UTopiAH’s life expectancy and death rate are below the Marijuana states, which as of 2017, filled the top quintile state rankings. See Part 16. These parts contain the 2015 Drug Enforcement Agency’s response to a 2011 petition from the Governors of Washington and Rhode Island to legalize Marijuana, a DEA Schedule One Drug. . The letter is viewable at https://www.deadiversion.usdoj.gov/schedules/marijuana/Incoming_Letter_Department%20_HHS.pdf#search=marijuana.

[Continued from Part 33]

Part 34. Marijuana Status of Research into the Medical Use, DEA, FDA, HHS, California Center for Medicinal Cannabis Research.

Status of Research into the Medical Uses for Marijuana

State-level public initiatives, including laws and referenda in support of the medical use of marijuana, have generated interest in the medical community and the need for high quality clinical investigation as well as comprehensive safety and effectiveness data. In order to address the need for high quality clinical investigations, the state of California established the Center for Medicinal Cannabis Research (CMCR, www.cmcr.ucsd.edu) in 2000 “in response to scientific evidence for therapeutic possibilities of cannabis5 and local legislative initiatives in favor of compassionate use” (Grant, 2005). [Footnote 5 -In this quotation the term cannabis is interchangeable with marijuana.] State legislation establishing the CMCR called for high quality medical research that would “enhance understanding of the efficacy and adverse effects of marijuana as a pharmacological agent,” but stressed the project

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“should not be construed as encouraging or sanctioning the social or recreational use of marijuana.” The CMCR funded many of the published studies on marijuana’s potential use for treating multiple sclerosis, neuropathic pain, appetite suppression and cachexia. However, aside from the data produced by CMCR, no state-level medical marijuana laws have produced scientific data on marijuana’s safety and effectiveness.

FDA [FOOD AND DRUG ADMINISTRATION] approves medical use of a drug following a submission and review of an [NEW DRUG APPLICATION] NDA or [BIOLOGICS LICENSE APPLICATION] BLA. The FDA has not approved any drug product containing marijuana for marketing. Even so, results of small clinical exploratory studies have been published in the current medical literature. Many studies describe human research with marijuana in the United States under FDA-regulated [INVESTIGATIONAL NEW DRUG] IND applications.

However, FDA approval of an NDA is not the only means through which a drug can have a currently accepted medical use in treatment in the United States. In general, a drug may have a “currently accepted medical use” in treatment in the United States if the drug meets a five­ part test. Established case law (Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)) upheld the Administrator of DEA’s application of the five-part test to determine whether a drug has a “currently accepted medical use.” The following describes

the five elements that characterize “currently accepted medical use” for a drug 6 :[footnote 57 FR 10499, 10504-06 (March 26, 1992). ]

1. the drug’s chemistry must be known and reproducible

“The substance’s chemistry must be scientifically established to permit it to be reproduced into dosages which can be standardized. The listing of the substance in a current edition of one of the official compendia, as defined by section 201(j) of the Food, Drug and Cosmetic Act, 21 U.S.C. 3210), is sufficient to meet this requirement.”

1. there must be adequate safety studies

“There must be adequate pharmacological and toxicological studies, done by all methods reasonably applicable, on the basis of which it could fairly and responsibly be concluded, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, that the substance is safe for treating a specific, recognized disorder.”

iii. there must be adequate and well-controlled studies proving efficacy

• “There must be adequate, well-controlled, well-designed, well-conducted, and well-documented studies, including clinical investigations, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, on the basis of which it could be fairly and responsibly concluded by such experts that the substance will have the intended effect in treating a specific, recognized disorder.”

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1. the drug must be accepted by qualified experts

“The drug has a New Drug Application (NDA) approved by the Food and Drug Administration, pursuant to the Food, Drug and Cosmetic Act, 21 U.S.C. 355. Or, a consensus of the national community of experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of the substance for use in treating a specific, recognized disorder. A material conflict of opinion among experts precludes a finding of consensus.” and

1. the scientific evidence must be widely available.

“In the absence of NDA [New Drug Application] approval, information concerning the chemistry, pharmacology, toxicology, and effectiveness of the substance must be reported, published, or otherwise widely available, in sufficient detail to permit experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, to fairly and responsibly conclude the substance is safe and effective for use in treating a specific, recognized disorder.”

Marijuana does not meet any of the five elements necessary for a drug to have a “currently accepted medical use.”

Firstly, the chemistry of marijuana, as defined in the petition, is not reproducible in terms of creating a standardized dose. The petition defines marijuana as including all Cannabis cultivated strains.

[Ed. Petitions were submitted in 2011 to the DEA, by Governors Chafee of Rhode Island and Gregoire of Washington, to repeal rules placing Marijuana in Schedule I of the Controlled Substance Act, contending it is accepted and safe for medical use, with low abuse potential. The DEA Administrator requested HHS evaluate scientific and medical information with recommendations. The Secretary HHS, Controlled Substance Staff, Center for Drug Evaluation and Research, FDA replied to the DEA in 2015.]

Different marijuana samples derived from various cultivated strains may

have very different chemical constituents including delta 9-THC and other cannabinoids

(Appendino et al., 2011). As a consequence, marijuana products from different strains will have different safety, biological, pharmacological, and toxicological profiles. Thus, when considering all Cannabis strains together, because of the varying chemical constituents, reproducing consistent standardized doses is not possible. Additionally, smoking marijuana currently has not been shown to allow delivery of consistent and reproducible doses. 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.

As to the second and third criteria; there are neither adequate safety studies nor adequate and well-controlled studies proving marijuana’s efficacy. To support the petitioners’ assertion that marijuana has accepted medical use, the petitioners cite the American Medical Association’s (AMA) 2009 report entitled “Use of Cannabis for Medicinal Purposes.” The petitioners claim the AMA report is evidence the AMA accepts marijuana’s safety and efficacy.

[Ed. Petitioners included Governors Chafee of Rhode Island and Gregoire of Washington, who asked the DEA to repeal rules placing Marijuana in Schedule I of the Controlled Substance Act, contending it was accepted for medical use, safe, and with low abuse potential. The DEA, in turn, received scientific and medical information with recommendations from the Secretary HHS, FDA, Controlled Substance Staff, Center for Drug Evaluation and Research, in 2015.]

However, the 2009 AMA report clarifies that the report “should not be viewed as an endorsement of state-based medical cannabis programs, the legalization of marijuana, or

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that scientific evidence on the therapeutic use of cannabis meets the same and current

standards for a prescription drug product.’’ 7

[Footnote7 In this quotation the term cannabis is used interchangeably for marijuana.]

Currently, no published studies conducted with marijuana meet the criteria of an adequate and well-controlled efficacy study. The criteria for an adequate and well-controlled study for purposes of determining the safety and efficacy of a human drug are defined under the Code of Federal Regulations (CFR) in 21 CPR 314.126. In order to assess this element, FDA [FOOD AND DRUG ADMINISTRATION] conducted a review of clinical studies published and available in the public domain before February, 2013. Studies were identified through a search of PubMed8

[footnote 8 8 The following search strategy was used, “(cannabis OR marijuana) AND (therapeutic use OR therapy) AND (RCT OR randomized controlled trial OR “systematic review” OR clinical trial OR clinical trials) NOT (“marijuana abuse”[Mesh] OR addictive behavior OR substance related disorders).” ]

for articles published from inception to February 2013, for randomized controlled trials using marijuana to assess marijuana’s efficacy in any therapeutic indication. Additionally, the review included studies identified through a search of bibliographic references in relevant systematic reviews and identified studies presenting original research in any language. Selected studies needed to be placebo-controlled and double-blinded. Additionally, studies needed to encompass administered marijuana plant material. There was no requirement for any specific route of administration, nor any age limits on study subjects. Studies were excluded that used placebo marijuana supplemented by the addition of specific amounts of THC or other cannabinoids. Additionally, studies administering marijuana plant extracts were excluded.

The PubMed search yielded a total of 566 abstracts of scientific articles. Of these abstracts, a full-text review was conducted with 85 papers to assess eligibility. Of the studies identified through the search of the references and the 566 abstracts from the PubMed search, only 11 studies met all the criteria for selection (Abrams et al., 2007; Corey-Bloom et al., 2012; Crawford and Merritt, 1979; Ellis et al., 2009; Haney et al., 2005; Haney et al., 2007; Merritt et al., 1980; Tashkin et al., 1974; Ware et al., 2010; Wilsey et al., 2008; Wilsey et al., 2013). These 11 studies were published between 1974 and 2013. Ten of these studies were conducted in the United States and one study was conducted in Canada. The identified studies examine the effects of smoked and vaporized marijuana for the indications of chronic neuropathic pain, spasticity related to Multiple Sclerosis (MS), appetite stimulation in human immunodeficiency virus (HIV) patients, glaucoma, and asthma. All studies used adult subjects. ·

The 11 identified studies were individually evaluated to determine if they successfully meet accepted scientific standards. Specifically, they were evaluated on study design including subject selection criteria, sample size, blinding techniques, dosing paradigms, outcome measures, and the statistical analysis of the results. The analysis relied on published studies, thus information available about protocols, procedures, and results were limited to documents published and widely available in the public domain. The review found that all 11 studies that examined effects of inhaled marijuana do not currently prove efficacy of marijuana in any therapeutic indication based on a number of limitations in their study design; however, they may be considered proof of concept studies. Proof of concept studies provide preliminary evidence on a proposed hypothesis involving a drug’s effect. For drugs under development, the effect often relates to a short-term clinical outcome being

Footnote 7 In this quotation the term cannabis is used interchangeably for marijuana.

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investigated. Proof of concept studies often serve as the link between preclinical studies and dose ranging clinical studies. Thus, proof of concept studies generally are not sufficient to prove efficacy of a drug because they provide only preliminary information about the effects of a drug.

In addition to the lack of published adequate and well-controlled efficacy studies proving efficacy, the criteria for adequate safety studies has also not been met. Importantly, in its discussion of the five-part test used to determine whether a drug has a “currently accepted medical use,” DEA said, “No drug can be considered safe in the abstract. Safety has meaning only when judged against the intended use of the drug, its known effectiveness, its known and potential risks, the severity of the illness to be treated, and the availability of alternative remedies” (57 FR 10504). When determining whether a drug product is safe and effective for any indication, FDA [FOOD AND DRUG ADMINISTRATION] performs an extensive risk-benefit analysis to determine whether the risks posed by the drug product’s side effects are outweighed by the drug product’s potential benefits for a particular indication. Thus, contrary to the petitioner’s assertion that marijuana has accepted safety, in the absence of an accepted therapeutic indication which can be weighed against marijuana’s risks, marijuana does not satisfy the element for having adequate safety studies such that experts may conclude that it is safe for treating a specific, recognized disorder.

[Ed. Petitioners included Governors Chafee of Rhode Island and Gregoire of Washington, who asked the DEA to repeal rules placing Marijuana in Schedule I of the Controlled Substance Act, contending it was accepted for medical use, safe, and with low abuse potential. The DEA, in turn, received scientific and medical information with recommendations from the Secretary HHS, FDA, Controlled Substance Staff, Center for Drug Evaluation and Research, in 2015.]

The fourth of the five elements for determining “currently accepted medical use” requires that the national community of experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of the substance for use in treating a specific, recognized disorder. A material conflict of opinion among experts precludes a finding of consensus. Medical practitioners who are not experts in evaluating drugs are not qualified to determine whether a drug is generally recognized as safe and effective or meets [NEW DRUG APPLICATION] NDA requirements (57 FR 10499, 10505).

There is no evidence that there is a consensus among qualified experts that marijuana is safe and effective for use in treating a specific, recognized disorder. As discussed above, there are not adequate scientific studies that show marijuana is safe and effective in treating a specific, recognized disorder. In addition, there is no evidence that a consensus of qualified experts have accepted the safety and effectiveness of marijuana for use in treating a specific, recognized disorder. Although medical practitioners are not qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, we also note that the AMA’s report, entitled “Use of Cannabis for Medicinal Purposes,” does not accept that marijuana currently has accepted medical use. Furthermore, based on the above definition of a “qualified expert”, who is an individual qualified by scientific training and experience to evaluate the safety and effectiveness of a drug, state-level medical marijuana laws do not provide evidence of a consensus among qualified experts that marijuana is safe and effective for use in treating a specific, recognized disorder.

As to the fifth part of the test, which requires that information concerning the chemistry, pharmacology, toxicology, and effectiveness of marijuana to be reported in sufficient detail, the scientific evidence regarding all of these aspects is not available in sufficient detail to allow adequate scientific scrutiny. Specifically, the scientific evidence regarding marijuana’s

[page 27]

chemistry in terms of a specific Cannabis strain that could produce standardized and reproducible doses is not currently available.

Alternately, a drug can be considered to have a “currently accepted medical use with severe restrictions” (21 U.S.C. 812(b)(2)(B)), as allowed under the stipulations for a Schedule II drug. Yet, as stated above, currently marijuana does not have any accepted medical use, even under conditions where its use is severely restricted.

In conclusion, to date, research on marijuana’s medical use has not progressed to the point where marijuana is considered to have a “currently accepted medical use” or a “currently accepted medical use with severe restrictions.”

Continued next Part 35]

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