Medical Marijuana and Drug Safety

May 07, 2019
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

Clearly the use of marijuana for medical and recreational purposes is a major topic of conversation these days. Social media is buzzing. More and more states are moving to formally allow growth and sale of marijuana for both uses. The Democrats and Republicans are talking about it and there is significant support in both parties at the state level and some at the federal level.

The legality seems complex (I am not a lawyer). Based on published documents the status seems to be as follows.

FDA

A good place to start in terms of regulation is the FDA website where FDA notes that:

“The FDA has not approved marijuana as a safe and effective drug for any indication. The agency has, however, approved one specific drug product that contains the purified substance cannabidiol, one of more than 80 active chemicals in marijuana, for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older. The FDA has also approved two drugs containing a synthetic version of a substance that is present in the marijuana plant and one other drug containing a synthetic substance that acts similarly to compounds from marijuana but is not present in marijuana. The FDA is aware that there is considerable interest in the use of marijuana to attempt to treat a number of medical conditions, including, for example, glaucoma, AIDS wasting syndrome, neuropathic pain, cancer, multiple sclerosis, chemotherapy-induced nausea, and certain seizure disorders.”

“Several states have either passed laws that remove state restrictions on the medical use of marijuana and its derivatives or are considering doing so. The FDA supports researchers who conduct adequate and well-controlled clinical trials which may lead to the development of safe and effective marijuana products to treat medical conditions. We have talked to several states, including Florida, Georgia, Louisiana, New York and Pennsylvania, who are considering support for medical research of marijuana and its derivatives to ensure that their plans meet federal requirements and scientific standards.”

 

FDA also has a good set of Q&A on medical marijuana. This is well worth reading. FDA makes several points:

  • To date, the agency has not approved…cannabis for the treatment of any disease or condition in adults and children but has approved one cannabis-derived and three cannabis-related products. (Q3 & Q20)
  • Other than Epidolex (CBD), FDA has not approved any other products with CBD. We are aware that some firms are marketing CBD products to treat diseases or for other therapeutic uses, and we have issued several warning letters to such firms. (Q4)
  • THC and CBD products may not be sold as dietary supplements. (Q9)
  • It is not legal in interstate commerce to sell a food to which THC or CBD has been added. (Q10)
  • Hulled hemp seed, hemp seed protein powder, and hemp seed oil may be used in human food as they are generally recognized as safe (GRAS). (Q12)
  • The FDA has sent warning letters in the past to companies illegally selling CBD products that claimed to prevent, diagnose, treat, or cure serious diseases, such as cancer. Some of these products were in further violation of the FD&C Act because they were marketed as dietary supplements or because they involved the addition of CBD to food. (Q14)
  • FDA notes that in some circumstances patients can gain access to cannabis or cannabis-derived products through expanded access and right-to-try programs. (Q18 & Q19)
  • The FDA has sent warning letters in the past to companies illegally selling CBD products that claimed to prevent, diagnose, treat, or cure serious diseases, such as cancer. Some of these products were in further violation of the FD&C Act because they were marketed as dietary supplements or because they involved the addition of CBD to food.
  •  The FDA is aware that there are potential adverse health effects with use of cannabis products containing THC in pregnant or lactating women. Published scientific literature reports potential adverse effects of cannabis use in pregnant women, including fetal growth restriction, low birth weight, preterm birth, small-for-gestational age, neonatal intensive care unit (NICU) admission, and stillbirth. Based on published animal research, there are also concerns that use of cannabis during pregnancy may negatively impact fetal brain development. (Q21)

Q7. Has the agency received any adverse event reports associated with cannabis use for medical conditions?

Answer: The agency has received reports of adverse events in patients using cannabis or cannabis-derived products to treat medical conditions. The FDA reviews such reports and will continue to monitor adverse event reports for any safety signals, with a focus on serious adverse effects. Information from adverse event reports regarding cannabis use is extremely limited.

FDA Position

The former commissioner of FDA, Dr. Scott Gottlieb, has made statements in support of further research on medical cannabis. See: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611047.htm

“Over the past decade, we’ve seen a growing interest in the development of therapies derived from marijuana and its components. Proponents of “medical marijuana” advertised its uses for a wide number of medical conditions, such as cancer, multiple sclerosis, post-traumatic stress disorder and anxiety – just to name a few of the touted conditions. The FDA has been supportive of research in this area for many years. But marijuana is a Schedule I compound with known risks. Research to demonstrate that marijuana or its components could be safe and effective in the treatment of medical disorders should be held to the same standard as other drug compounds. And certainly it should not be held to a lower standard, as some proponents would suggest. The FDA has an active program to assist drug developers who want to investigate marijuana or its components through properly controlled clinical trials, to demonstrate the potential for safe and effective uses.

We meet regularly with researchers as they plan and carry out their trials. We have also formed a Botanicals Team that provides scientific expertise on botanical issues for researchers developing drugs derived from plants, such as marijuana. That team published guidance for industry on clinical studies involving botanical drugs, as well as quality controls for lot-to-lot consistency.

The FDA will continue to support rigorous scientific research on potential medical treatments using marijuana and its components that seek to be developed through the appropriate scientific channels.”

FDA Enforcement

FDA looks at marketed products making “egregious” health claims and has issued over a dozen Warning Letters to companies marketing unproven products, derived from marijuana, that claim to treat or cure cancer or other diseases.

For example see the Warning Letter issued for the product ArisiTol which FDA noted had literature claims for breast cancer, arthritis, “walking pneumonia”, multiple sclerosis, Chrohn’s (sic) Disease, aging, memory loss and others. See the FDA warning letters on CBD from 2015-2018.

FDA has also noted that it has tested some marketed products and found that many did not actually contain the levels of CBD that they claimed to contain!

Safety Surveillance of Marijuana

FDA notes its data and databases are limited. FAERS (FDA Adverse Event Reporting System) focuses on collecting reports for marketed drugs and information on marijuana is incomplete. FDA and other federal agencies and entities are looking to for new sources of data on marijuana. There are over one hundred AEs including SAEs and deaths reported in FDA’s FAERS database.

Social Media & Activities

Suffice it to say, social media is buzzing about cannabis and marijuana. A random log in to Instagram noted 13.3M posts on #cannabiscommunity for example. There is now kosher certified marijuana. There is now an “International Church of Cannabis” located in Colorado.

Safety Information

So what is the safety record of marijuana?

First let’s understand that we are not talking about studies of pharmaceutical grade products manufactured under Good Manufacturing Products (GMP) but rather about products made from dried leaves, flowers, stems, seeds from the Cannabis sativa plant. Formulations, excipients, fillers etc. will vary from batch to batch, product to product. Routes of administration include smoking in hand-rolled cigarettes, pipes or water pipes, vaporizers and ingested as foods including brownies and cookies and drinks including tea. Some marijuana is extracted using various solvents including butane to produce oils or waxes or solids containing THC. These may contain very high doses of THC and may use toxic solvents (butane).

So comparisons, which are hard enough for controlled trials of drug products, are to be looked at with normal scientific skepticism. It is hard to know whether adverse events were due to the marijuana, the excipients and fillers, production and manufacture problems, tampering etc.

Having said that, there are some generally accepted AEs and safety effects. See the document from the US National Institute on Drug Abuse (US NIDA).

Short term brain effects: altered senses (e.g. seeing bright colors), altered sense of time, altered mood, impaired body movement, difficulty problem solving and thinking, impaired memory.

Long-term effects: alterations in brain development particularly in teenagers. Effects may be permanent. Hallucinations, paranoia and worsening symptoms in patients with schizophrenia have been reported.

Other effects: Breathing problems due to smoke inhalation that can be similar to tobacco induced lung problems (cough, more frequent lung infections etc.). Whether lung cancer increases is unknown. Cardiac problems include tachycardia and possible increase risk of heart attack. Problems with child development during pregnancy are noted and include an increased risk of brain and behavioral problems in the baby. THC gets into breast milk.

Gateway drug: There is some evidence that marijuana may be associated with subsequent use of other, harder drugs though data suggests that the majority of users do not go on to other drugs.

Addiction: The NIDA notes that “Marijuana use can lead to the development of a substance use disorder, a medical illness in which the person is unable to stop using even though it’s causing health and social problems in their life.” Some data suggests that 30% of users may develop some degree of dependence. Withdrawal symptoms include “grouchiness”, sleeplessness, decreased appetite, anxiety and cravings.

Bottom Line Regarding Drug Safety and PV

FDA is really not regulating marijuana the way it regulates approved drugs. With only 3 current exceptions, there are no FDA approved drugs or foods.

Formulations and modes of delivery are very variable.

Dosing is uncontrolled and unknown.

There is no systematic tracking of SAEs, non-serious AEs by the FDA or any other governmental agency in any formal way.

Clinical trials are underway on various indications but, as is always the case when product or similar product is available from other sources than the investigator, studies are logistically hard to do. Patients may “supplement” their study treatment with other products they purchase. The situation is improving but as long as marijuana remains a Schedule 1 drug, research is difficult to do in the US. There is active research being done abroad in Canada, Europe, Israel and elsewhere.

It is hoped that state approvals will require some level of SAE and non-serious AE reporting in a voluntary and non-punitive manner from the public (users) and in an obligatory way from the manufacturers and sellers similar to the system set up by the Food, Drug and Cosmetic Act and FDA.

Comments

Use of medical marijuana is clearly here to stay. Even if we wanted, as a nation, to stop its use (which we don’t seem to), it would be impossible. We learned that from alcohol Prohibition in the 20th century. Let us hope we do not waste resources on that but rather put them into making marijuana use as safe as possible – as we do for tobacco and alcohol.

It is the author’s hope that someone at the national level will pick up the ball to formalize and centralize data collection to evaluate the safety of medical marijuana even if legality remains ambiguous. Clinical trials will be useful if doable, particularly for efficacy, but the vast amount of data that will be generated from use in the market is where the safety action is. Efforts should be directed here.

WE NEED RELIABLE DATA.

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