White Coat Underground

Clinical Marijuana Research Update

Human beings are fundamentally narcissistic, and this narcissism can be antithetical to good science and good medicine. We place far too much confidence in our individual abilities to understand what happens to us, and we place far too much importance on our own experiences, inappropriately generalizing them. That’s why science is so important in medicine—to avoid basing life-or-death decisions on something some guy thinks he might have heard once.

In my recent piece on medical marijuana in Forbes, commenters took me to task for what they perceived to be a host of errors in my reasoning. Some of these deserve to be specifically addressed, but not before a summary of the topic.

Marijuana’s legal status is a political issue, not a scientific one. I will leave the politics to those cursed with such things. But I’m responsible for medical decisions, and as much as is possible, I have to look at data dispassionately. I have no doubt the individuals find marijuana beneficial for a wide range of problems—this may be a basis for study, but is not adequate data to prescribe a powerful pharmacologic agent.

In 2000, the University of California established the Center for Medicinal Cannabis Research. This month, they released a summary of results to date.

The federal government has historically made it very difficult to study marijuana. The state of California, though specific legislation, was able to encourage a significant amount of research into the clinical use of marijuana, and this month’s report is a summary of their work to date. So far CMCR has produced four published clinical studies and one poster/abstract.

The first study, by Abrams, et al, deals with painful HIV-associated sensory neuropathy (HIV-SN). This is a painful condition that can be caused by HIV infection or by certain treatments for HIV. This is a good place to start, as current treatments are disappointing. The study enrolled 55 patients with HIV-SN, and randomly assigned some to smoke real joints, and other to smoke joints with the cannabanoids extracted. Fifty patients completed the five-day study, with some encouraging results, but there are a few problems. First, it’s unlikely that patients remained truly blinded to their assignment (unless they though the treatment group was given Grade F ditch weed). The authors recognized that unblinding might have been a problem. The authors also made an attempt to compare their data to studies of other drugs for this condition, but they did not compare cannabis directly to any other drug, including opioids.

This is a small study, and since the number needed to treat (NNT) found in this study and studies of other drugs was not dramatically different, head-to-head studies of marijuana, opioids, and standard drugs for this condition would be very useful. Given the benefits of opioids in a variety of pain conditions, including neuropathic pain, it would be important to compare the benefits and negative effects of opioids vs. marijuana. Finally, the authors concluded that the drug was generally safe during the five day study, as there were no major adverse events requiring subjects to drop out. I’m not certain this is a fair interpretation:

No patient withdrew from the study because of adverse events. One episode
of grade 3 dizziness related to study medication occurred in the cannabis group. One case of transient grade 3 anxiety possibly related to study medication was reported in each group. Both patients received a one-time dose of lorazepam.

These patients required a second medication to treat the symptoms of the drug. This may or may not be significant when compared to the level of pain relief or when compared to other drugs, but it cannot be concluded that the drug was entirely safe and well-tolerated, especially given what may be observed when there is more than 125 person-days of exposure.

A second study by Ellis, et al, also looked at painful HIV-related neuropathy, and addressed some of the issues with the Abrams study. This was also a small pilot study, but used a crossover design. The authors actually surveyed the subjects to see if they remained blinded, and by the end of the study, many subjects “knew” which toke was placebo and which was the good stuff. They also explicitly addressed one of the interesting questions that comes up in relation to marijuana research.

Because of funding mandates, these studies used smoked marijuana. Given the likely harm of long term smoking of anything, Ellis brought up the need to study non-smoked cannabis. Boosters often promote smoked cannabis as having “special” properties not available in extracts and derivatives, something these two studies, which each contained de-THC’d fatties, argue against.

More important is that while these results are encouraging, they are not enough to make a clear medical recommendation. Two small pilot studies are not sufficient to make significant clinical recommendations. They may give us good reason to study the use of marijuana or its derivatives for the treatment of HIV-related painful sensory neuropathy. Hopefully future studies will include comparisons to standard therapy, and clearer evaluation of long-term effects of marijuana ingestion in these patients.

References

Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, & Petersen KL (2007). Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology, 68 (7), 515-21 PMID: 17296917

Ellis, R., Toperoff, W., Vaida, F., van den Brande, G., Gonzales, J., Gouaux, B., Bentley, H., & Atkinson, J. (2008). Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial Neuropsychopharmacology, 34 (3), 672-680 DOI: 10.1038/npp.2008.120

Comments

  1. #1 David
    February 22, 2010

    there’s are several standard ways to run a proper control group for a trial when the subjects are able to detect whether they’re getting active treatment or not. Rather than a true placebo, treat subjects with low-dose or high-dose active treatment, and demonstrate a dose-response curve. The subjects are far less likely to know which dose arm they’re assigned to, with that design.

    for an example of a trial using that design, of a treatment that is easily detected by the subjects, see Neurology. 1998 Jul;51(1):48-55.

  2. #2 Donna B.
    February 22, 2010

    I think the delivery system is a problem. But there is always a trade-off in using any drug — does the possible good outweigh the possible harm?

    With some treatments — vaccines, antibiotics, insulin — there is overwhelming evidence that the good outweighs the bad. Not only that, the good is overwhelmingly good with very few bad side effects.

    If only that were true for other generally accepted treatments. It is unfortunately not. I suspect that bad outcomes are far too often overlooked or deliberately ignored in some instances. Plus, good outcomes for a short period of time (<5 years) often means research stops. Some treatments, ie, bariatric surgery often fail and cause serious health problems at 10 years out.

    I think you are asking more, a higher level of proof, from the research on marijuana than you would ask from other drugs or treatments. And I could certainly be wrong about that… but I think you have let the political elements influence your thinking.

  3. #3 Donna B.
    February 22, 2010

    The comment software doesn’t handle the “less than” symbol well, it seems. Please insert this after the ( in the next to last paragraph, please:

    (less than 5 years) often means research stops. Some treatments, ie, bariatric surgery often fail and cause serious health problems at 10 years out.

  4. #4 PalMD
    February 22, 2010

    It parses it as html. “& #60″ without the space equals <

  5. #5 Rob Monkey
    February 22, 2010

    Whew! I read your post here and thought, “gee, not bad reasoning, only one thing I’d point out to be a little iffy, what’s the deal?” Then I read the Forbes thing. Jesus, Pal, I love the blog, but that article was a stinker! You should have published this instead, it comes off much more reasonable. The one thing I have an issue with is the “Boosters often promote smoked cannabis as having “special” properties not available in extracts and derivatives” thing. As with anything people are really into, there’s lots of bad advice and dumb, dumb, dumb opinions about pot as medicine out there. It doesn’t have “special” properties when smoked, it simply gets into the body quicker and therefore allows patients to more easily control their dose. No offense, but if you wanted to deride their idea of it being “special,” you might have bothered to talk to someone who actually isn’t high at that particular time ;) It goes right with why a lot of patients don’t like Marinol: it works, but they’re FUCKING STONED. Someone who takes a toke or two can go to work and perform just fine, which is what we want out of the pain medication, no? Incidentally, you get the same results with vaporizing the marijuana as you do smoking it, and I’m seriously surprised that they didn’t use vaporizers in the study, it would have been even easier to control doses and prevent patients from unblinding.

    “Pot-smokers love being able to get high without the threat of legal repercussions” Wow, you start the article off with that? Come the fuck on man, that’s really how you’re going to color the average medical pot patient? The paraplegic and two cancer patients I know here in MI might differ with you on that.

    “Marijuana does not come in easily measured doses” Yeah, that’s an impossible hurdle to mount eh? I can write the HPLC method for you and run the damn instrument if you want. You’re right, it’s not as exact a dose as a pill, but that’s a direct consequence of legality and the amount of studies which have been allowed. It wouldn’t be very hard to do studies that were better designed than the one you reference, you just need better control over the experiment.

    You’re correct, the fact that pot has been difficult to study is not an argument for it. But it isn’t exactly scientific to decide to not study something because of old prejudices, now is it?

    As for saying that those who advocate for its use should advocate for further study, well, simply put, they are. Advocates are constantly petitioning to have it removed from Schedule 1 and for more studies to be done, but you also run into the sticky situation of it being a plant that can be grown by someone with a relatively basic understanding of plants and a minor investment. People are (justified or not) distrustful of pharmaceutical companies, and they don’t like the idea of having to buy a pill when it could be grown in a garden. Personally I’m fine with the pharmas, being a chemist, but if someone can grow their own medicine, well it runs into a really gray area. Nobody wants to extract ASA from willow on their own, but I’m sure marinol is pricey and a lot of people would like to take control of their own medicine.

    Anyway, the blog rocks, but maybe reference it next time you write for someone else. Forbes didn’t get the full PalMD experience its readers would surely have enjoyed (perhaps they’re cheapskates? Ironic)

  6. #6 PalMD
    February 22, 2010

    Part of the 6 pack of studies released is a vaporizer study…more on that later.

  7. #7 terence anton leary
    February 22, 2010

    what exactly was it about the CMCR report that didn’t do it for you? what evidence, hypothetically speaking, would it take for you to stand back and say, “ok, you convinced me, there is really no harm in it and there is definitely no cause for us to keep completely ruining peoples lives and families over cannabis”
    sometimes science scoffs in the face of what was once commonly perceived. The CMCJ study you are trivializing has been going on for 20 years and is the official “Gold Standard” drug testing that meets the FDA requirements for drug approval. 598 doctors from all over America signed off on it as the real deal and put their careers and reputations on the line to go and put this research out there for the rest of the world as scientific facts.
    also, cannabis being a “powerful pharmacological agent” is a good thing. being beneficial and efficacious yet not addictive and having no real adverse side effects makes it sound like a near perfect drug.
    have you ever tried it? it is not that bad. in fact, i hear that the more liberty and personal freedom you have, the more those ‘”paranoid” side effects go away.

  8. #8 MonkeyPox
    February 22, 2010

    Dude, Stoner-Americans have rights, for sure, but did you even read the article?

  9. #9 Dianne
    February 22, 2010

    Vaporization sounds like a promising route of delivery, based on the abstract (I haven’t gone searching for the article yet.) Some of the uses also sound promising, though none sound paradigm shifting wonderful at this point. But this makes medical marijuana just like any other new medication: first comes the hype, then the disappointment when it doesn’t fix everything, then people finally get down to figuring out how to use the thing properly. With any luck, we’re finally at stage 3. I predict that in 10 years marijuana or some extract will be a moderately useful drug in some small subset of diseases. Not the cure all, not the demon weed, but just another pharma product.

  10. #10 Isaiah Jimerson
    February 22, 2010

    HMMM. I wonder. Isn’t marijuana considered an herbal treatment? Still against herbal supplements? Didn’t native Americans use it ot relive pain and just to get high? I feel most people who want it legalized just want to get high anyway. They still haven’t overcome Woodstock yet.

  11. #11 ginger
    February 22, 2010

    “These patients required a second medication to treat the symptoms of the drug. This may or may not be significant when compared to the level of pain relief or when compared to other drugs, but it cannot be concluded that the drug was entirely safe and well-tolerated, especially given what may be observed when there is more than 125 person-days of exposure.”

    People are routinely treated for the symptoms of opiate administration – stool softeners, gut stimulants, sometimes bladder stimulants and blood pressure stabilizers – and those are the standard of care, aren’t they?

    I’ve got no dog in this fight, mind you; I think we need to understand the pharmacology better before we go around making recommendations, but I also believe that it’s not contradictory that sick people might benefit from pot even though it gets well people high.

  12. #12 DrugMonkey
    February 22, 2010

    yet not addictive

    This is not correct. Cannabis IS addictive. It produces a characteristic withdrawal symptoms so even those dualists who like to pretend that there is a difference between so called “psychological” and “physiological” addiction don’t have much ground. Furthermore, cannabis addicts meet diagnostic criteria for dependence just as do users of other drugs.

    The big question is what fraction of users, of course. The consensus data tends to slot in around 8-10% as compared to maybe 15% for cocaine and other stimulants and perhaps around 23% for injected heroin. (http://scienceblogs.com/drugmonkey/2008/04/recreational_drug_use_in_the_y_1.php)

    The question of what broader legalization will do to dependence rates is rather an interesting one but it is just not consistent with objective reality to pretend that cannabis is incapable of producing addiction.

  13. #13 DrugMonkey
    February 22, 2010

    I also believe that it’s not contradictory that sick people might benefit from pot even though it gets well people high.

    Of course not. Opiates, benzos, barbiturates and psychomotor stimulants (amphetamine, methamphetamine) are approved prescription medications and they certainly get well people high and can cause well people to become unwell people (dependence, addiction).

  14. #14 leigh
    February 22, 2010

    there is little debate about the difficulty in providing a constant “dose” of smoked cannabis. different individuals have different smoking efficiencies. individuals also tend to differ in their smoking behavior as a factor of THC content.

    vaporizers would make things far more standardized in terms of dose received, etc, but i don’t see how the unblinding issue is resolved by a vaporizer. either the typical THC effects are present or not. people can generally gather this.

    the issue here is that the evidence is not robust in the least and there are considerable remaining issues with experimental design.

  15. #15 PA Wedding Photographer
    February 22, 2010

    Yes – it is mentally addicting, but there is very few reported results of physical dependency. I believe this is due to the half life of the drug. Isn’t it true that Cocaine and Heroin both have extremely short half lifes therefore they are more addicting? Anyway – I think you seem at least open to studying it further. Keeping an open mind is better than assuming it is evil (closed case).

  16. #16 ZenMonkey
    February 23, 2010

    Very interested in vaporizer studies. The difference in smoking a joint and vaporizing is tremendous. With the former there are a host of other chemicals introduced, such as butane or other lighter fluid, and whatever’s in the rolling paper, and this stuff also contributes to the “high.” And a person smoking a joint may associate the high with symptom relief, even though in effect it’s more of a placebo.

    Most serious patients I know (that is, those of us who use marijuana for pain and illness) either use a clean glass pipe of some kind or, like me, a vaporizer. Since vapeing is recommended for medical marijuana patients it seems to me that these studies should focus on it more.

    I also would be interested to see studies on ingested cannabis, since this is another effective delivery system for patients who are unable to inhale for whatever reason.

  17. #17 terence anton wilson
    February 23, 2010

    Dude, yes i did read your article as well as the complete CMCR report, dude.
    would you mind addressing the questions i asked you in my comment?
    the science and methods that allow for twice as long of lifespans than recent ancestors is telling us that it is not bad for you.
    amotivational syndrome and arguments like that are hollow.
    a loser will be a loser regardless of cannabis consumption.
    we need a complete and total re-legalization across the board for people 21 and up. Period. either do that or start throwing drinkers in jail too.
    even you will concede that a glass of red wine PER DAY is good for you.

  18. #18 Mu
    February 23, 2010

    taw, you seem to be completely missing the difference between opening marijuana up as a restricted medical drug (aka getting it off class I status “no medical use”) and completely legalizing it as a recreational tool. Oxycodone is a legal drug, but you still get arrested if you don’t have a prescription for it and are using it to have fun.

  19. #19 Rob Monkey
    February 23, 2010

    Isiah, your entire comment is a waste of space. I guess in a way it’s technically an herbal drug, just like many, many other drugs were originally herbal drugs (do you classify aspirin as herbal?) The existence of marinol and sativex kind of kills your point anyway. The reason science-based medicine advocates don’t like herbals is because there’s slim to no evidence that they work. Pal may have his doubts, but I’d be surprised if he put this in the same category as echinacea or that other new agey stuff.

    “I feel they just want to get high.” Well I feel that someone with ulcerative colities would like to smack you upside the head for wanting to prevent them from getting treatment. The thing you seem to be missing is that in general, illegal use goes down or stays the same in areas where it’s available for medical patients. But hey, you’re not suffering a painful disease that could be treated, so fuck those other people eh?

    I don’t think it’s ridiculous to see a difference between psychological and physical addiction. I could get addicted to food, sex, video games, exercise and a host of other things that we wouldn’t make illegal. The difference between that kind of addiction and heroin seems pretty obvious to me. And, as others have pointed out, addictive properties don’t exactly condemn a drug to not be used, and the evidence is pretty damn clear that if it is addictive, it’s not nearly as addictive as morphine derivatives.

    Leigh, the reason a vaporizer would help with unblinding is because you don’t taste as much when you use a vap. If someone treated some pot to remove the cannibinoids and then had an experienced user smoke it, I almost guarantee they’d notice. Put the same thing in a vaporizer and the difference would be quite negligible. Whether “typical THC effects are present or not” is kind of the point of blinding it. If it tastes/smells the same and you see a difference in effect, then obviously the THC had an effect. No difference between treated and untreated pot? THC doesn’t have an effect. The point of preventing unblinding is not to prevent them from noticing ANY difference, it’s to restrict the difference to medical effectiveness.

    Where it really comes down to it for me is whether or not we’re getting our money’s worth to keep it illegal. As I’ve indicated, I know several patients in MI who are being helped immensely by this drug, and if you told one of them they were just a drugged up hippie who wanted his fix, they kick your punk ass, and rightfully so. I mean really, what’s next? Calling soldiers with PTSD pussies? Grow up, have a little compassion, and stop thinking Harold and Kumar is a fucking documentary.

  20. #20 Calli Arcale
    February 23, 2010

    ZenMonkey:

    I also would be interested to see studies on ingested cannabis, since this is another effective delivery system for patients who are unable to inhale for whatever reason.

    If patients are unable to inhale, I suspect any pain issues will not be troubling them for much longer. :-P

    Sorry, couldn’t resist. I know what you mean. People with reduced lung function may not get the same benefit from an inhaler, nebulizer, or cigarette as they cannot pull as much of it into their lungs. I would think a pill would be a much better delivery system for several reasons, not least of which the fact that you could make a delayed-release version of it. Inhaled stuff hits the bloodstream all at once; ingested stuff usually takes its time. Of course, ingested stuff has to put up with the digestive process, and that’s a problem too.

  21. #21 MonkeyPox
    February 23, 2010

    Marinol. FDA approved.

  22. #22 ZenMonkey
    February 23, 2010

    @Calli Arcale: The moment I hit “post” I realized I should have reworded that last line. Ha ha…oh well. I agree that there are even more variables with ingestion, and since it’s most likely the healthiest delivery system (compared with inhaling either smoke or even vapor), this is why I’d like to see it studied more.

    @MonkeyPox: I have a prescription for Marinol, though I haven’t tried it yet as it’s prohibitively expensive. I learned that it’s formulated specifically for the “munchie effect,” for AIDS and chemo patients and so forth, which doesn’t address other problems (spasticity, pain) that cannabis does. My doctor who prescribed it confirmed this when he warned me that his patients who used it gained a lot of weight.

  23. #23 leigh
    February 23, 2010

    Leigh, the reason a vaporizer would help with unblinding is because you don’t taste as much when you use a vap. If someone treated some pot to remove the cannibinoids and then had an experienced user smoke it, I almost guarantee they’d notice. Put the same thing in a vaporizer and the difference would be quite negligible. Whether “typical THC effects are present or not” is kind of the point of blinding it. If it tastes/smells the same and you see a difference in effect, then obviously the THC had an effect. No difference between treated and untreated pot? THC doesn’t have an effect. The point of preventing unblinding is not to prevent them from noticing ANY difference, it’s to restrict the difference to medical effectiveness.

    as the psychoactive effects of THC are as of yet inextricable from the purported medicinal effects, i think a regular pot smoker would be able to deduce that they’re getting the real thing- and is therefore still quite subject to the placebo effect. hell, a pot-naive person who catches a buzz off the active treatment probably gets the idea that they have the active treatment.

  24. #24 Prometheus
    February 25, 2010

    PA Wedding Photographer comments:

    “Yes – it is mentally addicting, but there is very few reported results of physical dependency. I believe this is due to the half life of the drug.”

    Yes and no. Cannabis/THC produces a physical dependence that is usually masked by the ~8 day half-life in body fat (compare this to the 2 hour half-life of morphine). The serum drug level “self-tapers” by drawing out THC from the fat when use is stopped.

    However, staff in drug rehab facilities are reporting a growing number of “cannabis-only” clients who are showing chracteristic signs of withdrawal (irritability, tremor, sleeplessness, etc.) which they attribute to use of marijuana with higher THC content.

    Additionally, the cannabinoid antagonist SR 141716A (Rimonabant – marketed in the EU for obesity until recently) causes immediate withdrawal behaviors in study animals that had been given THC for an extended period (this aspect of the drug hasn’t been tested on humans, as far as I know).

    So, it isn’t correct to say that marijuana/THC isn’t “physically addicting” – it is.

    The other issue – and one not addressed very well by any of the studies to date – is if THC’s apparent effectiveness is unique to THC (it does act on a unique set of receptors in the nervous system) or if it is a non-specific sedative/anxiolytic effect.

    THC’s long half-life could play a role in making its non-specific effects seem better than those of more “typical” anxiolytics and sedatives by eliminating the “peaks and valleys” seen with the shorter half-life drugs.

    On the other hand, if it is THC’s effects on the cannabinoid receptors (CB1, CB2 and the putative CB3) that give it unique effects not replicatable by other drugs (say, a long-lasting sedative/anxiolytic patch), then it should be investigated for clinical use.

    My objection to the research to date is that it hasn’t tried to separate the non-specific effects of marijuana (feeling euphoric or “high”) from effects that are unique to marijuana. If there is a purpose to “medical marijuana” apart from giving some people a license to use their favorite recreational drug, it needs to show that marijuana (or THC) is better at treating these symptoms (pain, nausea, etc.) than drugs already available.

    The argument – so often used – that smoking marijuana is somehow superior to taking Marinol (which is THC) orally is another problem. If marijuana is better than THC, then it must be something in the marijuana besides THC that is causing the desired effects. If so, we should be looking to find that compound and not messing around with a crude plant product.

    Personally, I don’t see any purpose in keeping marijuana (or any other “recreational” drug) illegal – it didn’t work with alcohol and it doesn’t appear to be working with cannabis. However, it is wasteful to use scarce research resources trying to create a loophole in the (admittedly stupid) drug laws. If marijuana/THC has some unique medical properties, it should be properly investigated; if not, then those who want to smoke it should work on a legislative remedy.

    Prometheus

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