A while ago, I wrote about how the Cleveland Clinic had recently opened a clinic that dispensed herbal medicine according to traditional Chinese medicine (TCM) practice. As regular readers of the SBM blog might expect, I was not particularly impressed or approving of this particular bit of infiltration of quackademic medicine into a major academic medical center, particularly given some of the amazingly pseudoscientific treatments espoused by the naturopath who was running the clinic. I also pointed out that, although herbalism is the most plausible (or perhaps I should say the least implausible) of modalities commonly associated with “complementary and alternative medicine” (CAM) or “integrative medicine”, it still exhibits a number of problems, the biggest of which is what I like to call either the delivery problem or the bioavailability problem. In brief, herbs, when they work, are adulterated drugs. The active ingredient is usually a minor constituent, embedded in thousands of other constituents that make up herbs, and it’s almost impossible to control lot-to-lot consistency with respect to content or active ingredients given how location, weather, soil conditions, rainfall, and many other factors can affect how the plants from which the medicines are extracted grow and therefore their chemical composition. To demonstrate the concept, I pointed out that it’s much safer and more predictable to administer digoxin to a patient who needs its activity on the heart than it would be for the patient to chew on some foxglove leaves, given that the therapeutic window (the difference between the doses needed to produce therapeutic effects and the lowest dose that will cause significant toxicity) is narrow.
Which brings me to medical marijuana, a.k.a. medical cannabis.
Before I continue, let me just state my position on marijuana, which is different than it was, say, 20 years ago. Today, I believe there’s no reason why marijuana shouldn’t be legalized and treated by states the same way as tobacco products and alcoholic beverages are; they should be heavily regulated and taxed. Among physicians, this appears to be a common view, at least if you can believe a poll I saw a while back (for which I can’t find the link, alas). It’s also, these days, more and more of a mainstream view. In any case, medical marijuana has been a topic I’ve been meaning to write about for a while, now, but my “Dug the Dog” tendencies have kept popping up over squirrels topics like the Food Babe, Facebook, ketogenic diets for cancer, and a variety of other topics.
Medical marijuana arrived in my state in 2008, when the voters approved a measure permitting it. After some time for the state to draft regulations, the law was implemented, and I had the strange (to me at the time) experience of receiving notices about state regulations, requirements, and documentation should I wish to prescribe medical marijuana. Indeed, more than twenty states, plus the District of Columbia, have legalized medical marijuana. They’ve done so on the basis of a political movement among patients that make pot sound like a miracle drug that can help when no other intervention can. And it’s more than that. Medical cannabis has been touted as a near-panacea for everything from pain to chemotherapy-induced nausea to HIV- and cancer-induced cachexia to even curing cancer itself. Yes, there’s a lot of hype out there, and there are a lot of claims that sometimes go viral on various social media, even though the evidence to support the claims is often, to put it mildly, less than rigorous.
Indeed, the acceptance of medical marijuana appears to be far more driven by politics than it is by science, as was pointed out in a recent New York Times article about the impending legalization of medical cannabis in New York State:
New York moved last week to join 22 states in legalizing medical marijuana for patients with a diverse array of debilitating ailments, encompassing epilepsy and cancer, Crohn’s disease and Parkinson’s. Yet there is no rigorous scientific evidence that marijuana effectively treats the symptoms of many of the illnesses for which states have authorized its use.
Instead, experts say, lawmakers and the authors of public referendums have acted largely on the basis of animal studies and heart-wrenching anecdotes. The results have sometimes confounded doctors and researchers.
[Ed. Note: This post was written yesterday, which, as it turns out, was one day before New York State became the 23rd state to legalize medical marijuana.]
The article then goes on to give several examples, such as Alzheimer’s disease, lupus, Sjogren’s syndrome, Tourette’s syndrome, Arnold-Chiari malformation and nail-patella syndrome, and in particular rheumatoid arthritis:
Yet there are no published trials of smoked marijuana in rheumatoid arthritis patients, said Dr. Mary-Ann Fitzcharles, a rheumatologist at McGill University who reviewed the evidence of the drug’s efficacy in treating rheumatic diseases. “When we look at herbal cannabis, we have zero evidence for efficacy,” she said. “Unfortunately this is being driven by regulatory authorities, not by sound clinical judgment.”
As is the case with so much herbalism—and, make no mistake, medical marijuana is the new, popular herbalism of the moment—claims have far outstripped the evidence. Also, as pointed out in the NYT article, even advocates of medical marijuana admit that “the state laws legalizing it did not result from careful reviews of the medical literature.”
That’s the understatement of the year, and even famous doctors like Sanjay Gupta are getting in on the act with a report, “Cannabis Madness,” full of a lot of anecdotes and rhetoric about “policy against patients.” Again, I believe that marijuana should be legalized, regulated, and taxed, just like alcohol and tobacco. If marijuana is going to be approved for use as medicine rather than for recreational use, however, the standards of evidence it must meet should be no different than any other drug, and for the vast majority of indications for which it’s touted medical cannabis doesn’t even come close to meeting that standard.
There are definitely compounds with potential medicinal use in the marijuana. No one, even the most die-hard drug warrior, denies that. These compounds are called cannabinoids, which is a term that describes a family of complex molecules that bind to cannabinoid receptors, which are proteins on the surface of cells. There are two types of cannabinoid receptors, type 1 (CB1) and type 2 (CB2). These receptors are seven transmembrane G-protein coupled receptors (so named for the seven protein domains that span the membrane), a class of receptor I’m pretty familiar with, because one of the receptors I study is of the same class, which looks like this:
The details of how this happens aren’t essential for this post, but when these receptors are stimulated by the binding of cannabinoid molecules, including endocannabinoids (produced by mammals), plant cannabinoids (such as (−)-trans-Δ9-tetrahydrocannabinol, more commonly referred to by its abbreviation THC, produced by the cannabis plant) and synthetic cannabinoids (such as HU-210), downstream chemical signaling pathways are initiated from the receptor to the inside of the cell, thus producing the effects on the cell and organism. There is mounting evidence that there are more than two types of cannabinoid receptors. In any case, CB1 receptors are found widely in the central nervous system, where they modulate a variety of responses, and are also found in other parts of the body, for instance, the pituitary gland, thyroid gland, lungs, and kidney, as well as fat cells, muscle cells, liver cells, and in the digestive tract. CB2 receptors, on the other hand, are expressed primarily in the immune system, the gastrointestinal tract, and, to a much lesser extent than CB1 receptors, in the brain and have been implicated in modulation of immune responses. In particular, stimulating CB2 receptors cannabinoids could be potentially useful as anti-inflammatory drugs. Over the last couple of decades, endocannabinoids and cannabinoid receptors have been implicated a large variety of functions, including memory, pain, energy metabolism, and more. It is thus plausible that manipulation of cannabinoid signaling could have therapeutic effects in a variety of areas.
Unfortunately, one of the problems with medical marijuana, as noted in the NYT article is that enthusiasm for weed as a cure-all has far outstripped existing medical evidence. This disconnect between the existing evidence base ranges from thin to nonexistent, depending on the condition. One of the most frequent claims I see is that cannabis can be used to treat cancer. I’m not going to address that claim specifically in this post, except very briefly, because I think it’s a large enough topic to warrant its own post. Suffice to say that interesting preclinical studies have been exaggerated beyond all evidence, but nonetheless certain cannabinoids could have potential in the treatment of certain cancers. I might also review the evidence base for cannabinoids and autism, given how I’ve been seeing discussions of its use starting to pop up lately on the usual sites. In other words, stay tuned for parts two and three spread out over the next several weeks, whenever no squirrels distract Dug the Dog.
In all fairness, in this country, at least, studying the medicinal properties of marijuana and its constituents is not easy, given that it is currently an illegal drug, as was discussed in the NYT article. It’s not for lack of interest, but mainly because the law (and therefore the Drug Enforcement Agency) classifies it as a schedule 1 drug with “no currently accepted medical use.” Scientists who want to do research on marijuana and its constituents—particularly clinical trials—must register with the DEA and submit an investigational new drug (IND) application to the Food and Drug Administration for human trials. Moreover, the National Institute on Drug Abuse is the only supplier of legal, research-grade marijuana. On the other hand, while doing research on marijuana is difficult in this country, researchers in other countries that have long had much more lax laws and regulations should have an easier time of it.
Another issue is how to do a proper placebo control. Given that many of the conditions for which medical marijuana is touted are conditions with a large subjective symptomatic component, such as pain, nausea, fatigue, or lack of appetite, clinical studies of medical marijuana are going to require really good placebo controls. Given that at least one of the active components causes a high, it’s arguably even more difficult than in the case of, for instance, acupuncture, to design studies with adequate controls. That’s why most of the more rigorous studies have used specific purified cannabinoids. For example, in this study, a titanium pipe loaded with doses of THC varying potencies is used rather than plant, while this study of cannabis for neuropathic pain used high-dose cannabis, low-dose cannabis, and placebo cigarettes.
Be that as it may, let’s look at the evidence base for conditions for which medical marijuana might provide a benefit. Remember, again: I’m leaving out cancer and autism for another day. Leaving these aside, here are the potential medical uses for marijuana for which evidence exists that ranges from reasonably good to suggestive.
Chronic pain. It’s been known for a long time that cannabinoids modulate pain responses; so it’s plausible that either smoked marijuana or cannabinoids isolated from marijuana (or synthetic cannabinoids) could be useful for chronic pain. Fortunately, this is one of the more widely-studied uses for medical cannabis. For example, a recent review of uses of cannabinoids for the treatment of non-cancer pain concluded that there was evidence that cannabinoids are safe and modestly effective in neuropathic pain, citing preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis. As is the case with most reviews, more study was recommended. This particular review included smoked cannabis, oromucosal extracts of cannabis based medicine, nabilone (a synthetic cannabinoid), dronabinol (a synthetic delta-9-THC), and a novel THC analogue. Most studies have only been short term, and adverse events have tended not to be serious. The current general recommendation is that cannaboids should probably not be used as first line agents “for conditions for which there are more supported and better-tolerated agents,” and adverse effects are not well studied.
Appetite stimulation. I’ve never smoked marijuana, but those who have, have told me about the “munchies,” something that anyone who’s ever seen a comedy in which characters smoke post has likely seen used as fodder for jokes. Given its ability to stimulate appetite, it is therefore plausible that medical cannabis might be useful for appetite stimulation in patients with cachexia due to cancer or HIV/AIDS. (Cachexia is the “wasting” that can occur in advanced cases of malignancy and AIDS, among other diseases.) Unfortunately, a recent Cochrane review noted variable outcomes and concluded that the “efficacy and safety of cannabis and cannabinoids in this setting is lacking” and noting no good evidence of long-term effects on AIDS-related mortality and morbidity. Regarding cancer cachexia, Peter Lipson noted several years ago a study that failed to find any benefit from cannabis extract for cancer-related cachexia, speculating that maybe the mechanisms that cause appetite suppression in cancer are different than the mechanisms by which cannabinoids modulate appetite.
Currently, there are few controlled trials cited at the NCI website, which, taken together, find that oral THC has variable effects on appetite stimulation and weight loss in patients with advanced malignancies and human immunodeficiency virus (HIV) infection. A PubMed review by yours truly also found the evidence rather sparse. For instance, this randomized trial testing cannabis extract (CE), THC, and placebo (PL) reported that “no differences in patients’ appetite or quality of life were found either between CE, THC, and PL or between CE and THC at the dosages investigated.” Another randomized trial comparing megestrol acetate (Megase) and dronabinol found that “megestrol acetate provided superior anorexia palliation among advanced cancer patients compared with dronabinol alone” and that “combination therapy did not appear to confer additional benefit.” A more recent small randomized trial tested THC versus placebo and found that “THC may be useful in the palliation of chemosensory alterations and to improve food enjoyment for cancer patients.” To be honest, I was shocked at how sparse the literature is covering this particular indication. Indeed, as the NCI notes, there are no randomized controlled trials of smoked cannabis for this indication in cancer patients.
Nausea/antiemetic. Despite many advances in anti-emetics (anti-nausea and vomiting) agents, cancer-induced nausea and vomiting (CINV) is still among the most troubling symptoms cancer patients face. There are two FDA-approved cannabis products for this indication, dronabinol and the synthetic cannabinoid nabilone. The NCI cites several clinical trials and meta-analyses finding that these two drugs are efficacious against CINV, and the National Comprehensive Cancer Network guidelines recommend these drugs as treatment for breakthrough nausea and vomiting due to chemotherapy. One systematic review from 2001 found that cannabinoids were slightly more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride, but were not more effective in patients already using large doses of antiemetic drugs. A more recent systematic review and meta-analysis found that cannabinoids were superior to conventional drugs but that “adverse effects were more intense and occurred more often among patients who used cannabinoids.” In children with cancer undergoing chemotherapy, a Cochrane systematic review concluded that “cannabinoids are probably effective but produce frequent side effects” and that the review “suggests that 5-HT(3) [seratonin] antagonists with dexamethasone added are effective in patients who are to receive highly emetogenic chemotherapy although the risk-benefit profile of additional steroid remains uncertain.”
Inflammatory bowel disease (IBD). Last fall, the first clinical trial of cannabis in IBD was reported by a group of Israeli researchers. It was a small trial (21 patients), in which subjects were assigned randomly to groups given cannabis, twice daily, in the form of cigarettes containing 115 mg of Δ9-tetrahydrocannabinol (THC) or placebo containing cannabis flowers from which the THC had been extracted. A clinical response was achieved in 10 of 11 patients receiving cannabis with THC and 4 of 10 in the placebo group. Overall, this was a small study, but intriguing. No difference in complete remissions between the groups was observed, but that could easily be because of the small numbers. As with many conditions, all one can conclude is that more research is needed.
There is, of course, a laundry list of other conditions. Cannabinoids have been shown to lower intraocular pressure, making them potentially useful for treating glaucoma, although using cannabis to treat glaucoma is impractical in the vast majority of patients (see below), and there exist better treatments. After that, other conditions for which medical cannabis is frequently recommended include schizophrenia, for which a Cochrane Review concludes that there is no good evidence for or against the use of cannabis for schizophrenia. For epilepsy, data from double-blind randomized controlled clinical trials is lacking, although clinical trials are finally being done.
Overall, the evidence base, from my interpretation, ranges from nonexistent (most indications) to suggestive (anti-inflammatory), to fairly good (ant-emetic). However, most of the good clinical trials didn’t use marijuana cigarettes as most patients get them, but rather either purified cannabinoids (or synthetic analogues) or cannabis cigarettes spiked with varying amounts of THC. Indeed, all of these studies tend to suggest that purified drugs from cannabis or synthetic drugs based on compounds designed to mimic either endocannabinoids or cannabinoids from marijuana will be the future. I realize that that’s not what medical marijuana activists want to hear. I also realize that it is likely I will be lambasted as a “pharma shill” or as so conventional that I can’t think outside the box, but I’ve endured those attacks before when I’ve criticized other forms of herbalism. In any case, mine, I believe, is a reasonable interpretation of the currently existing medical literature.
Moreover, contrary to what advocates will claim, cannabis, particularly smoked cannabis, is not without adverse health effects, as was recently reviewed in the New England Journal of Medicine. Potential medical effects reported in long time users include motor vehicle collisions (not unreasonable to expect because driving while high is not a good idea), chronic bronchitis (not surprising as a result of smoke inhalation), schizophrenia (one wonders whether correlation really suggests causation here), depression, and addiction to other drugs, although the risk for cancer due to marijuana smoke appears to be much lower than with tobacco cigarettes. True, drug warriors and moralists will frequently exaggerate the risks in order to promote their agendas, but that doesn’t mean that cannabis is perfectly safe and doesn’t produce significant side effects or complications.
Then there’s the delivery problem.
Delivery, purity, highs
Let’s consider, for a moment, a generic herb that has medicinal properties. I began this post by briefly discussing the problems with herbs as medicine, but I didn’t discuss delivery. If one were to come up with a delivery method for an effective herb, one would be hard pressed to come up with a worse method than burning it and inhaling it. Consider the case of tobacco. The combustion of dried tobacco leaves produces a toxic stew of gases with carcinogenic effects. Of course, the main reason tobacco is so addictive is because it does have an active drug in it, specifically nicotine, which rapidly reaches the circulation through the alveolar sacs in the lungs. However, that nicotine is mixed with numerous combustion products that can cause cancer and contribute to the numerous other diseases to which smoking tobacco has been linked.
This brings us back to delivery. People have been using marijuana for the high and for medicinal purposes for a very long time, but cannabinoids were only first isolated from the plant in the 1940s, and the main active ingredient, (−)-trans-Δ9-tetrahydrocannabinol (THC), wasn’t discovered until the 1960s. Now, like the case with cigarette smoke and its delivery of nicotine to the bloodstream, the THC and other active cannabinoids delivered to the bloodstream through smoking marijuana are mixed in a similarly toxic stew of combustion products. While it is probably true that marijuana smoke is less carcinogenic than tobacco smoke, it has the same potential for respiratory irritation and deposits four times as much tar into the lungs as a typical cigarette, mainly because marijuana is usually smoked unfiltered. However, occasional marijuana use appears not to have a significant effect on lung function up to seven joint-years of lifetime exposure. (I chuckled when I read that term; it means one joint a day for seven years or one joint a week for 49 years). Of course, this hardly compares to a typical tobacco smoker, who smokes anywhere from a half pack to two packs a day (10-40 cigarettes), and those using medicinal marijuana can be expected to be smoking at least a couple of times a day. Medical cannabis advocates even basically admit that this is true.
In any case, if one were going to decide on a drug delivery device for cannabinoids, one could hardly design a worse device than burning the leaf and inhaling the gases, where the active drug is just one of hundreds of products of combustion, all loaded with particulate matter and tar. Sure, toking one joint a day probably doesn’t do appreciable lung damage in the intermediate term, but smoking one cigarette a day probably doesn’t either. In the case of glaucoma patients, a condition for which there is some evidence of efficacy, it’s been noted that patients would have to be toking up several times a day:
Since at least 2009, for instance, the American Glaucoma Society has said publicly that marijuana is an impractical way to treat glaucoma. While it does lower intraocular eye pressure, it works only for up to four hours, so patients would need to take it even in the middle of the night to achieve consistent reductions in pressure. Once-a-day eye drops work more predictably.
Yet glaucoma qualifies for treatment with medical marijuana in more than a dozen states, and is included in pending legislation in Ohio and Pennsylvania. At one point, it appeared in New York’s legislation, too.
What’s more, for some of the ailments, such as glaucoma, patients would have to toke up every three to four hours day and night to maintain therapeutic levels in the bloodstream or tissues. Routinely consuming that much weed would be incapacitating.
Clearly, even if marijuana is efficacious for some conditions, there are serious drawbacks to burning the plant and inhaling the smoke as a drug delivery system. Other problems exist, not the least of which are the psychoactive effects of THC, which cause much of the “high” that pot smoking produces. To paraphrase one of the ophthalmologists in the NYT, his 60-year-old patients with glaucoma don’t want to be stoned all the time to get the beneficial effect of medical marijuana. The high is a particular problem for children, but none of this has prevented parents with autistic children from claiming that pot can treat autism, complete with seemingly-heartwarming anecdotes. One can imagine the temptation to simply keep the child toking until he becomes mellow and more “manageable.”
Of course, medical marijuana being in essence herbalism, with the same claims for efficacy of the “whole plant” due to synergy of its ingredients and the same attitude that “natural is better,” it’s not surprising that the same problems exist that are routinely observed for any herb sold for medicinal purposes. These problems include as inconsistent potency and purity, adulteration with contaminants—or even questions of whether the plant being sold is actually what is being claimed. Indeed, a fascinating story that sounds very familiar to those of us who have been paying attention to adulterated herbs and supplements was published a month ago in The Seattle Times:
Tonani, 38, decided several years ago to try pot. And it has worked for her, she said, especially strains low in the psychedelic chemical THC and high in the non-psychoactive ingredient cannabidiol, known as CBD.
As a medical-marijuana patient, Tonani knows it can be hard to find the rare strains that don’t make you high — and it can be even harder to get the same kind of pot consistently.
Testing shows that some marijuana strains are not what they purport to be in name, chemical content and genetics. This is particularly concerning for patients seeking pot low in intoxicants and high in pain-relief or other therapeutic qualities.
One strain widely known for its high-CBD and popular among medical-marijuana patients is called Harlequin. But when Tonani and a leading Seattle pot-testing lab analyzed 22 samples of Harlequin from various growers and dispensaries, five of them were high in THC and had virtually no CBD, which means people trying to take medicine were just getting high instead.
Again, this is a very common problem with herbal medicines, and cannabis, when smoked or ingested as the plant, is an herbal medicine.
Medical cannabis: Politics versus science
There’s no doubt that what is driving the legalization of medical marijuana in so many states has far more to do with politics than with science. Right now, for all but a handful of conditions, the evidence is slim to nonexistent that cannabis has any use as a medicine, and those conditions, such as CINV and chronic pain, can often be treated more reliably with purified or synthesized active components. Moreover, for one condition for which there is reasonably good evidence for the efficacy of cannabis and/or cannabinoids, namely chronic pain, politicians are reluctant to approve medical marijuana, as described in the recent NYT article:
Often state legislators have been motivated not just by constituents in distress, but also by the desire to restrict access to limited patient populations so that legal marijuana does not become widely available as a recreational drug in their states.
For example, while there is research suggesting that marijuana alleviates certain kinds of chronic pain, Mr. Lang noted, legislators in Illinois were reluctant to legalize its use in such a broad patient population. The state’s list of qualifying conditions is lengthy partly because lawmakers tried instead to specify a number of diagnoses that result in pain, some quite rare.
“I’ll bet there are hundreds of conditions that cause pain, and now 30 are listed,” Karen O’Keefe, director of state policies at the Marijuana Policy Project, said of Illinois’s legislation.
So, for one indication for which there is reasonably good evidence for the use of cannabis, legislators in Illinois were reluctant to approve its use, while approving its use for a lot of indications for which there is no evidence to support them. Clearly, this is a policy area that cries out for better science, given how legislators are being swayed by anecdotes that do not demonstrate that cannabis is effective and stories of “persecution” for growing medical marijuana, rather than by well-designed randomized clinical trials. Add to that the conflict with currently existing federal law, which outlaws cannabis as a schedule I drug, and the political situation is a mess, making doing research to find out for what indications cannabinoids have efficacy much more difficult. Antidrug zealots hugely exaggerate the danger of pot smoking, while pro-medical marijuana zealots claim that “cannabis cures cancer.” (It doesn’t, as I will discuss in the next installment.)
Moreover, THC can have biphasic activity:
THC has what doctors and researchers know as biphasic activity. “At low doses it has certain effects, and at high doses it has opposite effects,” Dr. ElSohly explains. “Somebody using to get high at the right dose will be calm, happy, getting the munchies, and all of that,” Dr. ElSohly says. Someone using at the right dose could see medicinal benefits, too. But take in too much THC, and you can become irritable, even psychotic. “There are more emergency room admissions today than ever because of marijuana use,” Dr. ElSohly says. “That’s simply because of the psychoactive side effects of the high THC content that the public uses.”
This makes standardization and getting the dose right more important for medical cannabis than for most other drugs, which is why I’m not enamored of smoking pot as a THC/CBD delivery system. At the risk of being too personal and “anecdotal,” I couldn’t smoke pot if I wanted to, for recreational or medicinal uses, whatever my feelings about its legalization. I can’t smoke cigarettes, either, and have never tried either pot or cigarettes. The reason is simple. Inhaling just secondhand smoke sends me into fits of coughing—and has since I was a child. Inhaling smoke directly into my lungs has been and still is more or less unthinkable. And I’d bet I’m not alone, either.
My personal sensitivities aside (which are obviously not shared by most people), I see two critical unaddressed questions with respect to cannabis. The first issue is standardization. I’m sorry, herbalists and pot smokers, but smoking a dried plant just isn’t it, particularly given the relatively low doses of active compound needed for optimal effects. That means pharmaceutical-grade material. If cannabis is a therapeutic drug, it should be treated like every other therapeutic drug and be subject to clinical trials. The second issue is comparative effectiveness research. It’s not enough just to say cannabis (or whatever cannabinoid drug or derivative you might wish to use) is “efficacious” against this disease or this condition. We need to know how efficacious it is compared to the existing standard of care. In most cases, even for indications for which there is evidence of efficacy, the existing evidence base suggests that cannabis is less effective than existing treatments, with the possible exception of its use as an antiemetic. Yet none of this sways the zealots, just as similar evidence with respect to other herbs doesn’t sway believers in herbalism. Meanwhile, medical cannabis is rapidly becoming big business.
That’s because cannabis is the new herbalism. A more balanced, science-based approach is desperately needed.