by Lizbeth Adams PhD

Reefer Sanity: IRB Review of Marijuana Research

A History of Cannabis and Regulation of the Drug

Cannabis—also known as marijuana—has been used by humans for at least 2,500 years according to written records, and perhaps as long as 10,000 years. Its medical use as an anticonvulsant, an analgesic, and a hypnotic has been documented since the early 19th century. Despite the drug’s widespread use, it was outlawed by a number of states in the early 1900s, and the federal government in 1937. Just before marijuana became illegal across the nation, Americans had the chance to view Reefer Madness, a 1936 propaganda film that luridly portrayed the purported dangers of the drug.

Marijuana use continued nonetheless during the 20th century, becoming an important element of the countercultural revolution of the 1960s. A 2016 National Survey on Drug Use and Health reported 23.9 million people aged 12 years and older had used cannabis in the previous month. Currently, nine states plus the District of Columbia have legalized marijuana for recreational use (that is, no prescription required), and thirty states have legalized medical marijuana. Legal marijuana sales reached $9.7 billion in North America alone in 2017. However, the drug remains illegal on the federal level.

As is true of many botanical substances in widespread use, scientific evidence is lacking regarding the consequences of short-term or long-term use of cannabis when used either medicinally or recreationally. Safety—including addiction potential—and efficacy have not been firmly established. The progress of research on cannabis is hindered by the fact that the drug is classified as a Schedule I substance “with no currently accepted medical use and a high potential for abuse.” (The Schedule I class also includes heroin, LSD, ecstasy, and peyote). The supply of cannabis that can be used for research purposes is controlled by the Drug Enforcement Administration (DEA) and National Institute on Drug Abuse (NIDA) government. Some cannabis researchers have deemed the research product to be inferior, expressing concerns about the product’s provenance, potency, and storage length and conditions.

Potential Uses and Abuses of Cannabis

The main psychoactive chemical in cannabis is tetrahydrocannabinol (THC), but there are potentially hundreds of additional compounds in the plant that are chemically related to THC and referred to collectively as cannabinoids (CB). Many different formulations and routes of delivery are available, including inhaled (smoked), ingested as food or tea, topically applied, and used in a nasal spray. In virtually all of these formulations, chemical constituent analysis is not reliably available.

The strongest evidence for the effectiveness of cannabis is for the treatment of chronic pain in adults, as an anti-emetic in the treatment of chemotherapy-induced nausea and vomiting, and for improving patient-reported outcome (PRO) of spasticity symptoms in multiple sclerosis. There is more limited evidence that CB may improve short-term sleep outcomes in some conditions, and that CB may be efficacious for use in anxiety, PTSD, and decreasing weight loss in wasting conditions such as HIV/AIDS. Validation of a number of other potential uses for CB—including for IBS, ALS, Huntington’s disease, Parkinson’s disease, cancer cachexia, and epilepsy—await the accumulation of more research before conclusions may be drawn.

The therapeutic potential of cannabis may be significant, but potential adverse events must also be studied. There is some evidence of a statistical association between CB smoking and testicular germ cell tumors, prediabetes, acute myocardial infarctions, stroke, and respiratory problems (including COPD). Additionally, an association may exist between CB use and motor vehicle accidents, low birth weight of infants, long-term cognitive impairment, and the development of schizophrenia or other psychoses. There is moderate evidence of a statistical association between cannabis use and the development of other substance use disorders, although causality has not been established.

What Research is Being Done?

Because of the difficulty in obtaining product and funding, much historical research evidence is derived from observational studies, not Randomized Control Trials (RCTs) (PubMed lists a mere 35 published RCT studies conducted on cannabis). Observational studies are particularly susceptible to the problems of constituent analysis and dose standardization discussed below as well as shortcomings in providing clear definitions of study populations, confounders, and reporting of methodologies—especially as pertaining to endpoint scoring. However, increasing awareness of cannabis as a potential therapeutic is reflected in ClinicalTrials.gov, which lists 732 total studies, of which 138 are actively recruiting. This uptick in funded research creates an opportunity for IRBs to further an important line of inquiry.

According to the National Academies report, these five areas of inquiry are of the highest priority:

  1. Phase I studies to solidify information about PK, PD, DR curves for different cannabinoids, including information about different routes of administration.
  2. Health effects on understudied endpoints in conditions such as PTSD, epilepsy, and cancers. For example, given the evidence that prolonged cannabis use impairs memory and cognitive function, the synergy between chemotherapy-related cognitive impairment and cannabis-related cognitive impairment merits evaluation, and may bear upon monitoring changes in decisional capacity.
  3. Health effects on vulnerable populations (young and old, pregnant). For example, if cannabis proves effective in conditions that are more prevalent in older adults (e.g., diabetic neuropathy) it will be important to characterize drug-drug interactions in a population prone to polypharmacy.
  4. Addiction and overdose potential.
  5. Pressure to establish standards of validity of cannabis products.

Challenges of Research in Botanical Medicine

As is elucidated more fully in the whitepaper Botanical Medicines in Research, research using botanical compounds presents unique challenges. Principal among those are the fact that botanical compounds are complex mixtures of molecular constituents that are difficult to standardize and characterize, an issue further complicated by the timing of the harvest, method of extraction, and growing conditions. The Western science paradigm of pharmaceutical development and testing of a single molecule delivered in pure form at relatively high concentrations does not fit the realities of how botanical compounds are used.  Furthermore, systematic collection of safety data is generally lacking for botanical products with a long history of use.

How Can IRBs Assist in Validating Cannabis as a Potential Therapeutic Agent?

With the increasing interest in cannabis research, IRBs could be faced more and more with the challenging questions that research poses. Here are some steps and concerns IRBs can consider when reviewing cannabis research:

  1. When reviewing any research on botanical products, including cannabis, an IRB should enlist an expert in botanical medicine. Herbalists can advise on plant phylogeny, growing and harvesting practices, and methods of extraction and manufacturing that may bear significantly on the therapeutic potential and safety profile of a plant, and can comment on methodology used to conduct constituent analysis and standardization.
  2. Given that the delivery of cannabinoids by smoking is a crude and dose-variable method of delivery that co-delivers harmful compounds, it will be important to develop alternative delivery systems, and to understand their pharmacokinetics and pharmacodynamics when designing later phase studies.
  3. Because of the (poorly understood) addiction potential of cannabis, IRBs should bear in mind the current recommendation by the NAS that studies be limited to less than six months in duration.
  4. As our understanding of the etiology of the opioid crisis has matured, we now grasp the consequences of not studying abuse potential in parallel with therapeutic potential. It is critically important to build in outcome measures pertaining to addiction potential.
  5. Research in botanical products will remain hobbled by inconsistencies in the amount and type of molecule(s) used as an intervention in any given trial. IRBs can have a voice in ensuring that chemical constituent analysis and standardization of the investigational product is included in the study design.

Cannabis shows potential as a therapeutic agent that could satisfy unmet needs in pain management, mental health, and motor neuron diseases, among other conditions. The promise of cannabis as well as other plant-derived compounds can best be realized by furthering research that is carefully designed and takes into account the unique challenges of botanical medicine.

Tags: , , , , , , , , ,