NCCIH Deputy Director David Shurtleff, PhD, tells MCN about cannabis research, safety concerns and the impact of federal policy.
Dr David Shurtleff is Deputy Director of the National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health. He tells MCN about cannabis research, safety concerns and the impact of federal policy on clinical studies.
Could the wider use of medical cannabis in healthcare help alleviate the opioid crisis?
We hope that this may be true—for medical cannabis or individual cannabinoids or both—but more research is needed. Some survey data suggest that the availability of medical marijuana is associated with reductions in opioid use and in the prescription of conventional pain medications, but other analyses don’t show this pattern.
Some evidence from well-controlled clinical trials shows that cannabis or individual cannabinoids may be helpful for various types of chronic pain; but these trials also suggest that, in some studies, the benefit may be small, and some patients may experience adverse events. In addition, we know very little about the efficacy, dose, routes of administration, or side effects of commercial cannabis products available to patients through dispensaries in states that have legalised the use of marijuana.
There is evidence from animal studies suggesting that an extract from Cannabis sativa (64.5% CBD content, 4% THC, with other minor cannabinoids and terpenes) may reverse thermal hyperalgesia. Other studies with animals suggest that administering THC along with opioids may make it possible to control pain with a smaller dose of opioids; however, there isn’t conclusive evidence that this is true in people.
Clearly, more needs to be learned about cannabinoids for pain management and about whether they can help to reduce the use of opioids for pain. The National Institutes of Health—of which we at NCCIH are part—supports research on the potential therapeutic benefits of cannabis or cannabinoids, including pain studies. Our particular focus at NCCIH is on the potential pain relieving properties of the less-studied components of cannabis—the minor cannabinoids (meaning cannabinoids other than THC) and terpenes found in the cannabis plant.
In 2019, NCCH awarded approximately $3m to support nine studies investigating the potential pain-relieving properties and mechanisms of action of diverse phytochemicals in the marijuana plant, including both minor cannabinoids and terpenes; and we plan to fund more.
How does the legislative landscape in the US, where cannabis is illegal under federal law but increasingly legal on a state level, complicate the use of cannabis for medicinal purposes? Would a more standardised regulatory approach help patients and practitioners?
NCCIH and other NIH agencies don’t make policy. We’re a research agency; while our research may inform policies developed by others, we don’t make policy decisions ourselves.
Certainly, given the increased availability of cannabis products throughout the United States, there is a need for more research on both the potential benefit and harm associated with these products. Even if a more standardised regulatory approach went into effect today, patients and practitioners would still have difficulty making informed decisions about using cannabis or cannabinoids for medical purposes because there are so many gaps in the evidence on dosing, routes of administration, side effects, effectiveness for a given medical condition; and safety. People in this country are accustomed to the idea that if a drug is on the market it must have been shown to be safe and effective, but the situation is different for cannabis. Although some states have made it legal, the Food and Drug Administration (FDA) hasn’t approved the cannabis plant as being safe and effective for any medical use.
Certain individual cannabinoids have been FDA approved for specific medical uses, but they’re not the medical uses of greatest interest to large numbers of people, such as relieving pain.
In general, it’s challenging to do research on whole plants or other crude natural products because of their complexity and variability. This isn’t unique to cannabis; it’s also true of the other natural products NCCIH studies, such as herbal dietary supplements.
Conducting research on individual cannabinoids is not as difficult as studying the cannabis plant, but there’s a lot we still don’t know about many of these substances. The focus on THC has left us with a significant gap in understanding the properties of the many other substances in cannabis. The cannabis plant contains more than 100 cannabinoids; as well as other potentially useful substances, including more than 100 terpenes, so there’s much to learn and explore. Many of these constituents, alone or in combination, may have pain relieving properties.
The NCCIH has provided funding for research into synthesising cannabinoids in yeast: what would be the main benefits of synthesising cannabinoids, rather than growing the cannabis plant?
A major advantage is that it’s less expensive than growing the plants and extracting and purifying the cannabinoids. Genetically engineering yeast to produce drugs that would otherwise be obtained from plants has other advantages, too: brewing a batch of yeast is a lot quicker than growing a crop; and the process may be more environmentally sustainable, protect from supply volatility, and would improve chemical consistency.
Using yeast cells as drug factories isn’t a new idea – insulin has been made this way for several decades – but it’s harder to develop a process for some drugs than others. A few years ago, we helped to support pioneering research at Stanford University to produce both opioids and a cancer drug that comes from the opium poppy in yeast cells; the processes for producing these drugs in yeast are very sophisticated and complex.
Are there any side effects or safety issues with medical cannabis or CBD that patients may not be aware of?
Yes. Common adverse events associated with cannabinoids include dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.
In addition to these side effects that people would notice, CBD may also have undesirable effects that the user wouldn’t be aware of but that could lead to serious problems. One such effect is possible damage to the liver. During the research that led to the FDA’s approval of Epidiolex – the purified CBD product that’s been approved to treat two rare types of epilepsy – it was found that CBD has the potential to cause liver injury. This risk can be managed when Epidiolex is taken under medical supervision because blood tests can detect the problem early on, before it gets serious; however, the problem could go unnoticed in people who take CBD on their own.
The Epidiolex research also showed that CBD may interact with other medicines. As with the liver problems, this is something that can be managed if CBD is taken under medical supervision, but it could be an issue when people take it on their own.
Drug interactions are a concern for cannabis products in general, not just CBD. NCCIH is supporting a research centre on natural product-drug interactions, looking at interactions involving cannabis and its components; and is determining the extent of these interactions with both THC and CBD. These cannabinoids influence the activity of enzymes that metabolise other drugs.
There have been studies in laboratory animals showing harmful effects of CBD on the male reproductive system, including infertility. It’s not clear whether the same problems can happen in people.
There’s reason for concern about the quality of commercial CBD products. Some contain substantially more CBD than the label says, some contain substantially less; and some contain THC, which shouldn’t be there.
Are there any recent developments or issues within the field of cannabis research that you would like to highlight?
One issue that’s important to the research community is the laws and regulations related to cannabis research in the United States. They’re complicated, and multiple government agencies are involved – but research is still possible, and we hope more scientists will conduct research in this area. We held a workshop in December 2018 on how to conduct cannabis and cannabinoid research within the current regulatory framework. This meeting brought together government officials, industry representatives, and scientists who are currently doing research on cannabinoids, and they all shared a lot of valuable insights and practical advice. The proceedings of the workshop are available on our website.
One particular issue with the current regulations is that marijuana is a Schedule I drug; so while research is possible, it is more challenging to do and there is a concern that the Schedule I status of marijuana could be a deterrent to investigators who want to work in this space. Another issue is that the University of Mississippi is the only entity in the United States registered with the DEA to cultivate cannabis for research purposes, which the University does under a contract with the National Institute on Drug Abuse (NIDA).
Having only a single domestic source limits the diversity of products and formulations available for research. In addition, some researchers would like to be able to conduct studies on products that people are actually using – such as products available through state marijuana dispensaries – rather than the marijuana made available by NIDA, which is not currently permissible. There seems to be bipartisan support for facilitating marijuana research. The House Energy and Commerce Committee held a hearing on cannabis policies in January, but no changes in policy have been made yet.
On the research front, NCCIH continues to solicit cannabinoid research; as it is a critically important part of our work to explore nonopioid approaches for chronic pain. One aspect of this research we want to capitalise on is exploring the biological activity of an active constituent of marijuana – CBD, for example – assayed together with ‘entourage’ compounds. Investigations of an active phytochemical in the presence of its ‘entourage’ compounds may lead to, for example, enhanced pain relief different from the single active component alone.
There are also a couple of prominent safety issues that have been in the news. The Centers for Disease Control and Prevention (CDC), FDA and others have been investigating the problem with severe lung injury associated with vaping that emerged last year. The illnesses have been linked to vaping products that contain THC and to vitamin E acetate in those products. In addition, we’re seeing reports in the medical literature of children eating cannabis products and becoming sick enough to need emergency medical care. It’s important for the public to be aware that cannabis products need to be kept in child-resistant containers and out of the reach of children.
David Shurtleff, PhD
National Center for Complementary and Integrative Health