THIS ARTICLE IS A COLLATION OF THE SUBMISSION BY DAVID EVANS OF A JAMA RESEARCH BY MICHAEL HSU ET AL, PLUS COMMENTS BY JOHN COLEMAN AND BERTHA MADRAS

Comment by John Coleman, – john.coleman.phd@gmail.com- 14 December 2025 

Subject: Re: FROM DAVID EVANS MOST RECENT META ANALYSIS OF THERAPUETIC USE OF CANNABIS

Bertha,

You raise an interesting point, i.e., could someone argue (and who would it be?) that because cannabis was a medicine prior to the 1938 Amendments to the Food and Drug Act, is pre-market approval required, or can it be considered “grandfathered-in”? My copy of the 1936 National Formulary lists the only cannabis medicine as a tincture and gives the formula for the medicinal composition (see below). The 1937 Marihuana Tax Act prohibited prescribing and dispensing marihuana without a federal registration and payment of a special tax. That, in effect, dissuaded its use as a medicine, and by 1941, it was removed from the U.S. Pharmacopeia.

In 1968, Harvard Professor Timothy Leary brought his case to the Supreme Court. Leary and his daughter had been arrested entering Texas from Mexico with a kilo of marijuana. In deciding for Leary, the Court invalidated much of the Marihuana Tax Act of 1937, under which Leary had been convicted in lower courts. This problem was addressed by Congress in 1970 with the enactment of the Comprehensive Drug Abuse and Control Act, Title II of which is the Controlled Substances Act. This ended the uncertainty and placed cannabis (marihuana and THCs) in Schedule I, confirming that it was not approved for use in treatment in the U.S.

The 1938 Food, Drug, and Cosmetic Act grandfathered all drugs on the market at the time the bill was enacted. They did not require additional safety and effectiveness testing required for all new drugs. But this came with a caveat requiring grandfathered drugs to retain the same formulation and chemical composition as before the 1938 Act. This means that the Tincture described in the attachment would have to be replicated today, assuming such an argument might prevail. Personally, I think the CSA of 1970 mooted this issue forever, and anyone making such an argument today would likely be laughed at … (But it is an interesting hypothesis!)

John Coleman

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Comment by Bertha Madras,  <bertha_madras@hms.harvard.edu> Sent: Sunday, December 14, 2025 

Subject: Re: FROM DAVID EVANS MOST RECENT META ANALYSIS OF THERAPUETIC USE OF CANNABIS

Let us not forget that FDA approval is highly desirable for a drug to be included in S2-S5, but it is not essential. A number of drugs were “grandfathered in”.  I am unaware of any recent drug that landed in a “medical” S2-S5 schedule  without FDA approval. Perhaps Philip Drum is aware of them.  That’s how HHS shaped their argument, on the basis of 8-factor analysis and not FDA approval.

The best rebuttal for how S1 prevents research is to use CBD as an example. It was S1 (and generic CBD remains there) but GW decided to invest in it, did the clinical trials, generated Phase 3 data sufficiently adequate for the FDA to approve. Then Epidiolex eventually was removed from CSA (de-scheduled) because of any evidence it has abuse liability.

Bertha K Madras

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Submission by DAVID EVANS – December 14, 2025 

MOST RECENT META ANALYSIS OF THERAPEUTIC USE OF CANNABIS – 11.26.2025

Approximately 27% of adults in the US and Canada report having ever used cannabis for medical purposes. An estimated 10.5% of the US population reports using cannabidiol (CBD), a chemical compound extracted from cannabis that does not have psychoactive effects, for therapeutic purposes.

Observations  Conditions for which cannabinoids have approval from the US Food and Drug Administration include HIV/AIDS–related anorexia, chemotherapy-induced nausea and vomiting, and certain pediatric seizure disorders. A meta-analysis of randomized clinical trials reported a small but significant reduction in nausea and vomiting from various causes (eg, chemotherapy, cancer) when comparing prescribed cannabinoids (eg, dronabinol, nabilone) with placebo or active comparators (eg, alizapride, chlorpromazine; standardized mean difference [SMD], −0.29 [95% CI, −0.39 to −0.18]). A meta-analysis of randomized clinical trials among patients with HIV/AIDS reported that cannabinoids had a moderate effect on increasing body weight compared with placebo (SMD, 0.57 [95% CI, 0.22 to 0.92]). Evidence-based guidelines do not recommend the use of inhaled or high-potency cannabis (≥10% or 10 mg Δ9-tetrahydrocannabinol [Δ9-THC]) for medical purposes. High-potency cannabis compared with low-potency cannabis use is associated with increased risk of psychotic symptoms (12.4% vs 7.1%) and generalized anxiety disorder (19.1% vs 11.6%). A meta-analysis of observational studies reported that 29% of individuals who used cannabis for medical purposes met criteria for cannabis use disorder. Daily inhaled cannabis use compared with nondaily use was associated with an increased risk of coronary heart disease (2.0% vs 0.9%), myocardial infarction (1.7% vs 1.3%), and stroke (2.6% vs 1.0%). Evidence from randomized clinical trials does not support the use of cannabis or cannabinoids for most conditions for which it is promoted, such as acute pain and insomnia. Before considering cannabis or cannabinoids for medical use, clinicians should consult applicable institutional, state, and national regulations; evaluate for drug-drug interactions; and assess for contraindications (eg, pregnancy) or conditions in which risks likely outweigh benefits (eg, schizophrenia or ischemic heart disease). For patients using cannabis or cannabinoids for treatment of medical conditions, clinicians should discuss harm reduction strategies, including avoiding concurrent use with alcohol or other central nervous system depressants such as benzodiazepines, using the lowest effective dose, and avoiding use when driving or operating machinery.

Conclusions and Relevance  Evidence is insufficient for the use of cannabis or cannabinoids for most medical indications. Clear guidance from clinicians is essential to support safe, evidence-based decision-making. Clinicians should weigh benefits against risks when engaging patients in informed discussions about cannabis or cannabinoid use.

Source: www.drugwatch.org