Book of the Week: Russell Brown on weed
An essay and review by Russell Brown in response to a newly-published guide to the future: medical cannabis
A friend of mine has suffered for some time with Complex Regional Pain Syndrome, an often-excruciating autoimmune condition triggered by nerve damage (in her case, in a workplace accident). The first medication she was prescribed made her feel terrible. The second, an anti-convulsant, made her feel drowsy and act strangely in public. Or so she was told – she can't remember most of the month she was on it. What she can remember clearly is the suicidal thoughts. She refused the third drug offered.
Then she discovered that weed helped. She preferred outdoor cannabis – it was less likely to mess with her head – but, as one does in a black market, took what she could get at the time. It was enough that she could dispense with other medications and manage her screen printing work (she'd already had to leave the job where she'd been injured). She found a new doctor and reported to him her cannabis self-medication. "You're doing the right thing," he told her, even though she was breaking the law.
This year, she moved from New Zealand to Seattle, to be with the love of her life. She's really happy, not just for the love, but because in Seattle she can go to a weed dispensary, describe her symptoms and have someone "advise a cannabis specific to my needs – i.e. not strong but will relieve pain".
Although there are a number of studies lending weight to the idea, including a double-blind, placebo-controlled, crossover study in 2013 that found "significant" benefit for CPRS patients for whom nothing else had worked, and that low doses were as good as higher ones, the case for cannabis in treating neuropathic pain is not yet conclusively made. Or, rather, the case for a particular cannabis product in a particular dose, by a particular means of administration, is not made.
As the authors of the 2017 National Academies review The Health Effects of Cannabis and Cannabinoids noted in their Discussion of Findings on the efficacy of cannabinoids for treating chronic pain, the evidence is kind of a mess. Overseas studies scrutinised in the earlier review that most influenced their findings mostly used a pharmaceutical product, Sativex, while US studies often used cannabis flower.
Further, they wrote, "many of the cannabis products that are sold in state-regulated markets bear little resemblance to the products that are available for research at the federal level in the United States". That's because US federal law has long required that nearly all cannabis used in medical trials must be supplied by National Institute on Drug Abuse, which in turn obtains it solely from the University of Mississippi.
The US Drug Enforcement Agency, which sets the policy, recently promised to license new suppliers. But until it does, cannabis research in America must be conducted with federal weed which is not only untouched by the mad science of modern cannabis-breeding and its cannabinoids, flavonoids and terpenes, but, according to a study at the University of Northern Colorado this year, is genetically unlike any pot anyone is actually using, recreationally or medically.
It might be that the buds my friend buys in Seattle are in fact more effective than not only the federal cannabis, but than the clinically-trialled pharmaceutical product. It's possible – let's go wild and upgrade to a "probable" – that the guy at the weed dispensary provides better counsel on this than any doctor in New Zealand could. That's how weird things are things with medicinal cannabis at the moment.
Nonetheless, the National Academies reviewers found "substantial" evidence of cannabinoids' efficacy in treating chronic pain, even as they begged for more and better research. Surely, no one with a capacity for empathy would deny my friend her relief in that light, or criminalise her for seeking it.
It's to the advantage of Dr Shaun Holt, the co-author of Medical Cannabis: A brief guide for New Zealanders, that he's a clinical trials specialist: he understands what the system of medical evidence doesn't say as much as what it does. Although his niece and co-author Emma Dalton wrote the first draft of the book, it's Holt's name on the cover that will lend it credibility.
That's particularly the case with respect to the evidential chapters that are the meat of the book and function as an accessible summary of significant evidential reviews – in particular, the National Academies review and a 2018 Canadian government briefing for doctors. Holt and Dalton do a good job of explaining why, even for chronic pain, where the evidence is certainly promising, "there are few, conclusive, proven benefits for cannabis, so far".
For some of the conditions that cannabis is being recommended for, there is almost no formal evidence. For irritable bowel syndrome, for instance, the authors can cite but one small study, using dronabinol (a synthetic form of THC), which showed no benefit. And yet, last year, the Health select committee heard from Timaru man Mark Crotty, whose life had been destroyed by severe and intractable Crohn's disease, a related condition – and rescued after he decided to break the law and try cannabis. Crotty was compelling. He wasn't lying, or imagining his profound relief. It's just that there are no clinical trials that replicate his personal experience.
The authors cite another, better-known story captured on video in 2016. American ex-cop Larry Smith, twisted and jerking with the dyskinesia that comes with his Parkinson's disease, puts a drop of cannabis oil under his tongue and within minutes his symptoms just fall away. He stands up tall, with wonder on his face. His voice comes back. It's not hard to understand why anyone looking at the video would perceive a miracle cure. And yet, the current clinical evidence for supposing that cannabis would help others with the disease is underwhelming.
How do we resolve these compelling cases of personal relief with clinical trials that simply don't show such a level of efficacy? In a chapter headed 'Medical cannabis in the real world', the authors list reasons why individuals might experience results that are not shown in trials, from the placebo effect to the ways group studies can obscure individual benefits.
The authors observe that even clinically-proven treatments don't work for everyone, and that real individual benefits can be obscured in group trials. And then, of course, there's the fraught matter of which cannabis in what dose.
But if it might work, why not give it a try? Because there are potential harms as well as benefits. As we have heard many times in the broader cannabis debate this year, cannabis use – and particularly heavy use by young people – is associated with increased risk of psychosis and the persistent condition of schizophrenia. Some researchers believe the causation runs the other way (ie, that people with a genetic predisposition to schizophrenia are more likely to self-medicate with cannabis) and some even think cannabis may help. But the consensus is that cannabis use raises the relative risk of psychosis – along with various other factors, including loneliness, unemployment and living in a bad neighbourhood, some of which may be even more influential.
The authors are frank about that risk, and quite correctly warn that people with a family history of mental illness should avoid cannabis. But they have nothing to say about how the findings of studies conducted around general cannabis use (and abuse) might be reflected in a medical setting. This is probably because that evidence, too, is lacking.
This does matter. Patients with neuropathic pain in New Zealand still have few legal options for obtaining cannabis, but they're highly likely to be offered one or more gabapentinoids, sometimes off-label, for conditions where the drugs might work.
And yet the Medsafe datasheets for the two common gabapentinoids, gabapentin and pregabalin (Lyrica), note that in controlled trials, they doubled the rate of suicidal ideation in patients. (Yes, the drug that made my artist friend suicidal was gabapentin. She wasn't warned, just ordered to stick it out for a month.) As a horrifying BBC documentary showed in 2017, where pregabalin use moves to the streets, as it has in Northern Ireland, the consequences are appalling: debilitating addiction, cardiac damage, overdose, suicide. If the risks of pregabalin were assessed on the same basis as those of cannabis, it would never be prescribed.
Gabapentinoids and opioids can also be extremely unpleasant for patients to take. Indeed, this is the thing you will hear most often from the likes of Mark Crotty, Larry Smith and my artist friend in Seattle: their quality of life has improved because they've been able to stop taking – or at least downsize – the daily fistful of pills they'd been on. It's not hard to understand how someone might even accept slightly less efficacy in return for being able to think clearly and not feeling suicidal.
They might even enjoy their medicine, which further complicates things. We're not supposed to enjoy medicines and there are relatively few that, used as directed, straddle the line between therapeutic use and pleasure. (Viagra stands out, so to speak.)
The ultimate complication is that many of the claims made for cannabis as a medicine are at least somewhat plausible. It's not crazy to suppose that cannabis may eventually produce a treatment for some cancers: work on the use of cannabinoids to treat glioma, an aggressive form of brain tumour, has moved from mouse models to human patients in Phase II trials and a 2018 evidence review concluded they "might be used successfully in the treatment of [glioma]". But that is not, yet, a medicine.
This is a fantastically complex plant: more than 140 cannabinoids have been identified, along with 120 terpenes, the aromatic chemicals that give weed its flavours and aromas. Of the 20+ flavonoids in the plant, some appear exclusively in cannabis. Many of these molecules not only have putative medical properties, they appear to modulate each other's effects. The authors sympathetically canvas the idea of the "entourage effect" – the idea that whole plant may have benefits greater than those of isolated molecules – but don't venture on the evidence for the concept. (Surprise! It's mixed.)
"It is worth noting," they write, "that pharmaceutical companies are not comfortable with this idea of using the whole of a natural product. They are used to working with single molecules that they can patent, and this is almost exclusively their business model. They will sell you a vitamin C pill but not a bag of oranges."
The book has the odd glitch. The short section on "synthetic cannabis" is poor. It ventures that the chemicals in synnies are different to the endocannabinoids our bodies produce and those derived from plants, and that "they appear to be extremely dangerous", without really explaining why.
In truth, there is debate over whether they should be called cannabinoids, rather than cannabimimetics, given that they come from several different classes of chemical whose sole common trait is that they bind to the same receptors in the brain and nervous system as natural cannabinoids do (unlike THC, they are full agonists for those receptors, meaning their effects are far stronger).
They largely weren't "designed to produce similar psychoactive effects to cannabis", as the book claims – many are simply escapees from failed pharmaceutical research. And their dose-response curve is frightening – all the 70-odd synnies deaths in this country are essentially accidental overdoses. A concluding paragraph warning of "impurities" could have been usefully replaced with an explanation that they are not the same thing as synthetic THC (variously known as dronabinol, marinol and syndros), a medical product mentioned elsewhere in the book.
I did find myself leafing back and forth for the most useful parts. It's understandable that the authors didn't want to clog up a text for lay readers with citations, but an index would have made it more user-friendly.
It would also – even at the cost of delaying publication – have been helpful to see some explanation of the draft regulations that give form to our new medicinal cannabis law. These are poorly-understood outside the industry and I'd have appreciated some clarity on the fact that while the first range of products will not enjoy the background of clinical trials that would win Medsafe approval, they should – by virtue of the requirement that they be made under Good Manufacturing Process (GMP) – contain what it says on the label and be as free from contaminants as any pharmaceutical product.
Even though it's outwardly not intended for them, it would have been helpful for doctors to read that too. Groups of GPs at two recent medical conferences got themselves in a lather imagining professional liability risks if they were to prescribe approved, regulated products. As the authors note, a unique feature of our situation with medicinal cannabis is that it is both a "new", unproven drug and one that has been widely used for many years.
It's still relatively difficult to find local doctors prepared to prescribe even cannabidiol (CBD), the non-psychoactive cannabinoid assessed by the World Health Organisation being safe with no potential for abuse, even though they're now allowed to without restriction. If doctors won't prescribe cannabis products, it does not mean that people will not use cannabis. It simply means that they will use riskier products – there are outright fraudsters selling to sick people right now – and place themselves in legal peril. There are social and ethical, as well as clinical, dimensions to all this, and doctors need to consider those.
On the other hand, you don't have to spend long in medicinal cannabis Facebook groups to encounter people who have moved past merely liking their medicine to ascribing essentially spiritual powers to it – and believing the pharmaceutical industry and its products are irredeemably evil. Not to mention people who frequently give the impression that they should just ease up on the weed. They may be preaching for cannabis for conditions where it simply doesn't help, or is even actively harmful (Hepatitis C, for example – where there actually is a pharmaceutical miracle cure). They may like this book no more than the hostile GPs do.
The authors predict just such a range of responses to their work – they've set out on a middle course and have generally made a very good job of doing so. They explicitly offer no view on cannabis and the law – but Dr Siouxsie Wiles has no such qualms in a short, blazing introduction to the book. She concludes, on the matter of next year's referendum, that "you should be asking yourself just one question: should our laws around cannabis really be supporting organised crime and placing users in harm's way?"
It's worth reiterating that my friend in Seattle doesn't get her blessed relief from a doctor. She doesn't have to petition a specialist or pay hundreds of dollars for unsubsidised medicine (the inconsistency of evidence for cannabis has another unhappy effect – Pharmac won't fund it). She goes to the weed shop, spends a few dollars and gets something pretty mild that lets her live her life. She fairly quickly worked out what the right mix for her was: around 6 percent THC and 10 percent CBD.
Our new medicinal cannabis regulations do not and will not provide for this kind of retail ease. They are, rather, a generally creditable attempt to fit cannabis into the existing pharmaceutical system. Neither, it should be said, does our current black market – which, outside of a small specialist scene, provides only high-THC weed. It may be that it's something more like what happens in Seattle that keeps everyone, anxious doctors and needy patients, happy. It also happens to be a system we won't see without a 'Yes' vote in next year's referendum.
Medical Cannabis: A brief guide for New Zealanders by Dr Shaun Holt and Emma Dalton (Potton and Burton, $29.99)
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