The Unredacted HHS Docs

What do they say? What do they mean? What difference do they make?

Thanks to Matt, whoever it was that leaked HHS’s scheduling recommendation to Bloomberg a while back, and FOIA, I was up all night last night reviewing the unredacted copy of HHS’s 252-page analysis. A month ago, I went through a similar exercise with the heavily-redacted copies. Although HHS had revealed only scattered fragments and snippets of its analysis back then, I read the tea leaves and gave my best guesses as to what the agency’s analysis might say. My key predictions were that we would eventually learn that HHS

1. recommended that DEA move cannabis to schedule III;

2. established a “newly-minted standard” for currently accepted medical use based on “state-level data regarding widespread medical use of marijuana under state law” and deference to the “State laws and State licensing bodies [that] collectively regulate the practice of medicine” under our federalist system;

3. applied that new standard to conclude that cannabis does, in fact, have a currently accepted medical use;

4. “include[d] a broader and more current data set” in its analysis; and

5. “focus[ed] less on the sheer amount of illegal marijuana use and more on marijuana’s abuse potential and safety profile compared to other substances of abuse” when compared to past rescheduling proceedings.

Having reviewed the unredacted documents carefully now, I’m happy to report that my predictions were pretty much spot on across the board. We’ll probably do multiple posts on the implications of HHS’s analysis. For now, though, I’m just going to describe the key standards and conclusions underlying HHS’s analysis and flag a couple of things that really jumped out at me.

My analysis proceeds in three parts. First, I provide a high-level overview of the key statutory findings underlying HHS’s conclusion that cannabis belongs in schedule III. Second, I discuss those three findings in greater depth, unpacking HHS’s basic rationale for each of them. Third, I highlight a few features of HHS’s analysis that I found especially interesting or noteworthy.

PART I: THE BASICS

As mentioned, we now know once and for all that HHS has in fact recommended that DEA reschedule cannabis from schedule I to schedule III. Under the statute,¹ HHS must make three specific findings before it can make such a recommendation:

1. Cannabis has a potential for abuse less than the drugs or other substances in

   schedules I and II;

2. Cannabis has a currently accepted medical use in treatment in the United States; and

3. Abuse of cannabis may lead to moderate or low physical dependence or high

   psychological dependence.

To decide whether it can make those findings, the statute² requires HHS to consider eight factors:

1. Cannabis’s actual or relative potential for abuse;

2. Scientific evidence of its pharmacological effect, if known;

3. The state of current scientific knowledge regarding the drug or other substance;

4. Its history and current pattern of abuse;

5. The scope, duration, and significance of abuse;

6. What, if any, risk there is to the public health;

7. Its psychic or physiological dependence liability; and

8. Whether the substance is an immediate precursor of a substance already controlled.

Turning to the analysis HHS released to Matt, you’ll see that the agency walks through those factors one at a time on pages 6-61 of the 252-page .pdf document. Then from pages 62-66, it makes the three statutory findings necessary to support a schedule III recommendation before concluding that cannabis does, in fact, belong in schedule III. Pages 66-78 contain a list of references.

Before we move on to breaking down each of the three key statutory findings HHS has made, a basic roadmap of what’s in the remaining 174 pages of the unredacted .pdf may be helpful:

• Pages 79-84 are a July 17, 2023 Memorandum from the Assistant Secretary of Health, Office of the Assistant Secretary of Health (OASH), to the FDA Commissioner entitled “Part 1 Analysis.” The memo does two things. First, it communicates OASH’s analysis of Part 1 of HHS’s new two-part test for assessing whether a substance has a currently accepted medical use (CAMU). Second, it directs FDA to proceed with Part 2 of the analysis.

• Pages 85-98 include several tables and figures that support the OASH’s Part I analysis.

• Pages 99-252 are an August 28, 2023 report prepared by FDA’s Center for Drug Evaluation and Research (CDER) entitled “Considerations for Whether Marijuana Has a Currently Accepted Medical Use in the United States for Purposes of Section 202(b) of the Controlled Substances Act.” In it, FDA provides a detailed overview of the CAMU standard it and HHS have applied, summarizes the OASH’s analysis and conclusions under Part 1 of that standard, and then discusses its own analysis and conclusions with respect to Part 2. Pages 99-201 comprise the substance of FDA’s analysis. Pages 202-252 are supporting appendices and references.

Now that you have a sense of the big picture, both in terms of HHS’s core conclusions and the topics HHS has addressed, let’s look more closely at its rationale for each of the three key findings discussed above.

PART II: DIGGING DEEPER INTO HHS’s RATIONALE

A. Cannabis has a potential for abuse less than the drugs or other substances in schedules I and II.

The starting point for understanding HHS’s assessment of cannabis’s relative abuse potential is to understand what it means by “abuse.” On page 33 of the unredacted .pdf, HHS explains that it understands “abuse” to mean the “intentional, non-therapeutic use of a drug to obtain a desired psychological or physiological effect.”³ To assess cannabis’s relative abuse potential, HHS compared the “prevalence” of and “harms” associated with cannabis abuse to the prevalence of and harms associated with abuse of other substances, including “heroin (Schedule I), fentanyl (Schedule II), oxycodone (Schedule II), hydrocodone (Schedule II), cocaine (Schedule II), ketamine (Schedule III), benzodiazepines (Schedule IV), zolpidem (Schedule IV), tramadol (Schedule IV), and alcohol (FDA Office of Surveillance and Epidemiology, 2023).”⁴ In doing so, HHS cast a very wide net, “assessing all available preclinical, clinical, and epidemiological data,”⁵ but emphasized that it prioritized new studies—i.e., those that have become available since HHS completed its previous evaluation and recommendation in connection with DEA’s denial of the 2016 rescheduling petition.⁶

HHS acknowledged that non-medical use of cannabis was “high[ly] prevalent,” but concluded that “an overall evaluation of epidemiological indicators suggests that it does not produce serious outcomes compared to drugs in Schedules I or II.”⁷ Notably, according to HHS, the wide availability of especially high-THC cannabis products to consumers strengthened this conclusion. “Due to such availability,” it reasoned, “the epidemiological data described in this evaluation inherently include the outcomes from individuals who use marijuana and marijuana-derived products that have doses of Δ9-THC that range from low to very high, and yet the data demonstrate that these products overall are producing fewer negative outcomes than drugs in Schedules I or II.”⁸

Here are some notable snippets from HHS’s discussion of the abuse-related data:

• “The risks to the public health posed by marijuana are low compared to other drugs of abuse (e.g., heroin, cocaine, benzodiazepines), based on an evaluation of various epidemiological databases for ED visits, hospitalizations, unintentional exposures, and most importantly, for overdose deaths. . . . For overdose deaths, marijuana is always in the lowest rankings among comparator drugs. These evaluations demonstrate that there is consistency across databases, across substances, and over time and that although abuse of marijuana produces clear evidence of a risk to public health, that risk is relatively lower than that posed by most other comparator drugs.”⁹

• “The most notable conclusion from an evaluation of various epidemiological databases related to the medical outcomes from abuse of selected drugs is that for all measures that were evaluated from 2015 to 2020, the rank order of the comparators in terms of greatest adverse consequence typically places alcohol, heroin, and/or cocaine in the first or immediately subsequent positions, with marijuana in a lower place in the ranking. This pattern was also observed for PC data with regard to serious medical outcomes, including death, where marijuana was in the lowest ranking group.”¹⁰

• “Epidemiological data indicate that marijuana has the potential for creating hazards to the health of the user and to the safety of the community. However, as a relative finding on abuse liability, when comparing marijuana to heroin, oxycodone, hydrocodone, fentanyl, cocaine, ketamine, benzodiazepines, zolpidem, tramadol, and alcohol in various epidemiological databases that allow for some or all of these comparisons, marijuana is not typically among the substances producing the most frequent incidence of adverse outcomes or severity of substance use disorder.”¹¹

• “Evidence shows that some individuals are taking marijuana in amounts sufficient to create a hazard to their health and to the safety of other individuals and the community. However, evidence also exists showing that the vast majority of individuals who use marijuana are doing so in a manner that does not lead to dangerous outcomes to themselves or others.”¹²

B. Cannabis Has a Currently Accepted Medical Use in Treatment in the United States.

In developing its scientific and medical evaluation and scheduling recommendation, HHS “updated” its approach to assessing “currently accepted medical use in treatment in the United States” (CAMU), recognizing a new two-part standard. Part 1 largely mirrors the test that I predicted we would see (and advocated for) here and here.¹³ It asks whether “[t]here exists widespread, current experience with medical use of the substance by HCPs operating in accordance with implemented jurisdiction-authorized programs, where medical use is recognized by entities that regulate the practice of medicine.”¹⁴ Factors supporting such a determination include:

1. Whether a substantial number of health care professionals (HCPs) have gained clinical experience with at least one specific medical use of the substance under existing and implemented state authorized programs;

2. Whether a substantial number of entities that regulate the practice of medicine recognize at least one specific medical use of the substance; and

3. Whether an HCPs’ clinical experience with the medical use of the substance is of sufficient extent and duration to help evaluate potential clinical uses and longer-term toxicities and potential harms of the substance when used under medical supervision.¹⁵

If the OASH’s Part 1 analysis “supports the finding that marijuana has at least one CAMU in the United States,” then FDA proceeds to Part 2, assessing whether “[t]here exists some credible scientific support for at least one of the medical uses for which Part 1 is met.”¹⁶

Applying this standard to cannabis, the OASH undertook the Part 1 analysis and found that more than 30,000 HCPs are certified to recommend cannabis for more than six million registered patients under various state medical cannabis regimes.¹⁷ The OASH concluded that this “constitut[ed] widespread clinical experience associated with various medical conditions recognized by a substantial number of jurisdictions across the United States.”¹⁸ The OASH emphasized that “[f]or several jurisdictions, these programs have been in place for several years, and include features that actively monitor medical use and product quality characteristics of marijuana dispensed.”¹⁹ “Taken together,” it concluded that “the findings from Part 1 warrant an FDA assessment under Part 2 of [HHS’s] CAMU approach to determine if there exists credible scientific support for the use of marijuana for at least one of the medical conditions [the OASH identified during the Part 1 investigation].”²⁰

After conducting the Part 2 review, FDA concluded that there does, in fact exist “some credible scientific support for at least one of the medical uses for which Part 1 [was] met.”²¹ In conducting its Part 2 analysis, FDA assessed cannabis’s use as medicine for seven indications, “based in part on OASH’s findings under Part 1 of the CAMU test and in part on FDA’s own analysis of the landscape in which marijuana is currently used medically, including information from state-authorized programs on how and to what extent marijuana is being utilized for medical purposes.”²² Those seven indications were anorexia, anxiety, epilepsy, inflammatory bowel disease (IBD), nausea and vomiting, pain, and post-traumatic stress disorder (PTSD).²³ In the process, FDA conducted “reviews of studies investigating the safety and effectiveness of marijuana, relevant professional societies’ position statements, data from state medical marijuana programs and U.S. national surveys, and the labeling of FDA-approved products relevant to the analysis.”²⁴

FDA explained that for purposes of Part 2, certain “factors” supported “a positive finding,” i.e., that some credible scientific support exists for the medical use of cannabis in question. Such positive factors include

1. favorable clinical studies of the medical use of marijuana, although not necessarily adequate and well-controlled clinical studies that would support approval of a new drug application (NDA), having been published in peer-reviewed journals and/or

2. qualified expert organizations (e.g., academic or professional societies, government agencies) having opined in favor of the medical use or provided guidance to HCPs on the medical use.

Other factors “weigh against a finding that Part 2 of the CAMU test is met,” including:

1. where data or information indicate that the medical use of the substance is associated with unacceptably high safety risks for the likely patient population, e.g., due to toxicity concerns;

2. clinical studies with negative efficacy findings for the medical use of marijuana having been published in peer reviewed journals; and/or

3. qualified expert organizations (e.g., academic or professional societies, government agencies) having recommended against the medical use of marijuana (based on the available data at the time of their position statement).²⁵

After gathering and reviewing a broad swath data and several studies, expert opinions, and the “position statements of professional organizations relevant to the indications discussed,” FDA concluded that “the totality of the available data,” supports a finding “that, for purposes of the drug scheduling criteria in 21 U.S.C. 812(b), marijuana has a currently accepted medical use in the United States for: anorexia related to a medical condition; nausea and vomiting (e.g., chemotherapy-induced); and pain.”²⁶

FDA was quick to emphasize that while “the analysis and conclusions on the available data are not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication,” the totality of the evidence does “provide some level of support for the way marijuana is being used in clinical practice.”²⁷ In other words, the fact that FDA has concluded that cannabis ahs a currently accepted medical use for purposes of section 812(b)(1)(B) of the CSA does not mean that FDA has approved cannabis as safe and effective for marketing as a drug in interstate commerce under the Federal Food, Drug, and Cosmetic Act.²⁸

C. Abuse of cannabis may lead to moderate or low physical dependence or high psychological dependence.

Finally, HHS concluded that “abuse of marijuana may lead to moderate or low physical dependence, depending on frequency and degree of marijuana exposure.” While cannabis “can produce psychic dependence in some individuals,” HHS emphasized that “the likelihood of serious outcomes is low, suggesting that high psychological dependence does not occur in most individuals who use marijuana.”²⁹ In reaching these conclusions, HHS relied in part on some of the same data regarding how the effects of cannabis abuse compare to those associated with abuse of other controlled substances and alcohol that it relied on in its analysis of cannabis’s relative abuse potential.³⁰

PART III: SOME FINAL NOTES

Before I end this post, I want to flag a few additional features of the unredacted analysis that caught my eye:

• HHS emphasized the importance of the 2018 Farm Bill to the scope of its analysis, explaining that because that statute descheduled “hemp,” its analysis does not apply to hemp products or to “[p]roducts containing predominantly plant-derived CBD or marketed with the intent of offering consumers a plant-derived, CBD-containing product.”³¹ The agency added, however, that “[i]t should be noted some hemp-derived CBD products may containΔ9-THC or other cannabinoids in amounts sufficient to produce drug effects more associated with marijuana, and may or may not be legally within the definition of marijuana.”³² As a result, “their widespread use may contribute to the epidemiological data on marijuana use that is discussed in Factors 4, 5, and 6 of this scientific and medical evaluation.” In other words, unregulated intoxicating hemp products may, to some extent, be skewing the analysis to make the harms associated with cannabis abuse appear worse than they actually are.

• I found HHS’s decision to focus so much attention on how the harms associated with cannabis abuse compare to those associated with alcohol—a substance that Congress exempted from the CSA altogether—fascinating. “Typically,” the agency acknowledged, “substances that are not controlled under the CSA are not utilized as comparator drugs for scheduling placement considerations because they may not have been formally evaluated for abuse potential in standard preclinical and clinical abuse-related studies.”³³ Yet, HHS focused on alcohol anyway “because of its extensive availability and use in the United States, which is also observed for nonmedical use of marijuana (also known as recreational use of marijuana).”³⁴ Fair enough, but isn’t the same true of another substance that Congress exempted from the CSA despite its widespread availability, abuse, and harm profile that dwarfs that of cannabis, namely tobacco—a substance that appears nowhere in HHS’s analysis?³⁵

• HHS emphasized the “variability” of cannabis, explaining that “[l]ike any other botanical substance, marijuana plants are heterogeneous in nature and contain a complex chemical profile.”³⁶ In the past, HHS has treated this “variation in forms for [cannabis] consumption, composition of biologically relevant constituents, potency, and contaminants” as a barrier to assessing the appropriateness of rescheduling cannabis as a whole, encouraging petitioners to seek removal of a single strain instead.³⁷ In this most recent review, however, HHS acknowledged the issue but chose to address it by “focus[ing] to greatest extent possible on wide-ranging cannabis plant derived substances that are vehicles for the self-administration of Δ9-THC as the key biologically active substance on which the CSA’s current definition of marijuana is based.”³⁸

• HHS also lamented the lack of uniformity among state-level cannabis regulations and the total lack of regulation of the illicit market, describing it as a “safety” and “quality” problem.³⁹ Considered alongside the agency’s emphasis in Part 1 of CAMU test on the importance of longstanding and widespread experience regulating and using medical cannabis in treatment among state regulators and HCPs, respectively, I began to sense a theme running through HHS’s analysis. Perhaps the agency hopes its exhaustive analysis will nudge state lawmakers and regulators to take coordinated action to bring greater uniformity to the safety controls and regulatory requirements applicable to medical cannabis under state law.

• Another interesting feature of HHS’s analysis was its recognition of the relevance of data supporting the rescheduling of FDA-approved synthetic THCs to its analysis.⁴⁰ Those who have questioned the rationality of keeping cannabis in schedule I when pharma products like syndros and marinol are in schedules II and III, respectively, may view this as a step in the right direction.

1. See 21 U.S.C. 812(b)(3).

2. See 21 U.S.C. 811(b)-(c).

3. This is consistent with how HHS has defined abuse in this context for years. See https://www.fda.gov/media/71652/download at 7 (defining “abuse” to mean “[t]he intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect”).

4. See page 6/252 of the unredacted .pdf.

5. Id.

6. Id.

7. Id. at 63.

8. Id.

9. Id. at 58.

10. Id. at 46.

11. Id. at 10.

12. Id. at 7-8.

13. Matt and I laid the groundwork for that prediction in a Ninth Circuit brief years ago (see pages 49-50).

14. Page 80/252 of the unredacted .pdf.

15. Id.

16. Id.

17. Id. 83.

18. Id.

19. Id.

20. Id.

21. Id. at 112.

22. Id.

23. Id.

24. Id.

25. Id. at 112-13.

26. Id. at 116.

27. Id.

28. Id.

29. Id. at 65.

30. Id. at 64.

31. Id. at 3-4.

32. Id.

33. Id. at 6.

34. Id.

35. See 21 U.S.C. 802(6) (excluding “distilled spirits, wine, malt beverages, [and] tobacco, as those terms are defined or used in subtitle E of the Internal Revenue Code of 1986” form the CSA’s definition of “controlled substance”).

36. Page 20/252.

37. See, e.g., 81 Fed. Reg. 53688, 53698 (Aug. 12, 2016) (explaining “all Cannabis strains cannot be considered together because of the varying chemical constituents between strains”); id. at 53700 (“However, if a specific Cannabis strain is grown and processed under strictly controlled conditions, the plant chemistry may be kept consistent enough to produce reproducible and standardized doses.”).

38. Page 22/252.

39. Id.

40. See, e.g., id. at 197 (“Therefore, if the above approved formulations of THC were considered to have proven benefit for various indications, it is logical to conclude that a similar dose administered through a marijuana preparation would be relevant to informing potential therapeutic uses of marijuana for drug scheduling purposes.”).