Cannabidiol

Would you like some CBD gel with your tequila shooter?

There is an interesting article about transdermal cannabidiol (CBD) being useful for moderating the brain damage caused by binge drinking – here is the enthusiastic High Times review.  As positive as I am about CBD, I think a few caveats are in order.  First and most obviously this is a rat study and is far from proving anything in humans.

The original article is set to come out in Pharmacology Biochemistry and Behavior and is an interesting read.  In their introduction of what is known, they point out that previous studies have shown positive effects of antioxidants, including CBD,  on the neurodegenerative effects of alcohol.  They also note that CBD is poorly absorbed by the oral route, with a bioavailability of only 6%.

The initial part of the experiment looked at different strengths of CBD gel.  The blood levels of CBD for different formulations was measured, as well as what the differences were in neurodegeneration after alcohol binging.  There was a decrease noted, though it was only with the highest strength of the gel and there wasn’t a dose dependent effect noted (generally, effect should increase with increasing drug strength – this increases the confidence that the result is due to the drug, rather than statistical error/randomness).

The second part of the study used a different formulation altogether of gel vehicle, though one designed to deliver a similar plasma level to the gel strength that was effective in part one of the experiment. The authors report that the transdermal formulation and the intraperitoneal injection produced a similar reduction in neurodegeneration from alcohol toxicity.  Once again I have issues with the dose response relationship as they also seem to demonstrate that the intraperitoneal injection produces blood levels of CBD that are an order of magnitude greater than those achieved with the patch and yet the neuroprotective effect is not significantly different between the two.

In the conflict of interest section it is also noted that two of the four authors have significant shareholdings in Alltranz, a company which has recently been issued a patent for the transdermal administration of cannabidiol  Transdermal patches are an excellent way to deliver medications and have shown particular success with fentanyl and nicotine.  Transdermal cannabinoids would be a welcome addition to clinical practice and I wish Alltranz well with their further developments.  However,  I don’t believe that you can draw any conclusions from this study about whether transdermal cannabidiol is useful in humans for warding off neurological injury from alcohol excess.  It wouldn’t be wrong to take a CBD capsule after a night of heavy drinking; in that there may be benefit and there is unlikely to be any harm.

 

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Cannabidiol as part of treatment for nicotine addiction.

It seems that cannabidiol research is happening in the UK as well.  Today’s paper is from Addictive Behaviours and is entitled: “Cannabidiol reduces cigarette consumption in tobacco smokers: Preliminary findings”  I had previously not heard about cannabinoids in nicotine addiction, but apparently there is a Cochrane review on the effects of rimonabant (a CB1 receptor antagonist), which found that rimonabant was able to increase the chances of quitting nicotine, however this agent has been removed from the marketplace due to causing depression and suicide.

Animal research has shown that CBD may be useful in addiction and also functions as an anxiolytic, which could be useful in treating the anxiety often associated with nicotine withdrawal.

This British study took 24 smokers and randomized them to receive either a placebo inhaler or an MDI inhaler containing 400 ug of CBD per puff that they were to use anytime they felt the urge to smoke.  What they found was a significant decrease in the number of cigarettes smoked (about 40%) in the CBD group, compared to a non-significant and much smaller decrease in the placebo group.  There was not a significant decrease to cigarette cravings.

It is certainly not possible to speak to mechanism with this sort of study, but the authors do put forward a number of possibilities.  What is clear is that more treatments are needed to deal with nicotine addiction, both in the West and to the burgeoning populations of smokers in the developing world.

 

 

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Crohn’s, Cannabis and Israel

Of the many diseases out there, Crohn’s disease is usually up in the top 5 of diseases that one really wants to avoid.  It is a cause of chronic pain and often addiction, often leads to multiple surgeries, has effects all over the body and often waxes and wanes with little predictability.  The medications used to control it have significant side effects and produce long term side effects of their own.  Many patients become resistant to medications or are unable to tolerate their side effects.  So there is considerable effort that goes in to finding new treatments.  Are cannabinoids the next big thing for Crohn’s?

For anyone new to this topic, there is an enthusiastic review of both THC and cannabidiol (CBD) in Phytotherapy Research.  The authors recommend further research with CBD as a nonpsychoactive antiinflammatory.  And it looks like this study has been completed, results pending out of Meir Medical Center in Israel.

But the paper that I wanted to talk about today is “Cannabis Induces a Clinical Response in Patients with Crohn’s Disease:a Prospective Placebo-Controlled Study”, also from Israel.  So why is all this research getting done in Israel?  It turns out that getting cannabis research done in Israel has been much easier than in the US.  Apparently the procedure has been that the study had to be cleared only by the hospital’s IRB, much less onerous than the years of delay one faces getting similar research done in North America.  Once cannabis has shown benefit for a condition in Israel, then it can be prescribed for that indication.  There are even Israeli hospitals that have vaporizers for patients.  Unfortunately, this liberal attitude seems threatened by changes to legislation, leading some doctors and patients there to go on a hunger strike.

On to the paper! This was unfortunately a very small study, looking at whether patients who were unresponsive to other therapies could benefit from twice daily cigarettes containing 11.5 mg THC (vs placebo).  The patients data was recorded initially, after 8 weeks of treatment and then two weeks after.  The primary objective of the study was to induce remission and while there was a strong positive trend (5/11 had remission in the study group, vs only 1/10 in the placebo group) the results were not significant.  There were other positive findings in the study:  90% of patients in the study group had a clinical response vs 30% in the placebo group; there was a significant increase in quality of life; three steroid dependent patients in the cannabis group were able to stop their steroids during the study and there was no difference in side effects between the two groups.

The biggest problem with this study is the small size – despite showing a strong trend towards benefit, the study group was just too small to show this clearly.  The other big problem with this study was the lack of blinding.  All but two patients were able to tell if they received the cannabis or not.  With this kind of study, this lack of blinding could exaggerate the effect.  This problem may partly be resolved by just doing studies with CBD, or more elegantly, have a three arm study, comparing THC, CBD and placebo – without psychoactive effects, patients would not be able to tell which non-THC group they are in.

The last issue to mention with regard to this study was that the effect of the cannabis seemed to disappear after 2 weeks of cessation.  This raises the question of addiction for many physicians and while this is a reasonable concern, poorly managed Crohn’s patients often end up given frequent prescriptions for narcotics, far more addictive drugs.  The other drugs used to treat Crohn’s all have their side effects also, so this would need to be balanced against the long term risks of cannabis, which so far seem quite minimal.

As with so many other studies, this one ends with, “Future larger controlled studies should look into the role of cannabinoids in controlling inflammation and symptoms in IBD”.

 

 

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Cannabinoids and Seizures – Is now the time?

…the antiseizure properties of (THC) have been demonstrated in a wide variety of experimental animal species…The possibility that (THC) or other cannabinoids may be useful or detrimental in major seizure needs further investigation.”   Consroe, et al. JAMA, 1975

 

“In the case of epilepsy, there is actually very limited direct scientific data supporting the use of smoked marijuana or oral cannabinoids in humans as antiepileptic agents….Overall it might be argued that what is called for is a large-scale double-blind randomized trial that rigourously tests the effects of smoked marijuana in a large population of human epileptics.  However, continuing legal complexities, significant concerns about psychoactive properties, some potential for addiction liability, and the sheer complexity of the chemical exposure that results from smoking marijuana all represent notable obstactles to initiation of such a study.” Hofmann and Frazier, Experimental Neurology, 2013

 

How disappointing that after almost 40 years, so little has changed from a clinical perspective.  I recently had the good fortune to meet Dr. Alan Shackleford who presented part of this video on using cannabinoids to treat epileptic children.  Unfortunately there is no state of the art clinical material to review regarding this.  The most thorough review of the topic in general is the article listed above by Hofmann and Frazier; it deals predominantly with animal studies, which are useful and essentially the only way that cannabinoids have been able to be studied for this condition.  The authors list three  contentions without hesitation – that endocannabinoids have effects on the excitability of neurons, administering external cannabinoids can prevent or modify seizure activity and epileptic syndromes produce natural alteration in endocannabinoid activity.

More human studies are obviously needed, but two recent animal studies deserve mention.  The first involves cannabidiol (CBD), a non-psychoactive cannabinoid, from the June, 2012 issue of Seizure.  This study showed that CBD was largely free of motor impairment side effects and was effective in a wide variety of rodent seizure models.  Among the interesting things arising from this is the mechanism involved – CBD is not thought to act directly on CB1 or CB2 receptors and the means by which CBD reduces seizures is still not understood.

Similar results were reported with cannabidivarin in the British Journal of Pharmacology Dec, 2012.  This group of authors reported on a general therapeutic effect of a different cannabinoid, cannabidivarin on a similar spectrum of rodent seizure models.  The thing that ties these studies together and most likely all further research in the area is the presence of GW Pharmaceuticals who have applied for a patent on the use of these agents for seizures.  GW Pharmaceuticals is the maker of Sativex and clearly wants to be leading the research in this area.  Perhaps they will be the ones to finally get human research off the ground.

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Inconsistency and Social Anxiety

As I was preparing for this post, my thoughts were with the word, non-psychoactive, used so liberally in my last post.  How can I describe a drug that I am ascribing properties of anti-anxiety and anti-psychosis and still call it non-psychoactive.  Certainly psychoactive is an inexact term.  Alcohol is psychoactive, as are Prozac, dextromethorphan, nutmeg and even water in high doses.  But the difficulty usually comes in making people happy in a rapid way.  Changing mood with acute agents including alcohol, marijuana, MDMA and tobacco is generally thought of as a moral failing by the PC (Pharmaceutical Calvinist) crowd.  They are still somewhat unhappy with SSRIs as unnaturally increasing happiness.

So with more precision:  cannabidiol does not produce any acute intoxication.  It does not get you high. Period.

But is it psychoactive in other ways?

A group in Brazil has been working on this problem.  Their most recent article involved giving CBD to subjects who were socially phobic and made to prepare for a public speech.  They found that anxiety levels were significantly lower in the CBD patients vs those who had not received the medication.  In a previous study by the same group, they were able to show using functional MRI that CBD acts in the limbic and paralimbic system, where anxiety is believed to originate.  The next step would be to measure CBD against a standard anti-anxiety agent like diazepam or an SSRI to compare effect with harms.  The benzodiazepines are fairly addictive, which has limited their use and the side effects of SSRIs are intolerable for many people.  CBD seems to show promise.  If only research could be carried on in Canada or the US.

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Is Cannabidiol all it’s cracked up to be? And where can I get some?

I was just at a meeting where a big chunk of the conversation was about cannabidiol.  Cannabidiol is kind of the missing link in the medical cannabis world.  THC is by far the better known cannabinoid, so here is an introduction to it’s less famous cousin.  Cannabidiol (CBD) is a non-psychoactive, let me say it again, non-psychoactive cannabinoid, found in naturally occurring in marijuana plants.  The percentage of CBD in plants has been decreasing recently, at least partly because growers have been trying to maximize THC content in their plants for better price and smaller shipping costs.  It turns out that CBD is useful to have in your plants though.  While CBD does not directly affect the cannabinoid receptors, it modulates the effect of THC on the receptors, often producing a reduction in the high, but with other very beneficial side effects.  CBD is an agent with anti-anxiety, anti-psychotic, anti-nausea and anti-cancer properties.  When people use cannabis that has a very high THC/CBD ratio, or no CBD at all, they are more likely to experience nausea, anxiety or paranoia than if they use strains that have a lower ratio.

So if I wanted to prescribe this non-psychoactive medication to my patient for any of the above conditions, knowing that this drug has been ingested by humans for thousands of years with no evidence of harm, how would I get it?

At the moment the only legal supply of CBD in Canada is in Sativex. which contains a high amount of THC as well as CBD.  But what if I had a patient who was not interested in the psychoactive effects of THC but wanted to see if they could benefit from the anti-inflammatory effects?  What I really need is Nabidiolex, but it doesn’t come separated.  If you want CBD in Canada, you have to take the THC as well.  This arises because cannabidiol is Schedule 2 in Canada, this non-psychoactive cannabinoid lumped in with THC.

But some might argue that it is possible to make THC from CBD.  And that is correct according to this paper, however I am going to suggest that most Canadians are able to find an easier source of THC than taking pure CBD and boiling it in a combination of benzene and p-toluenesulphonic acid for 2 hours before moving on to the bicarbonate extraction.

Did I mention it appears to work for inflammatory bowel disease too?

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