Friday, May 20, 2011

More About the Mysteries of Cannabis

In my last post on cannabis, I reviewed some observational evidence that smoking marijuana could be seriously bad news if you have psychosis or relatives who do, putting you at higher risk for psychosis yourself.  Ultimately there will be no gold standard randomized controlled trial - the design for that would be: randomize one group of teenagers at high risk for psychosis to smoking pot (hey, make it multi-arm - some will smoke LOTS of pot, and others less), and have another group not smoke pot, follow them through young adulthood, and see what happens.

Yeah, that's not going to happen.  But what we do have as evidence in several epidemiologic studies and some prospective cohort trials is that the more pot and the earlier a teenager starts smoking pot, the higher the risk of developing psychosis.  We also have some plausible biologic mechanisms (this study, for example, seems to show that folks with cannabis dependence and folks with schizophrenia have similar brain metabolism in key areas, which were significantly different than non-schizophrenic non-cannabis dependent folks).  And in animal studies, where randomized controlled trials can be done,  heavy doses of THC seemed to damage the brain.

I feel like music.  How about Austin's own Spoon, with Don't You Evah (right click to open in new tab).

Is the news all bad for funny cigarettes?  Any time one badmouths marijuana or questions its benefits one will find that a bunch of people pop up with all sorts of miraculous properties of cannabis.  And, in truth, cannabis is not just about THC, and is an exceedingly interesting plant with all sorts of intriguing cannabinoids in it.  As commenter Erik noted, cannabidiol seems to be neuroprotective and balance some of the more toxic effects of THC, suggesting that "vintage pot" with a better ratio between the two might be much healthier.  

I have used cannabinoids clinically (never in psychiatry, however) - there is an FDA-approved synthetic THC called marinol that we used to give out on the cancer ward in medical school, in Texas, to cachectic patients who had no appetite.  Back then before the proliferation of a ton of antiretrovirals we saw a lot more advanced AIDS - those patients also seemed to benefit from marinol to increase appetite.  I must say I did a number of consults on hospitalized cancer patients in Massachusetts, but never saw marinol prescribed up here.   If you look at the link to marinol you will find the DEA page describing that the purified synthetic THC is much safer than cannabis smoked au naturale.

Some of the DEA's points are valid  - lord knows what is in the cannabis you might buy from your friendly neighborhood dealer - and certainly in the case of immunosuppressed cancer and advanced AIDS patients, smoked joints could easily be adulterated with natural fungi that grow into big nasty (and deadly) fungus balls in the lung.  I saw a case of this fungus ball in medical school in a patient immunosuppresed with HIV who also happened to smoke a lot of pot.  It could have been from other sources, of course, but my attendings assured me they had seen it several times in AIDS patients who were heavy pot users.  It's not a pleasant way to go, and the treatments are horrible.

(Over time, you see enough cognitively bereft heavy pot users and psychotic heavy pot users and top that off with deadly fungus balls, and you can see why I'm none too fond of the stuff.  These types of experiences are anecdotal, but influential to any doctor in practice.  Part of being human, I suppose.)

Other DEA points are the same old conventional wisdom and faulty reasoning that led T. Colin Campbell to conclude that animal protein causes cancer from some rodent studies using isolated casein and aflatoxin.  Natural cannabis contains a mixture of cannabinoids with different effects - one can't necessarily extrapolate the effects of just THC to marijuana in general (though it seems more reasonable to do so with the modern "skunk" high-THC marijuana).  And "purified synthetic THC" could be kinda like casein without the whey in aflatoxin-poisoned rodents - a bad idea for pretty much anyone if you aren't a step away from death via advanced disease + starvation.

So, the lengthy intro aside, let's examine some of the evidence for marijuana that shows positive effects in the human brain.  Fortunately we have the Rolls Royce of academic reviews available - a Cochrane Review - Cannabinoids for the treatment of dementia.  

So what's the good news for marijuana?  Well, cannabis receptor 1 and 2 (CB1 and CB2).  CB1 is primarily active in the central nervous system, and CB2 is found more in the periphery, particularly on the white blood cells.  Some studies of cannabinoids seem to find them to be, in the whole, neuroprotective.  They regulate glutamate transmission (reducing neurotoxicity) and may reduce neuroinflammation.  They might protect the brain from toxic injury.  THC may also be what is called a cholinesterase inhibitor, which is a class of drugs that are now used to treat Alzheimer's.

Small open label trials showed that marinol (synthetic THC) reduced agitation and helped weight gain in dementia patients.  Another small trial of cannabidiol showed it helped with sleep.  But, as Peter has been known to say, small, third-rate studies are small, third-rate studies, and do little more than give us a reason to design larger, better studies that might prove a point or two.  The great thing about a Cochrane review is those scientists comb MEDLINE and OVID and conference reports and ongoing research trials and PUBMED for the awesome studies.  Those that are randomized, controlled, and done with acceptable follow-up and inclusion criteria.   And when you comb the literature for that sort of study with respect to cannabis products and dementia, you find one study that wasn't even the greatest of studies (15 patients, using marinol), so the reviewers ultimately have to say there is no reliable evidence that cannabis should be used clinically in dementia patients.

And what about non-dementia, non-psychosis studies - neuroimaging studies, for example?  After all, I treat a particular population - one apt to be anxious, depressed, demented, or psychotic.  If you are none of the above, are not at high risk for psychosis (ie no family members with psychotic disorders and no personal history), and like to spend the days smoking out on your mom's basement couch - how risky is it to your brain?  Well, a neuroimaging review seems to indicate there are metabolic changes in the brain related to smoking pot, but no one is sure what it means.   Other kinds of studies of neuropsychologic testing also show mixed results.

What seems to be the consensus when one reads general articles meant for psychiatrists (in Psychiatric Times, for example), is that marijuana in the brain is perhaps best conceptualized as a potent nerve growth factor.  In a young, growing brain (a teenager), likely replete with plenty of nerve growth factor, extra nerve growth factor has the potential to be disastrous - lighter fluid on a briskly burning fire.  In an older, demented brain (a smoldering, dying fire), nerve growth factor may well be therapeutic, but there isn't enough good evidence to conclude that is the case.

Is marijuana "paleo?"  The anthropologists can answer that question far better than I can.  Is it healthy?  I can name circumstances which encompass the majority of my patients in which there is some reasonable evidence that it is most likely very unhealthy and risky.  I'm willing to withhold judgment about it's ultimate therapeutic value in other cases (like dementia) until more evidence is in.   And certainly there will, logically, be a difference between artisan variety vintage stuff than the "skunk" high-THC brands of today.

And let's not forget the underlying evolutionary principle - human babies born of natural eating and natural living mothers and fathers are strong and amazing and not broken.  We are not automobiles  - when left to an evolutionary diet and activities we are likely to thrive, as we always have.  And cannabis has the potential to be a potent long-term brain-altering substance.  There's an old adage in psychiatry:  Don't fix what ain't broken.

In the modern world, well, let's hope the science researchers design and implement some good studies that can answer our questions!


  1. I have used MArinol for MS and Spinal cord injuries.......but I am much more interested in the CB2 receptor biology because of it neuroimmunological effects on the brain. It is not an area that has been well penetrated by research just yet. The CB1 receptor gets all the press. It is likely that endocannabinoids function as both neuromodulators and immunomodulators, there is already evidence that within the central nervous system they serve as retrograde synaptic messengers that play a modulating effect on the orexin and leptin axis. Again, this is another reason I am very interested in this area. My treatise on longevity puts leptin signaling at position two of importance so this system as a modulator of that axis obviously is important. I think for psychiatry the way this system interacts with the dopamine reward tracts and sleep pathways is critical to the effects on dementia and depression. The promise of the agonists of the CB 2 receptor is for neuropathic pain treatment and direct modulation of the brains immune system. I also find it interesting that the CB 2 receptor is also found on the BM of microglia strongly pointing to a role in stem cell recruitment for neuro regeneration

  2. Speaking as a nurse, I see marinol, but megace is more common. Megace is a progesterone like substance (AND speaking as a female, progesterone is EXCELLENT at making you want to eat everything you see and still want more).

    Re: pot being a bad thing, I agree. I have never met a functional human being who was a heavy pot user. I have met a lot of apathetic people who had trouble with weight, and I have met mentally ill people. I have never met a normal high functioning person who smoked a lot of pot. Like any dependant person, people who like pot will do whatever they can to defend it. I love coffee and I would probably also argue vehemently in favor of coffee being good for you. The concept of not having coffee is scary to contemplate lol.

    In spite of the fact instinct tells me pot is harmful, perhaps we are merely observing a sign of prodromal psychosis. Has it been considered that psychotics are more at risk to respond to pot and therefore abuse it, similar to how they are supersensitive to nicotine? It may be that people who already have abnormally functioning brains (prepsychotic) tend to abuse drugs with dopaminergic properties + calming properties. We tend to see drugs like cigs and pot being abused commonly in psychotic populations and these drugs have similar dual stimulant/sedative roles. They also abuse alcohol a lot, and alcohol is another stimulant + sedative type drug.

  3. Cannabis has been used for thousands of years - endocannabinoid receptors are the most prevalent in our bodies. We have only 'demonized' it the past 100 years and the fear factor has been effective - as is shown here.

    We come out of the woodwork when misinformation based from fear is propagated as science because we have enough misinformation to deal with. As for the fungus problem - that is more to do with the bad growing practices and not the actual pot itself.

    There are a lot of people who have used the synthetic THC say it does not work as well as the real thing - why? Probably because there are a lot more cannabinoids within the plant than just the demon THC. When you look at the actual history of the plant - and it's demonization - one sees strong cognitive bias here - with the "I've seen bad things happen to people who use it" but there are often extenuating causes - like the fungus issue. Handing it over to the for profit corporate pharmaceutical industry is the last thing we need. We've used it for thousands of years - a century of paranoia can hopefully be overcome ...

    Dr. Robert Melamede on Endocannabinoids

  4. It is a factually incorrect statement to say this receptor is most prevalent in our body. It does not come close to that. You may be biased toward "natural THC" but let's leave the hyperbole alone when it comes to science

  5. John - yeah, CB2 looks to be very interesting - WBCs, Bone marrow, microglia, brainstem...

    Woo - the denial aspect of addiction is powerful, but I will perhaps give my pro-pot readers and commenters the benefit of the doubt and not accuse them all of being hopelessly addicted pot-heads without a rational ability to weigh evidence pro and con. Some are just ornery and argumentative ;-)

    Xeno - today's skunk pot is nasty stuff even compared to pot of 20 years ago - do any pro-pot folks disagree with that?I've never heard of cannabidiol being available for anything but research. I don't think "paranoia" is how I would define my thinking about pot, but whatever floats your boat.

  6. I remember seeing a TV show about Bob Marley (PBS's American Masters, IIRC) where they asked him about the Rastafarian and ganja. He had an amazingly insightful comment basically saying look at who's telling them not to smoke, referring to the imperialists ruling Jamaica at the time. Of course, I'm not comparing Marley to our run of the mill pothead.

    Ultimately, it doesn't need to be criminalized. We just need better information on it. People will make the best choice they can. I kind of have to agree with Wooo2's sentiment about the herb being just a symptom and not the cause of a problem. Sort of like how perhaps hypoglycemia is the root cause of alcoholism.

  7. Richie Poulton (a friend of my husbands) from the Dunedin Longitudinal study ( said to us that if there is one thing he would test his kids for it would be the gene that increases the likely-hood of schizophrenia with smoking dope during adolescence, and if they had that he would do everything in his power to stop them smoking it until they were past that window (I think about age 25)

  8. I can't find any information on this but I'm currently taking St. John's Wort(internet oversharing?) and my appetite has gone through the roof! I got stoned once(with bill clinton and we didn't inhale) and this is the exact same feeling. Vivid colours, warm body and insatiable appetite.
    Worth considering especially as I've seen so much contradictory information about this drug(maoi? ssri? etc etc.). Similar feeling to eating a lot of dark chocolate which is also a cannabanoid(and opiod). Why didn't Coleridge write about dark chocolate instead(or at least sugar)?
    I offer up the following book title to any interested party "Confessions of an American sugar eater" perhaps about weight loss with a low carb diet.

  9. Based upon that standard of harm there is no defensible use of sugar except as a wound-packing. (look it up)

    Yes, mentally ill people use cannabis and are more likely to use cannabis before seeking treatment with a psychiatrist. They are also more likely to use alcohol, tobacco, hallucinogens, cocaine, stimulants, chiropractic, homeopathics and acupuncture. People do crazy things to relieve distress; not news.

    Given that....

    I agree that much of the pot produced now is too damned strong and have plenty of evidence as I live in Northern California. The trade-off being that most people simply smoke less and reduce their intake of tars and combustion byproducts.

    The pot smokers i've observed seem to be able to regulate their cannabis intake to the level where they can hold conversations, walk around and play hackey sack. I dont think dose regulation isn't much of a problem.

    What you haven't mentioned about cannabis is that in addition to regulating appetite food tastes better to cannabis users. Without other evidence than hipsters at farmers market I'd say cannabis leads to consumption of fresh leafy greens and locally grown vegetables. There are even reports that organic vegetable gardening is a side effect of growing pot.

    Not the worst stuff on the planet.


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