis. They introduced byproduct into the chemical mix. A heroin addict took the toxic mix and died.
Congress to responded to incidents like this with the Federal Analogue Act. Before the Federal Analog Act, DEA had to prohibit substances one-by-one according to the reticulated process outlined in § 811 of the CSA. As the above anecdote illustrates, it is easy to take advantage of this system. Tweak the molecule slightly and you’ve got a legal drug. The Federal Analog Act attempts to block this behavior without stepping on the toes of research by making things a bit fuzzy, imposing a class-wide restriction on controlled substance analogues using a standards-based test, and layering on a “human consumption requirement.” In brief, according to 21 U.S.C. § 813, to the extent a substance having a similar structure and effect to a scheduled drug is intended for human consumption, that substance can be treated as a Schedule I substance.
Problem solved? Not quite. The Analogue Act is difficult for law enforcement to work with. Joe Rannazzisi, the former DEA Deputy Assistant Administrator, Office of Diversion Control (and a “frontman in the government’s war against opioid abuse) explains the issue in detail and is worth reproducing:
Since the 1970s, domestic clandestine chemists have attempted to manipulate the molecular structures of controlled substances to create synthetic drugs that would have the same pharmacologic properties of a controlled drug, but not expose the chemist or distributor to criminal violations under the Federal Controlled Substances Act.
In the 1970s and 1980s, clandestine chemists introduced synthetic alternatives to the Schedule II drug fentanyl into the illicit marketplace. These drugs were distributed to heroin abusers who were unaware that the drug they were purchasing was 100 to 500 times more potent than morphine.
Congress responded in 1986 by passing the Controlled Substance Analogue Enforcement Act (Analogue Act), which provides: “[a] controlled substance analogue shall, to the extent intended for human consumption, be treated . . . as a controlled substance in schedule I.” 21 U.S.C. § 813.
The Analogue Act provided law enforcement authorities with the authority to investigate and prosecute clandestine chemists who had been manufacturing and distributing dangerous drugs with impunity due to a loophole in the CSA. The Analogue Act did not control designer drugs per se, but rather allowed certain substances to be treated as Schedule I controlled substances to the extent intended for human consumption.
In an Analogue Act prosecution, criminal liability depends upon a finding, in each particular prosecution, that the substance is a “controlled substance analogue” and that the substance was intended for human consumption. This requires extensive use of expert witnesses to prove substantial structural similarity and similar pharmacologic effect.
Where the Federal Analogue Act Falls Short
There’s the rub. The Analogue Act looks great in theory. But in practice, it is a pain to use. In an Analogue Act prosecution, a prosecutor needs to obtain expert testimony to meet the burden of proof. Contrast that with a regular CSA prosecution for unlawful activity with a Schedule I substance, which merely requires proving unlawful possession or distribution. Put a drug in Schedule I, and these issues go away.
Hence, why obscure analogues get placed into Schedule I. And the analysis putting these analogues in Schedule I is perfunctory. Although both HHS and DEA put together an analysis according to statutory factors in 21 U.S.C. 811(c), the Schedule I analysis boils down to (1) is a drug FDA approved and if not (2) is it like another drug in Schedule I?
Scheduling these analogues—even when their abuse is not a serious problem—is a grievous policy blunder and not the actions of an Administration that says it wants to promote research. In research and development, scientists need substances with known properties to use as tools or aids in their research as benchmarks or comparators. For example, LSD has known properties. But most researchers cannot use LSD as a benchmark or comparator to research. Why? LSD is a Schedule I substance, subject to the stiffest registration requirements and manufacturing quotas. Even with those who can use LSD, it is often impractical or inconvenient. So instead, researchers turn to analogues. because when not intended for human consumption, it is totally legal to use these analogues in research off-the-shelf, free of draconian CSA controls.
But it is too easy to lay blame on DEA for over-scheduling these substances without seeing the entire picture. Although I vehemently disagree with the scheduling of some of these compounds (and particularly the manner the agency is going about doing it), bigger picture, I also understand where it might be coming from.
The number of rule benders and breakers in this industry is legion. From illegal delta-9 gummies to folks talking about mailing marijuana seeds, this industry seems intent on pushing every boundary with DEA. I am a fervent defender of religious freedom; but reliance on RFRA is becoming fast, loose, and perhaps, irresponsible.
Nothing encapsulates boundary pushing more than the “bath salt” or “herbal incense” concept. For those who don’t know, as Rannazzisi explains, this loophole or hoax is where a vendor sells a psychotropic drug as a “bath salt” or the like. The purpose of this is to circumvent drug laws. Under the Analogue Act, for an unscheduled drug to be deemed a Schedule I substance, it must be intended for human consumption. So, sell it as a “bath salt” and everything is hunky dory, the theory goes.
Little wonder DEA takes hard lines. Imagine having a child that consistently bends and breaks house rules. Your job is to maintain order. You might be a disciplinarian as well, sometimes over disciplining. Whether one agrees with the federal war on drugs or the existence of a federal agency to police local drug trafficking is beside the point. So long as DEA exists, it has a job, and that parent abuse and diversion, which means keeping its house in order.
The Federal Analogue Act Meets Fentanyl Analogues
The issue of controlled substance analogues and the Analog Act, however, takes on outsized importance when one considers the proliferation of fentanyl analogs. Shane wrote about these dangerous substances previously. In short:
DEA asked HHS to conduct an eight-factor analysis on the entire fentanyl analogue class and make a scheduling recommendation for the class.
FDA said it could not do it because
the class is vast in the number of hypothetical covered substances;
data on the pharmacological effect and epidemiological data showing harms and overdose deaths are available for fewer than 30 fentanyl related substances; and
among the individual fentanyl related substances for which pharmacological activity has been studied, FDA has identified examples of substances lacking in mu-opioid agonist activity, the presumed pharmacology that would lead to opioid-related harms.
In response, the Biden Administration developed an interagency proposal to place the entire fentanyl substance class on schedule I of the CSA based on the presumption that their pharmacology, and therefore their potential for abuse, will mirror that of fentanyl due to their structural similarity.
According to the FDA witness, banning all fentanyl analogues would provide law enforcement with the tools they need to respond to the trafficking and manufacture of synthetic fentanyl-like products. But because not all may demonstrate pharmacology like fentanyl or warrant control as schedule I substances, there would be also process by which an fentanyl related substance could be moved to a lower schedule, or de-scheduled entirely, if the data show it doesn’t belong in schedule I:
First, if this process leads HHS to conclude that the substance has less potential for abuse than substances in schedule V (the least restrictive schedule under the CSA), HHS would convey that conclusion to the Department of Justice (DOJ) and provide its analysis, and DOJ would be required to remove the substance from the CSA schedules within 90 days. Second, if the process leads HHS to conclude that the substance has some potential for abuse, but less than that of substances in schedules I and II, HHS would likewise convey the conclusion to DOJ and provide its analysis, and DOJ would be required, within the same time period, to remove the substance from schedule I and reschedule it in schedule III.
Here is my million dollar question: why is the Biden Administration acting as if fentanyl related substances are only substance where the analogue paradigm fails? Why propose a special scheduling paradigm for fentanyl related substances? What justifies that? Why stop there? Are we accommodating Big Pharma?
What we really need isn’t a clumsy fix for the opioid epidemic. We need a fix to the Analogue Act across the board. Believing in “research” for everyone and not just Big Pharma does not mean accommodating the research of opioid analogues and not everything else. It means fixing a broken system and making it easier for all legitimate medical researchers to research analogues of all kinds. That means doing two things. First, a change should also make law enforcement job’s easier and close the unseemly loopholes described above. DEA shouldn’t have to feel like it needs to reflexively place every drug in Schedule I to effectively do its job. Second, it should protect bona fide research.
Good news. I’m here to help: The CSA Modernization Act of 2022
The fact of the matter is that just about anyone that distributes or uses analogues other than bona fide suppliers or researchers are selling analogues for human consumption. So, here is my proposal. This proposal would (1) protect research and (2) give DEA the tools it needs to do its job, including cracking down on the opiate epidemic—a win-win. And it would help everyone including psychedelic research companies, pharma, and DEA. The only people who lose out are those trying to bend or break the rules or sell unregulated intoxicating substances as “bath salt.” I can’t think of a constituency that could justifiably oppose this amendment.
Matt’s revisions to Analogue Act would do as follows (Call it the “CSA Modernization Act of 2022” or “The Controlled Substance Analogue Modernization Act of 2022”):
21 U.S.C. 813(a)(1): A controlled substance analogue shall be treated for the purposes of any Federal law as a controlled substance in schedule II.
21 U.S.C. 813(a)(2): Notwithstanding section (1), a controlled substance analogue that (i) is not intended for human consumption or (ii) which has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially different from the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II shall not be treated as a controlled substance under any schedule.
21 U.S.C. 813(a)(3): In any action to enforce the requirements of this subchapter respecting a controlled substance against a person, it shall be presumed that the conditions in subsection (2) are not met and the burden shall be on the person to show that such conditions of such subsection are met. This subsection shall not apply in the case of a Schedule I or II registrant or where a person has submitted a research protocol to the Attorney General before the date of any administrative or judicial enforcement action and has received acknowledgement from the Attorney General of the submission.
21 U.S.C. 813(a)(4): The Attorney General shall not add a controlled substance analogue to any schedule unless (i) the Attorney General had received notification from the Secretary of Health and Human Services that the Secretary has approved an application under section 505(c), 512, or 571 of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 355(c), 360b, 360ccc] or section 262(a) of title 42, or indexed a drug under section 572 of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 360ccc–1], with respect to any drug containing the controlled substance analogue or (ii) the Attorney General has determined that the controlled substance analogue has a pattern of abuse similar to or greater than a drug in schedules I or II and cannot be effectively controlled without placement on the schedules.
21 U.S.C. 813(d)(1): The Attorney General shall maintain and publish a list of substances deemed to be substantially similar to Schedule I or II substances.
21 U.S.C. 813(d)(2): The Attorney General may add any substance to the list of substantially similar compounds by publication of an Interim Final Rule in the Federal Register, without regard to the procedures in 21 U.S.C. 811(a). This list shall be updated and republished on an annual basis in the Code of Federal Regulations.
21 U.S.C. 813(d)(3). In any enforcement action to enforce the requirements of this subchapter, any substance listed as substantially similar to Schedule I or II substances shall be presumed to be a controlled substance analogue. A person may rebut the presumption by showing that a substance is not substantially similar to a substance in Schedules I or II.
What does this all do? Several simple but important things that both makes DEA’s job easier and doesn’t cramp research. It basically creates a statutory research exemption and shifts the burden of proof away from the government in Analogue Act prosecutions.
These amendments eliminate the “human consumption” element and the “substantially similar” pharmacological effect from the government’s prima facie case. It makes the test for an analogue black-and-white and administratively simple.
This fixes the “bath salt” loophole and makes it easier for the government to crack down on analogue abuse. It makes enforcement easier dispenses with the need for the government to prove, on a case-by-case basis, the most onerous provisions of the Analogue Act. It also solves the government’s current issue with fentanyl analogues, effectively putting them all on Schedule II.
Why Schedule II?
See my prior article on PCP. Effectively, Schedule II gives DEA the same controls as Schedule I, including the same penalties for unauthorized use. The only difference is that Schedule I has more cumbersome research protocols. To the extent an entity wants to carry through an analogue through a clinical trials process, it shouldn’t have to jump through Schedule I loopholes.
These revisions do not require anyone to register with DEA to do research, but effectively makes showing that an analogue is not for human consumption or “substantially different” in pharmacological effect an affirmative defense.
Thus, the government can presume that all sales and distributions of analogues are illicit. That way, the burden is on “bath salt” sellers to show that it did not intend the product for human consumption.
The presumption would be reversed with those already registered with DEA having Schedule I or II licenses or those who have submitted a research protocol. This would provide legitimate manufacturers and researchers protection against the presumption and allow everyone else to give DEA notice ahead of time.
It prevents the overregulation of analogues that do not show a pattern of abuse similar to already controlled drugs.
Finally, with the “list” provisions, provided DEA gives prior notice given to the public, it allows DEA to bypass the structural similarity requirement in an enforcement action and makes DEA’s job even simpler. As long as it posts in the Federal Register and regulations its position that a substance is structurally similar, that fact would be presumed as well.
Before scheduling substances, the Controlled Substances Act requires DEA to obtain an evaluation from HHS. Whether DEA has complied with this aspect of the statute is an issue in the proceedings.