By the ASPET Science Policy Committee Drug Research Policy Subcommittee

Elijah Ullman, PhD
Marcus Delatte, PhD
David Jewett, PhD
Kevin Murnane, PhD
Shwetal Talele
Marah Wahbeh, PhD – Staff liaison
Peter Winsauer, PhD – Chair

A Policy Statement on Cannabis Rescheduling

Executive Summary

Background: In May of 2024, the Department of Justice (DOJ) placed a Notice of Proposed Rulemaking in the Federal Register⁶ that would transfer marijuana from schedule I of the Controlled Substances Act (CSA) to schedule III of the CSA. Although the current Administration of the federal government has not carried forth with the proposal, the Drug Policy Subcommittee of the American Society for Pharmacology and Experimental Therapeutics (ASPET) would like to make the membership aware of the ramifications of such a rule change and especially for those with preclinical and clinical research programs involving cannabis.

Schedule-Controlled Drugs or Substances: Drug scheduling by the Drug Enforcement Agency (DEA) is a federally-sanctioned, data-driven process intended to ensure the safety of consumers and the individuals that administer or conduct research with these drugs or substances. Among the five schedule classifications (I–V), schedule-I drugs are deemed to have no currently accepted medical use (CAMU) and to have the highest abuse liability and potential for producing physical and psychological dependence. As a result, special handling and security are required for these drugs, as well as DEA and Food and Drug Administration (FDA) review of all research protocols involving these drugs.

Prohibitions to Research: Drug scheduling can also create a regulatory burden that negatively impacts research, especially when the research involves schedule-I drugs. With respect to cannabis specifically, this burden may result in the following:

Limits or delays in the discovery of cannabis-related therapeutic products (e.g., chemical constituents in cannabis);
Limitations on the quantity and quality of data from studies evaluating cannabis-related therapeutic products;
Increases in the costs associated with conducting cannabis or cannabinoid research; and
Further propagation of the negative stigmas associated with marijuana use.

Given the burdens of working with schedule-controlled substances, there may be benefits to re-scheduling drugs such as cannabis when scientific data demonstrate its therapeutic potential or that of substances derived from it. Ideally, these benefits and others will result in increased research to collect high quality data and in the therapeutic use of substances such as cannabis and its chemical constituents to treat patients with unmet medical needs.

Primary Factors Supporting the Rescheduling of Cannabis: The scientific and medical evaluation of cannabis conducted by the Department of Health and Human Services (HHS) and required for rescheduling has identified CAMUs for conditions such as chronic pain, chemotherapy-induced nausea and vomiting, and spasticity due to multiple sclerosis. While many other medical conditions have been proposed for cannabis and are already included in many states’ medical marijuana programs (MMPs), the high-quality data needed to support all of these additional medical conditions is lacking. The scientific and medical evaluation of cannabis also concluded that cannabis had a lower potential for abuse and producing dependence than existing schedule I and II drugs. Although moving cannabis from schedule I to III will not entirely address the challenges mentioned above, the proposed rescheduling will better align state and federal laws regarding its use for medical and research purposes (see map below).

Final Recommendation: By supporting the rescheduling of cannabis from schedule I to III, the membership of ASPET recommends the reduction of the current federal prohibitions to cannabis research and facilitating the continued investigation into its use as a medicinal substance.

State Laws Regarding the Legal Use of Marijuana as of April 2025

Report Outline

Background
Brief History
Regulatory Burden for Conducting Research with Schedule-Controlled Substances
Requirements for Rescheduling of Cannabis
Diversion
Recommendations
References

Subcommittee Report on the Proposed Rescheduling of Cannabis

Background: In May of 2024, the Department of Justice (DOJ) placed a Notice of Proposed Rulemaking in the Federal Register,⁶ which would transfer marijuana from schedule I of the Controlled Substances Act (CSA) to schedule III of the CSA. At the time, this proposal was consistent with the Department of Health and Human Services (HHS) view that marijuana has:

currently accepted medical uses, and
a lower abuse potential and levels of physical or psychological dependence than other controlled substances.

As stated in the DOJ’s solicitation: “The CSA requires that such actions be made through formal rulemaking on the record after an opportunity for a hearing. If the transfer to schedule III is finalized, the regulatory controls applicable to schedule-III controlled substances would apply, as appropriate, along with existing marijuana-specific requirements and any additional controls that might be implemented, including those that might be implemented to meet U.S. treaty obligations.

In May of 2024, the Department of Justice (DOJ) placed a Notice of Proposed Rulemaking in the Federal Register, which would transfer marijuana from schedule I of the Controlled Substances Act (CSA) to schedule III of the CSA.

If marijuana is transferred into schedule III, the manufacture, distribution, dispensing, and possession of marijuana would remain subject to the applicable criminal prohibitions of the CSA. Any drugs containing a substance within the CSA’s definition of ‘marijuana’ would also remain subject to the applicable prohibitions in the Federal Food, Drug, and Cosmetic Act (‘FDCA’).” (p. 44597). Although the DOJ has set a July 22, 2024, deadline for these comments on this solicitation, there has been limited action on this proposed transfer. Nevertheless, the Drug Policy Subcommittee of the American Society for Pharmacology and Experimental Therapeutics (ASPET) would like to make their membership aware of the ramifications for such a rule change and for their preclinical and clinical research programs. Irrespective of our backgrounds as scientists, this change will be very important for unifying public policy on the potential use of these cannabis-related substances for research and as therapeutic products.

If marijuana is transferred into schedule III, the manufacture, distribution, dispensing, and possession of marijuana would remain subject to the applicable criminal prohibitions of the CSA.

The words “marijuana” and “cannabis” are often used interchangeably in various lay and scientific literature, which has unintentionally intertwined the historical and scientific understanding of each term. From a sociocultural perspective, the term “marijuana” has taken on various meanings and been associated with both positive and negative perceptions. For the purposes of this document, objective and scientifically-based definitions have been provided. Marijuana (marihuana) is a cultivated cannabis plant, whether for agricultural, recreational, or medicinal purposes. Cannabis is any raw preparation of the leaves or flowers from the plant genus Cannabis. This report will use “cannabis” as a shorthand that also includes cannabinoids, of which there are more than 150 found in the plant, along with numerous terpenes, flavonoids, and sterols.^14,15

From a sociocultural perspective, the term “marijuana” has taken on various meanings and been associated with both positive and negative perceptions.

In general, cannabinoids are any chemical compounds, either endogenous or exogenous, that act on the two major cannabinoid receptors of the cannabinoid system in humans (i.e., type-1 and type-2 receptors). This is not required for the definition of a cannabinoid, however, as some well-known plant-derived cannabinoids such as cannabidiol (CBD) have animals and isolated cellular/tissue samples. Further, without these quality data for the various qualifying conditions, information about the most effective dosages, routes, safety, adverse and long-term effects of cannabis is lacking or largely absent for the 57 qualifying conditions found in jurisdictional laws, as well as for the 18 most common qualifying conditions across all MMPs.¹¹ The National Academy of Science did, however, determine that there was conclusive or substantial evidence that cannabis or cannabinoids were effective for the treatment of chronic pain, chemotherapy-induced nausea and vomiting, and little affinity for these receptors.

The National Academy of Science did, however, determine that there was conclusive or substantial evidence that cannabis or cannabinoids were effective for the treatment of chronic pain, chemotherapy-induced nausea and vomiting, and little affinity for these receptors.

The primary endogenous compounds, which are derived from cell membrane phospholipids, are 2-arachidonylglycerol (2-AG) and anandamide. The exogenous compounds can be phytocannabinoids (plant-derived), synthetic (laboratory-derived), or semi-synthetic (cannabinoids from the cannabis plant that are produced synthetically in a laboratory).

Brief History: Prior to 1936, cannabis was sold over the counter and used commonly for a variety of illnesses in the United States.⁷ By 1936, however, every state had passed laws to restrict possession of cannabis due to the changing perceptions of marijuana as a dangerous and harmful substance, which resulted from a combination of public fear, anti-drug campaigns, strong federal laws, and international influences that effectively eliminated its over-the-counter availability. Complicating matters further was the passage of the Comprehensive Drug Abuse Prevention and Control Act in 1970 that provided five classifications for controlled substances (i.e., schedules I–V, with schedule I substances considered to have no medicinal purpose) and included cannabis in the list of schedule-I controlled substances. This additional codification of cannabis’ perceived dangers discouraged health-care providers from prescribing or recommending cannabis even though approved uses for semi-synthetic cannabinoids began to appear. For example, a synthetic ∆9-THC generically referred to as dronabinol (trade name Marinol) was approved by the Food and Drug Administration (FDA) in 1985 as a schedule-II controlled substance for nausea and vomiting associated with cancer chemotherapy in patients who failed to respond adequately to conventional antiemetics. Around the same time, an oral formulation of dronabinol (trade name Syndros) was approved for anorexia associated with weight loss in patients with acquired immunodeficiency syndrome (AIDS). Not surprisingly, approval of Marinol for the same indication then followed in 1992.

The next major step toward cultural acceptance of marijuana occurred when medical marijuana was approved by voters in California in 1996.

The next major step toward cultural acceptance of marijuana occurred when medical marijuana was approved by voters in California in 1996. However, the federal government opposed the proposition and threatened to revoke the prescription-writing abilities of doctors who recommended or prescribed marijuana even after the voters’ approval. This level of federal opposition continued until 2000 when a group of physicians challenged this policy and won the right to recommend—but not prescribe—medical marijuana.⁷ Since then, the misalignment between federal law, which classifies cannabis as a schedule-I controlled substance, and the various states’ marijuana laws for the legalization of medical and recreational use has only grown (see MARIJUANA LEGALITY BY STATE—Updated April 28, 2025 | DISA). Particularly emblematic of this misalignment between federal and state law is the uniqueness of each state’s legislation for the medical and recreational use of cannabis. With respect to the medical marijuana programs (MMPs), there are few commonalities among the programs. Areas of commonality typically include the:

provisions for procuring a certification/recommendation for the use of cannabis,
limits on the amount of cannabis that can be recommended to or procured by an individual,
legal protections for participants, state employees, designated caregivers, and health-care providers, and
a lack of protections for professions considered high risk such as construction, law enforcement, and national security.

Each MMP also creates a list of qualifying conditions for the use of cannabis, with the choice of these conditions based on the best scientific information available. However, federal classification of cannabis as a schedule-I substance has severely limited research on the efficacy of cannabis for treating certain medical conditions and research on cannabis in general.¹³ This has limited the quantity and quality of data available to support the various qualifying conditions chosen by the MMPs. As a result, MMPs are not based on high-quality data (i.e., double-blinded, placebo-controlled clinical trials), and are sometimes based only on human case reports, clinician intuition, or preclinical research involving spasticity due to multiple sclerosis.⁸ They also indicated there was enough evidence to support the use of cannabis for specific types of sleep disturbances, fibromyalgia, and chronic pain. Since then, moderate- to high-quality studies have shown the additional potential of cannabis for reducing seizure frequency in individuals with Dravet and Lennox-Gastaut syndromes, reducing posttraumatic stress disorder (PTSD) nightmares, and reducing tics in those with Tourette syndrome. Data from these studies also resulted in the FDA approval of an oral formulation of the phytocannabinoid cannabidiol (CBD) for the treatment of seizures (trade name Epidiolex).

Far more research will be required to address the lack of quality data regarding both the legal medicinal, as well as the legal recreational, use of cannabis.

Regulatory Burden for Conducting Research with Schedule-Controlled Substances: Far more research will be required to address the lack of quality data regarding both the legal medicinal, as well as the legal recreational, use of cannabis. Removing existing barriers that prevent researchers from conducting cannabis research is essential for this effort. Chief among these barriers is the federal law classifying cannabis as a schedule-I controlled substance. Currently, scientists interested in conducting research with a schedule-I substance must obtain a schedule-I license from the Drug Enforcement Agency (DEA) under the Registration Provision of 21 USC 822 subsection of the CSA, whereas those conducting research with substances classified under schedules II–V must obtain a separate DEA registration number or license to work with those substances. Along with the annual administrative/renewal costs for each license, the bureaucratic burden associated with maintaining each license is different. For instance, because schedule-I substances are supposed to have the highest potential for inducing a use disorder and misuse, and have no medicinal value, obtaining and possessing these drugs for research receives additional scrutiny. To obtain a schedule-I license, a researcher must submit their research protocols to the DEA and the FDA for review. These protocols are required to include expected methods, animal usage, dosages, and the timelines for the studies. The DEA also conducts a background check and performs site inspections—announced before the license is awarded to obtain approval for the proposed site, and unannounced inspections after the license is awarded.

During site visits, DEA inspectors examine the drug logs for each substance and ensure the researcher is securing these substances in a floor mounted, fireproof safe with double-locking mechanisms in a secure laboratory and building. Access to these substances by laboratory personnel is closely monitored, in that only individuals designated by the researcher are allowed access to the safe and to handle these substances in the laboratory setting. Finally, if the researcher wants to make any substantial changes to the methods, drugs, or drug usage in their experimental protocol, resubmission and re-approval from the DEA and FDA is required. Examples of schedule-I drugs include heroin, lysergic acid diethylamide (LSD), mescaline, methylenedioxy-methamphetamine (MDMA), and methaqualone (see Code of Federal Regulations, 1308.11).²

While schedule-II drugs are considered to have a reduced potential for producing use disorders, misuse, and physical and psychological dependence compared to schedule-I drugs, these drugs are still considered to have a high capacity for inducing these adverse conditions. Thus, the regulatory burden for obtaining, handling, and storing schedule-II drugs is very similar to that for schedule-I drugs. Although one difference is that researchers can conduct research with any drug under this schedule, not just those for which they have received approval by submitting their protocols to the DEA and FDA. Drugs under this schedule also have FDA-approved medical uses such as the treatment of severe pain, anxiety, insomnia, and Attention Deficit and Hyperactivity Disorder (ADHD). Among the drugs listed under this schedule are opioids such as codeine (formulations > 90 mg per dosage), fentanyl, morphine, meperidine, and oxycodone, barbiturates such as pentobarbital and secobarbital, and central nervous system (CNS) stimulants such as dextroamphetamine, methylphenidate, and methamphetamine (see Code of Federal Regulations, 1308.12).²

The potential risk for eliciting use disorders, misuse, and physical and psychological dependence is considered to be reduced for schedule-III drugs (though far from absent) compared to schedule-I and -II drugs. Moreover, drugs under this schedule are still FDA approved for pain control, anesthesia and appetite suppression, leading to the inclusion of opioids such as codeine (formulations < 90 mg per dosage) and buprenorphine, dissociative anesthetics such as ketamine, and CNS stimulants such as benzphetamine and phendimetrazine under this schedule. Anabolic steroids are also included under this schedule (see Code of Federal Regulations, 1308.13).² Due to the reduced incidence of adverse drug effects under this schedule, the regulatory burden is also less than that for schedule-I and -II drugs. For example, schedule-III drugs do not need to be stored in their own double-locked safe with laboratory and building security as required for schedule-I and -II drugs; these drugs can be stored in a locked drawer or cabinet that is inaccessible from above or below.

Schedule-III drugs do not need to be stored in their own double-locked safe with laboratory and building security as required for schedule-I and -II drugs.

Schedule-IV controlled substances are considered to have even lower misuse potential than schedule I, II, or III, and are considered to have a limited risk for producing physical or psychological dependence (e.g., Prescription of Controlled Substance: Benefits and Risks).¹⁰ This seems somewhat paradoxical given that schedule-IV substances include a wide variety of benzodiazepines such as alprazolam, clonazepam, clorazepate, diazepam, lorazepam, midazolam, temazepam, and triazolam, the CNS depressant/muscle relaxant carisoprodol, and the opioid analgesic tramadol (see Code of Federal Regulations, 1308.14).² All of these drugs have marked abuse liabilities and the potential for producing physical and psychological dependence. In fact, physicians and psychiatrists are now frequently prescribing antidepressants such as escitalopram (trade name Lexapro) and hydroxyzine (trade name Atarax) in place of benzodiazepines for anxiety disorders to avoid the potential for someone developing a benzodiazepine-induced physical dependence, which can produce a life-threatening withdrawal syndrome.¹²

Schedule-V drugs are considered to be the least likely controlled substances to be misused and to have a very limited potential for producing physical and psychological dependence. Examples of substances under this schedule include cough medicines with codeine, phenylephrine or pseudoephedrine, antidiarrheal medications that contain atropine and diphenoxylate, and anticonvulsants such as pregabalin, exogabine and ganaxolone (see Code of Federal Regulations, 1308.15).² These substances still require a prescription, and state-regulated limits may be placed on the amounts that a person can possess, especially for pseudoephedrine because it can be converted illicitly to methamphetamine.

Requirements for Rescheduling of Cannabis: As specified under the CSA (21 U.S.C. 801 et seq.), the Attorney General must request a scientific and medical evaluation of a drug or other substance from the Secretary of HHS before initiating proceedings to control, decontrol, or transfer a drug or substance to another schedule. In addition, the Secretary of HHS must also include their own recommendation(s) for any proposed changes. Thus, the rescheduling of cannabis under consideration was initiated by the Attorney General and followed the required scientific and medical evaluation by HHS.

Integral to that evaluation, and as set forth under the CSA for recommending or determining that a drug or substance should be controlled, is the consideration of eight factors:

the drug’s actual or relative potential for abuse;
scientific evidence of its pharmacological effect, if known;
the state of current scientific knowledge regarding the drug or other substance;
its history and current pattern of abuse;
the scope, duration, and significance of abuse;
what, if any, risk there is to public health;
its psychic or physiological dependence liability; and
whether the substance is an immediate precursor of a substance already controlled.

More generally, and evident from the descriptions of each schedule above, the schedule or level of control for a drug or substance is based on its:

potential for abuse,
any currently accepted medical use (CAMU), and
safety for use under medical supervision or capacity for inducing psychological and physical dependence when abused.

For those individuals interested in the respective conclusions of the eight-factor analysis for cannabis by the HHS, the information can be found in the Federal Register.⁶ For more general guidance, see Assessment of Abuse Potential of Drugs: Guidance for Industry.³ Finally, more detailed information about what constitutes “the potential for abuse” or a CAMU can be found in various published Congressional hearings and reports on prior efforts to schedule or reschedule drugs. For example, as stated in a brief on The Matter of MDMA Scheduling,⁵ the House Report (H.R.) on 18583 states that ‘the potential for abuse should not be determined on the basis of “isolated or occasional non-therapeutic purposes.”’ The report further states ‘that there must exist “a substantial potential for the occurrence of significant diversions from legitimate channels, significant use by individuals contrary to professional advice, or substantial capability of creating hazards to the health of the user or the safety of the community.”’ Another comment in the report noted that the scheduling of a drug should not have ‘to wait until a number of lives have been destroyed or substantial problems have already arisen (p. 18).’

Diversion: Although not always explicitly mentioned with the scientific and medical considerations for scheduling a drug or substance, another important consideration for the DEA is whether that drug or substance can be diverted for illicit use or financial purposes. Simply defined, diversion constitutes the use of a drug or substance for any purpose other than its approved medical indication. Examples include patients that sell their drugs as a method of earning money for food, expenses, or even purchasing other street drugs, or health-care providers that divert drugs from patients for personal use or to sell them to someone else. According to some sources (e.g., Prescription of Controlled Substance: Benefits and Risks),¹⁰ before prescription drug diversion became popular, illicit drugs were either imported from other countries or manufactured in clandestine laboratories. In a review of multiple studies by Preuss et al. (Prescription of Controlled Substance: Benefits and Risks),¹⁰ for example, 55% of prescription drugs were obtained free from a friend or relative, whereas 20% were obtained from a prescriber.

Drug diversion has further complicated the challenges faced by law enforcement agencies and further entrenched their position that drug diversion contributes to increased criminal activity, dangerous overdoses, and death.

Drug diversion, therefore, has further complicated the challenges faced by law enforcement agencies and further entrenched their position that drug diversion contributes to increased criminal activity, dangerous overdoses, and death. The recent opioid crisis has also likely contributed to the DEA’s position on this matter, because it was initiated by the over-prescription of opioid analgesics,^1,4 particularly oxycodone (i.e., Oxycontin), and the over-supply of opioids by pharmaceutical companies and pharmacy chains.⁹ This position has also made it difficult for law enforcement to accept the idea that laboratories conducting research on these substances could exist as exceptions to the potential for diversion—even though:

these same laboratories are often providing the safety and toxicological data that inform their scheduling decisions,
an Administrative Law Judge overseeing a hearing on the scheduling of two 5-HT2A receptor agonists, 2,5-dimethoxy-4-iodo-amphetamine (DOI) and 2,5-dimethoxy-4-chloro-amphetamine (DOC), recently permitted testimony on how scheduling can harm research, and
HHS indicated that there is a lack of data indicating diversion occurring from federal entities or activities.

Recommendations: Based on the information presented in this document, the ASPET Science Policy Committee recommends that its members support the rescheduling of cannabis from a schedule-I substance to a schedule-III substance for the following reasons:

The scientific and medical evaluation of cannabis conducted by HHS has demonstrated CAMUs for conditions such as chronic pain, chemotherapy-induced nausea and vomiting, and spasticity due to multiple sclerosis.
The same HHS evaluation indicated that cannabis had a lower potential for abuse and dependence than schedule I and II drugs.
Rescheduling cannabis from schedule I to III is a positive first step in reducing the regulatory burden associated with conducting cannabis research and allowing for the expansion of research on cannabis and cannabinoids to further understand its benefits as a therapeutic and its harms as a misused substance.
While proposed federal rulemaking such as this can be administration dependent, classifying cannabis as a schedule-III controlled substance would support a recommendation from HHS, allow the DEA to continue to monitor diversion until data regarding diversion from State programs and DEA-registered manufactures can be collected, and facilitate needed research into cannabis for medical and recreational use without further promoting its legalization of recreational use.
Although federal laws will still be more restrictive than many State laws, classifying cannabis and cannabinoids as a schedule-III substances will better align federal and state laws.

Rescheduling cannabis from schedule I to III is a positive first step in reducing the regulatory burden associated with conducting cannabis research and allowing for the expansion of research on cannabis and cannabinoids.

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