Fifteen members of the Society of Cannabis Clinicians -the doctors’ group founded by Tod Mikuriya in 1999 and now led by Jeffrey Hergenrather- met in Oakland Dec. 11. UCSF professor Donald Abrams recounted the obstacles he faced in conducting clinical trials with government-issued cannabis and getting his results published in peer-reviewed medical journals. The ensuing discussion focused on how SCC doctors might go about evaluating the effectiveness of high-CBD strains as they become available to patients in the year ahead.
CBD (cannabidiol) is a non-psychoactive cannabinoid. For many generations (of people and plants), cannabis in California and elsewhere has been bred to maximize psychoactivity, which is mainly a function of THC content. (Some “minor” cannabinoids, terpenes, and flavonoids also affect a plant’s effect.) Because CBD and THC are in an either/or relationship at the genetic level, breeding for high THC means breeding out CBD. So it was widely assumed that the Cannabis available nowadays in California contains only trace amounts of CBD.
Surprisingly, six strains with buds ranging from 5% to 7% CBD by weight have been detected in the year since Steep Hill analytic lab began testing samples from dispensaries and individual growers. Only two of these high-CBD strains have been made available to patients -and only intermittently, as the pounds delivered by the growers sell out in a day or two. “Soma A-plus” has been dispensed at Harborside Health Center in Oakland, and “Pineapple Thai” at Herbal Solutions in Long Beach. The other four strains are being grown out as clones and should be available by spring 2010 to collectives wishing to dispense them.
CHANGED GRAF The doctors want, eventually, to test the effectiveness of cannabis with consistent CBD/THC ratios in treating various conditions. One hoped-for advantage of high-CBD strains is reduced psychoactivity, which might enable patients to take larger doses while remaining functional. The California doctors are somewhat enviously and somewhat gratefully tracking the progress of G.W. Pharmaceuticals, the British company that has been growing cannabis and making and testing whole-plant extracts for medical use since 1998 —with government approval and backing from corporate partners Bayer, Almirall, and Otsuka.
G.W.’s flagship product is Sativex, an oral spray that contains about equal amounts of CBD and THC. The rationale for the combination was set forth in “A Tale of Tw Cannabinoids,” a 2005 article by doctors Ethan Russo and Geoffrey Guy in the online journal Medical Hypotheses. Here’s a summary:
“CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are further examined. The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.”
Sativex has been approved by Health Canada for treating neuropathic pain in multiple sclerosis and cancer. It is obtainable by prescription in 22 countries. GW has applied for and is awaiting approval of Sativex as a treatment for MS spasticity in the UK and Spain. The U.S. FDA has given GW approval to conduct a clinical trial in advanced cancer patients whose pain is not adequately controlled by opioids. (GW is close to finishing an extensive study to determine optimum dosages.) The company hopes recruitment of subjects won’t take more than a year. When the results are in, assuming they’re favorable, GW will apply for marketing approval from the FDA.
Dr. Notcutt’s Encouraging Input
The researcher who conducted Phase 2 trials on Sativex (to determine basic efficacy and optimum dosage range) back in 1999-2000 is Willy Notcutt, MD, a pain specialist at James Paget Hospital in Great Yarmouth, England. O’Shaughnessy’s recently asked Notcutt whether his approach could be adapted by California physicians and patients seeking to evaluate the efficacy of high-CBD strains. The setting was the International Association of Cannabinoid Medicine in Koln, and Notcutt was speaking for himself, not GW Pharmaceuticals, which expresses official corporate disdain for smoking as a delivery system and “the crude plant” as medicine.
Notcutt: Indeed… Those were “N of 1” trials. [In N of 1 trials, data is collected from individuals as their use pattern changes. The number N of patients involved in each study is one, hence the name.] The advantages of N-of-1 trials were first described by a chap named Guyatt in Toronto. The fundamental thing is that the patient acts as his own control.
O’S: Is there a standard design?
Notcutt: It’s very flexible, you can design it any which way you want to. Presumably the patients are currently using a high-THC strain. First you establish the baseline: what’s the patient’s [self-reported score on a] pain scale or the sleep line, or whatever parameters you want to measure. Then you start them on the current drug for a week. Then you put them on the new one. Then you switch them back to the current one, and so forth. You can do it as many times as you like until you say…
[Stefan offers to buy beer, thread not picked up]
“It can be done as many times as you want and for any period -one week, two weeks, six weeks. You can leave it open, you can do it single-blinded [not letting the patient know what he’s taking], you can do it double-blinded [neither doctor nor patient knowing which strain is being used]. But by far the easiest way to start out is to do a straight observational study: open observation and open label. The patients are going to tell you pretty quickly whether they prefer current drug or new drug. The advantage of going from current drug to new drug is, that is what a clnician actually does. That’s how medicine is practiced. I say ‘try this…’ ‘Not much help.’ ‘Now let’s try you on this new drug…’ ‘Yeah, well I think that drug has helped me…’
“I appreciate that you have a problem with standardization, but a lot of people [medical cannabis users] say, ‘I always get this type, I know how to work it, I fine tune it, if it’s a little weak or strong I smoke a little more or smoke a little less.’ Call that the current drug, which we assume is high-THC, and then compare it with high-CBD. That’s what you’re testing: the comparative efficicacy of high-THC and high-CBD cannabis.
“You’re using the patient as his own control and you plot it out: How many times do they smoke each day? What effects are they getting? It’s close to what you normally would do as a clinician. That’s how I evaluate a drug anyway. If you define your parameters, and gets reports from 20 patients, you can then get a feel for whether it works.
“I would suggest that it be done completely open-label at first.
“Guyatt’s is not the only paper on N-of-1 trials. I have one from the BMJ [British Medical Journal] from a few years ago sayng that this is the way we should be studying chronic disease. It’s a well-recognized, acceptable clinical approach. But people have gotten so fixated in the last 20 years on the randomized, placebo-controlled trial- (sarcastically) ‘the only way you can do it,’ ‘the gold standard.’
“I think the N-of-1 trial is the only way you study this cohort at this time, because of your problems with standardization. You have people doing it different ways… But your individual patient becomes your study. And then you can aggregate your studies. You can do some simple statistics on it: of 20 patients that started, five found it didn’t work for them at all. Now let’s look at the 15 that reported effect…
“Then you can go on and blind your subjects and not tell them which is which. Or blind the physician. Guyatt wrote about building in a placebo, but you needn’t go to that extent. That’s not how we do medicine. The RCT [randomized, controlled trial] is furthest from normal clinical practice.
“The N-of-1 trial is a good way of generating some data where no data exists. The first two or three GW studies were all N-of-1, until we knew that it worked. If the first nine of ten patients had said, ‘This doesn’t work,’ then you don’t go further.
“You have to start somewhere. An observational study has the force of common sense. It may be best suited when you have a longterm chronic illness and you need some information about whether a drug works…
“Do we give an orthopedic surgeon and an eye surgeon the same tools? No. So should we statistically evaluate every medical problem by the same technique? If we’re evaluating a drug where the blood pressure goes up or down, or the sugar level goes up or down in diabetes, we use one technique. Why use the same technique for a drug that has a completely different spectrum of activity, in an area where you don’t get nice, number data, where you get much softer data, you get subjective opinion. There’s a whole difference in the quality of the data -why use the same statistical tools?
“People are now starting to say that evidence-based medicine is becoming a tyranny that’s killing off research. I’m very interested in this because I’m the lead for research in our district I’m also the lead for research in my own field. If you start insisting on these big multi-center big studies, all randomized, and you don’t nurture the small studies -the little ones that come along, the N-of-1s that come along where the guy sits down and works on an idea, ‘try this out, try that out’ in a few patients, and generates a little bit more information that then leads to a bit of a better study…
“I still regard as one of the best studies ever, the guy who treated pain after shingles with amtriptyline or nortrypteline. All he did was he found out that when he used the amitriptyline, 60 percent of the patients hated it. When he used nortriptyline only about 30 percent of the patients hated it. A simple trial -but it changed our practice. We stopped using amitriptyline, we use nortriptyline. And now we know the reasons why. That was 10, 15 years ago. I’ve never seen that simple study replicated as a clinical trial of amitriptyline versus nortriptyline because there’s no money it for the drug companies.”
Notcutt offered to review any study design that the SCC docs come up with.
Fred Gardner edits O’Shaughnessy’s, the journal of cannabis in clinical practice, now online at www.pcmd4u.org. He can be reached at firstname.lastname@example.org.
By Willy Notcutt, MD