Under the Controlled Substances Act (CSA) in the United States, drugs that have the potential to be abused are scheduled into one of five Classes or Schedules (CI-V) as controlled substances. The scheduling method makes a distinction between drugs that have abuse potential and are not approved for medical use (i.e., Schedule I) and drugs that are approved for medical use and have abuse potential (Schedules II-V). In the classification, the higher the number of the Schedule, the lower the abuse potential of the drug and the less restrictive the conditions regarding its distribution, storage, and prescribing.

Schedule I, or Class I (CI), drugs are currently restricted to research in the U.S., meaning that they are not approved for medical use, and are deemed at highest risk for abuse.

Recent research on psychedelics and entactogens, both of which are Schedule I, is beginning to demonstrate the potential therapeutic effects of these drugs for various medical indications. Approvals of such drugs for medical or therapeutic use will inevitably result in the rescheduling of these drugs from their current CI status.

In Issue 19 of The Altascientist, we review:

• the regulatory environment and challenges (Drug Enforcement Administration
• the research site requirements associated with the development of Schedule I drugs for therapeutic 
• required preclinical studies of Schedule I drugs
• required clinical studies of Schedule I drugs
• specialized clinical assessments of Schedule I controlled substances
• formulation, manufacturing, and analytical considerations for Schedule I drugs

The main objective of first-in-human (FIH) trials is to determine the starting dose of a new drug, one that is low enough to provide minimal to no safety and toxicity risks and allows the highest dosage/benefit for the intended trial.

The manufacture of the drug product for clinical trials is of critical importance, as the formulation, manufacturing, and assessment of a drug candidate during FIH trials can

 be contributing factors in whether the drug safely provides the correct dosage and, ultimately, gains regulatory approval. Decisions made during early-phase development, when the compound is being used in a clinical research setting, provide significant learnings for its progression through later phase research. Integration is key — ensuring that information gathered at the clinic is efficiently incorporated into the manufacturing process is a major contributor to the goal of achieving marketing approval.