Science is slowly overcoming a legacy of prohibition, propaganda and prejudice
Cannabis is legal for medical use in 29 of the United States – and for recreational use in 11. Yet federally, cannabis is a Schedule I substance under the Controlled Substances Act 1970, alongside heroin, LSD and other hallucinogens, some synthetic opioids and the dangerous depressant gammahydroxybutyrate.
This category is reserved for drugs that have high potential for abuse, have no accepted medical use and are not safe to use even under medical supervision.
That’s despite cannabis having low dependency rates – an estimated 9% – and literally no lethal dose, while Schedule II opioids, mainly fentanyl, are killing 130 Americans a day (more than 47,000 in 2017).
The story of how a relatively benign substance acquired such an evil reputation is far more about racial persecution and political suppression in 20th-century America than it is about pharmacology or medicine.
If your instinct as a physician is still to recoil from the Reefer Madness drug, you may owe your attitude in part to Harry J. Anslinger, who ran the Federal Bureau of Narcotics for decades and fathered the War on Drugs. His campaign in the 1930s to demonise cannabis – rebranded “marijuana” for the Mexican connotations – began as a ploy to keep the then Department of Prohibition relevant; but it was also useful in the repression of people of colour, jazz musicians and other “subversives”.
Close to a century later, Anslinger’s legacy is visible in the relative sparseness of the science of cannabinoids as medicine, at least in the form of high-quality randomised controlled trials that synthesise nicely into meta-analyses. The studies tend to be small, observational and heterogeneous and to conflate therapeutic with recreational use.
Barriers to research still exist in regulation, supply and funding, according to the National Academies of Sciences, Engineering and Medicine. There are also inherent methodological challenges around delivery method and effective blinding.
It’s a case in which “absence of evidence is not evidence of absence”.
But the landscape is changing rapidly, especially in Australia, where it became legal to cultivate cannabis for medical and research purposes, under licence, in 2016. Since then 78 licences have been granted.
Research is suddenly “going gangbusters”, says Professor Iain McGregor, academic director of Sydney University’s Lambert Initiative for Cannabinoid Therapeutics.
“When we started in 2015, there was probably only one other centre for medicinal cannabis research in the world, and now we see a profusion of them all through Europe, the US, Canada and in Australia,” he tells The Medical Republic.
“The medicinal cannabis companies are starting to realise that the way to get products on to the market is the traditional route of running clinical trials and showing a benefit. We’re seeing pharma move in and buy stakes in some of these companies and that takes them more towards the pharmaceutical model.”
Federal Health Minister Greg Hunt’s commitment last month of $3 million for medical cannabis research was welcome, he said, but compared with some overseas research budgets of $US50 million a year, “it’s a drop in the ocean”.
A true panacea?
Pro-cannabinoid doctors risk sounding evangelistic thanks to the number and diversity of indications: chronic non-cancer pain and neuropathic pain, chemotherapy-induced nausea and vomiting, insomnia, epilepsy, MS spasticity, palliative care, emaciation and lack of appetite, poor gut motility, anxiety, PTSD, depression, migraine, and Tourette syndrome, give or take a few.
But the cannabis-as-panacea claim is grounded in physiology, in the endocannabinoid system, which was only discovered in the 1980s and early 1990s after a surge of interest that accompanied the HIV/AIDS epidemic.
It turns out that cannabinoid receptors – G-protein coupled receptors known as CB1 and CB2 – are everywhere: CB1 mainly in the central and peripheral nervous systems and the GI tract, and CB2 throughout the immune system.
The two main compound classes derived from cannabis plants, tetrahydrocannabinol (THC) and cannabidiol (CBD), have distinct but complementary and synergistic effects. Some conditions benefit more from THC (nausea, spasticity), others more from CBD (inflammation, anxiety, seizures), but almost all patients benefit more from a combination than from either separately.
The terpenes and flavonoids that give the plant its smell and flavour also seem to play some active role, in what is known as the “entourage effect”.
Unlike recreational cannabis, which has been bred to be overwhelmingly THC-dominant, prescription products contain varying ratios of psychoactive THC and non-psychoactive CBD. They come in the form of oils to be ingested or bud to be vaped, not smoked.
Cannabinoids’ multiplicity of effects is in itself a huge therapeutic benefit, says Dr Danial Schecter, a Canadian physician and the founder and medical director of the pioneering Cannabinoid Medical Clinic (Canabo). He is also the director of global medical services at Canopy Growth Corporation, whose Australian branch is Spectrum Therapeutics.
Speaking to TMR while in Australia last month to give education sessions, he said doctors “have a moral obligation” to give science-based answers to patients’ questions, educate themselves about cannabis and be prepared to offer it to the right candidates.
“It’s incredibly important that as a healthcare community we get past reacting to patients who are asking about medical cannabis by regurgitating the same things that we have learned in medical school: that cannabis is a gateway drug, that cannabis is something people use for recreational purposes,” Dr Schecter says.
“There are incredible advances that have been made in understanding why it can be beneficial for pain, for nausea, for spasticity, for sleep.
“We’ve learned that the endocannabinoid system is an incredibly important system that regulates a number of different physiologic and pathophysiologic processes. Cannabinoid receptors are everywhere.
“And one of the things that’s fascinating about medical cannabis is that it can affect more than one symptom. It can affect not only pain, but also nausea, sleep, appetite. And this is something that physicians can harness as a benefit. Because people who are living with pain have associated comorbidities: they have difficulty with sleep, appetite, depressed mood, anxiety, and physicians often will prescribe five classes of medication to treat these five different problems.
“In some patients, medical cannabis can not only be effective for the primary condition but for all of these associated conditions as well. And this is what we’re seeing in clinical practice: we’re seeing patients not only reduce their analgesics, but they’re also able to achieve a reduction in a number of other classes of medications.”
Besides a reduction in pain, Dr Schecter says, patients also report an effect on their affect: even when there is no “high”, the cannabis makes the remaining pain more tolerable.
There is some disagreement among clinicians about contraindications, but Spectrum advises against prescribing to people who are pregnant (even though there is no evidence it is teratogenic) or breastfeeding; are under 25; have a history of psychosis or anxiety disorder; have unstable cardiovascular disease; or have prior drug and alcohol addiction.
Because of the potential for side effects – dizziness, dry mouth and anxiety being among the most common – the prescriber’s motto is: Start low and go slow.
Dr Schecter says the only downside of cannabis compared with opioids is that it is not yet accepted by the broader medical community and is not covered as a benefit by insurance companies in North America (nor the PBS). “What we do want to emphasise when it comes to comparing cannabis to opioids is the fact that it is safer,” he says.
“Cannabis does not kill people. Opioids kill, opioids cause devastation to families, to communities, to countries. Cannabinoids are not a gateway drug, they are an exit drug. They are an exit from dependency on opioids.”
Reefer madness
One risk that is always cited in connection with cannabis is schizophrenia. The association was first proposed in a study of Swedish soldiers in the 1980s by Andreasson et al, followed by numerous attempts to show a causal relationship.
“It’s an old chestnut that’s been around forever,” says Professor McGregor, who advises anyone with a family history of mental illness to avoid cannabis.
“If people are acutely intoxicated with high doses of cannabis then you do get paranoia, delusional thinking and fragmented thoughts, which are all hallmarks of a psychotic state. That can happen to anyone.
“But the bigger question is whether there’s a link with schizophrenia, particularly in adolescence, and the jury is still out despite hundreds of research papers.”
He says the best estimate finds a two-fold association, but it’s not necessarily causal, and some large genome-wide association studies have suggested the schizophrenia may come first – that the same genetic predisposition also drives cannabis use.
“It’s worth also pointing out that antipsychotic drugs have dreadful side effects, and a lot of people with schizophrenia use cannabis to counteract the dulling and antimotivational effects that chronic antipsychotic therapy produces,” Professor McGregor says.
“[A UK researcher] calculated that if we stop 1500 children smoking cannabis, we might prevent one case of schizophrenia. And there are many, many high-achieving individuals who smoked a lot of cannabis as teenagers, [former US president] Barack Obama being an obvious example.”
The Lambert surveyed 640 GPs last year and found 57% supported medical cannabis. But while 60% had been asked about prescribing cannabis in the three months before the survey, less than 30% felt comfortable discussing it with their patients and only 7% knew how to help patients legally access cannabis.
Only 10% reported good knowledge of its medicinal effects, and a surprising 13% believed it to be more hazardous than opioids.
GPs are cautious, Professor McGregor says, because “they’ve seen too many people get addicted to opioids and benzodiazepines”.
“You’ve heard that cannabis will lead you to heroin or cocaine,” he says. “We actually see the opposite: you could use cannabis to help yourself get off these more sinister and potentially lethal medications.
“[In US] states where it’s been legalised you see quite significant reductions of prescription opioid use and mortality. Benzodiazepine and to a certain extent antidepressant and gabapentinoid use goes down as well, so there actually is a reverse gateway.”
The Lambert has run or is running trials showing the efficacy of CBD to wean people off alcohol, opioids, nicotine and methamphetamine. The organisation is working at getting CBD descheduled for smaller doses; currently it’s a Schedule 4, so doctors could prescribe it easily, if there were a product available to prescribe.
Professor McGregor says cannabis is “not completely benign” and people can form a dependence, “but it can be managed just the same way that GPs manage dependence in a whole range of other drugs”.
Pass the paperwork
In Australia, the only TGA-approved product is nabiximols (Sativex), a 1:1 THC-CBD blend in the form of an oral spray that is TGA-approved for MS spasticity. It is still a Schedule 8 substance, GPs can’t prescribe it and it is not PBS-listed.
To prescribe anything else, Australian physicians must apply in one of two ways, through the TGA’s Special Access Scheme Category B, or the Authorised Prescriber Scheme while also seeking state/territory approval – though NSW recently removed this extra layer.
The first scheme allows a physician to prescribe medical cannabis to a particular patient, while the second allows prescriptions for a particular condition, with authority required for each product, some of which will require an import licence.
In another challenge for the new prescriber, there is a dizzying array of products available. Since December 2017 the TGA has published guidance documents on prescribing for a range of conditions, as well as bibliographies of published studies and systematic reviews, which it is updating as new data becomes available.
The Office of Drug Control publishes a list of all the manufacturers and importers of medical cannabis in Australia with websites and phone numbers.
Cannabinoids are a last-line treatment, so you have to show that the patient has tried everything else first – namely opioids, if the indication is pain.
The take-up has been fairly sluggish, through a combination of factors including physician wariness, the time it takes to acquire approval, and cost, which can range from $5000 to $50,000 a year.
According to an estimate from Mr Hunt’s office, more than 11,000 patients have been prescribed cannabis, most of them in the past year, while the TGA says it has approved more than 20,300 SAS Category B applications.
“Cynics say this system was designed to fail,” Professor McGregor says. “I don’t think it was designed to fail, I think it was designed to be overly cautious.
“Germany’s scheme started at the same time as ours, and they had 180,000 prescriptions for medicinal cannabis in 2018 alone. And the sky hasn’t caved in Germany, or in Canada. So I think it would be possible to relax the current scheme without any major issues, so that we can spend more time talking and thinking about how to better deliver for those in need.”
Perth GP and UWA professor of primary care Alistair Vickery is one of 56 authorised prescribers in Australia, and a board member of Emerald Clinics, a network aiming to provide good data for the evaluation of cannabinoids as medicine.
He would dispute the statement that Australia’s regulation is too tight.
“I think we have a wonderful opportunity in Australia,” Professor Vickery says. “Other jurisdictions, Canada, Israel and North America, have a much looser arrangement, so there’s a lot of conflation of recreational-style cannabis where you don’t know what the dose is, you don’t know what the formulation is, you don’t know all of the products that are included. And the patients are demanding a level of control.
“Here in Australia, we know that the products we are prescribing have undergone very, very careful analysis. We know that what’s on the bottle is in the bottle, so I know exactly what dose I’m prescribing to which patient. That allows us, I think, to become world leaders in the evidence for cannabinoid-based medicines – because currently the evidence is mixed in with all of that recreational cannabis.”
Professor Vickery says the SAS authorisation process has sped up immensely over the past 12 months: what used to take his clinic weeks now takes a day or two.
To be an authorised prescriber takes a bit more commitment: “If you have seen enough patients, have enough experience, have done some training in cannabinoid-based medicines, then the TGA are happy to authorise you as a prescriber.”
Off-road
One rather large obstacle is Australian driving laws. Patients prescribed cannabinoids must be advised not to drive, as under current legislation in every state and territory they risk being charged if any THC at all is found in their system – even “CBD-only” oils may contain up to 2% THC – and having their third-party insurance voided.
This has nothing to do with driver impairment. THC can stick around in your system for a week, and none of the available tests can distinguish between THC consumed in the past hour or days ago. Almost 10,000 “drug-drivers” were prosecuted in NSW alone in 2016.
“There is a mismatch between the health regulations and the driving regulations,” Professor Vickery says.
“Police believe that THC is illicit. So any detectable amount, whether there’s impairment or not, is against the law and you will be charged. We think the legislation should be changed so that if THC is detected in a patient taking cannabinoid-based medicines that have been prescribed by a doctor, as long as they’re not impaired, that should be okay.”
The driving restrictions are a problem for younger patients who need to drive for their work – but Professor Vickery says the average age of his patients on cannabis is 72.
One of them is, Ian Hunter, a precisely 72-year-old Vietnam veteran and poster-boy for the use of therapeutic cannabis.
Mr Hunter had suffered pain ever since a tree fell on his back during the war, followed by the onset of osteoarthritis and wear and tear from rugby and other activities. He was sick of his endless pain pills, and was referred via his GP and a pain specialist to Professor Vickery.
“After day three, I had no pain left,” he says. “It was just like it had been sucked out of me, it was just wonderful. I don’t wake up in pain any more.”
Asked how it had affected his mood, he refers TMR to his wife, Nolleen.
“He’s a much nicer man!” she says immediately. “When someone has chronic pain, neurologically and psychologically it makes a lot of difference to their personality. And when they’ve got chronic pain the only way they can help themselves is to lie still, not doing anything. When you spend 14-15 hours lying down, it doesn’t make you very happy, and that reflects on your family.
“He’s a much nicer man,” she says again. “I think the children would agree with me.”
www.tga.gov.au/medicinal-cannabis-guidance-documents#guidance-docs
odc.gov.au/manufacturers-and-suppliers-medicinal-cannabis-products
sas.tga.gov.au/
