THE CLINICAL EVIDENCE
Any medicine touted for everything from autism to asthma sounds like snake oil. But there is biological plausibility for these claims. Researchers have identified two receptors – CB receptors, mostly in the brain, and CB receptors, mostly in the body
1 2 – that respond to THC, the psychoactive ingredient of cannabis. Pot works because it mimics what body-made molecules – the endocannabinoids, anandamide and 2AG – do.
We seem to be have been gifted with an endocannabinoid system that blisses out our brain and ratchets down inflammation in the body. Why? “It seems to have a protective role,” suggests Roger Pertwee, a pharmacologist at the University of Aberdeen who has pioneered the study of the endocannabinoid system.
we risk being raided by the FBI and DEA. We live in a schizophrenic state.”
Even when researchers have gained permission to do research, the cannabis can only be supplied by one authorised lab, at the University of Mississippi. The lab has been growing the same variety for decades, one that bears little resemblance to the chemovars now available through dispensaries.
In San Francisco, Abrams tried valiantly in the 1990s to set up a clinical trial to test the claims of dying AIDS patients that smoking weed outperformed their anti-nausea drugs. After more than a year trying to get permission from the National Institute on Drug Abuse, the penny finally dropped it was futile; the agency as he often tells journalists, sees itself as the National Institute “on” Drug Abuse, not “for” Drug Abuse.
So the January report of the National Academies of Science was hardly a surprise . The document, based on reviewing 10,000 publications, found “modest” evidence for the effectiveness of cannabis to treat nausea and vomiting in adults undergoing chemotherapy, for chronic pain, and to alleviate spasms in multiple sclerosis. It did not, however, deliver a verdict for a long list of illnesses including epilepsy, inflammatory bowel disease, Parkinson’s Disease, post-traumatic stress, anxiety, insomnia and cancer. “For these conditions, the report states, “there is inadequate information to assess their effects.”
But bits of information are trickling through. In May, a report in the New England Journal of Medicine offered strong evidence an oily, strawberry-flavoured formulation of pure cannabidiol (made by British company GW Pharmaceuticals) reduced the severity of seizures in children with a rare form of epilepsy known as Dravet’s syndrome .
Most of the 400 pages in the hefty NAS tome report on the adverse effects of cannabis, like a raised risk of schizophrenia or road accidents or chronic cough. This, says Piomelli, reflects what researchers obtained funding for: “There is a bias towards the null hypothesis – that cannabis causes harm.” Those harms exist, he agrees. “But society is asking for answers about its benefits, and that’s not a question that researchers have been able to answer.”
ISRAEL STAKED ITS CLAIM in the field of cannabis research back in the 1960s. It was the beginning of the pot-smoking hippy revolution. But no one actually knew what the psychoactive ingredient of pot was.
Raphael Mechoulam, a chemist at the Hebrew University of Jerusalem, saw an opportunity. In 1964 he was the first to show the psychoactive ingredient was THC. His research flourished in a regulated but permissive environment: his chief source of cannabis was the local police station. His group also isolated the natural equivalents of cannabis made by the brain, using pigs (with great difficulty, given the researchers were in Jerusalem). In 1992 they identified anandamide, the so-called bliss molecule, and in 1995 its more prosaicallynamed partner, 2-arachidonoyl glycerol or 2 AG. These brain-made counterparts of THC are known as endocannabinoids.
Meanwhile the Israeli public began to clamour for medical cannabis. Just as in San Francisco, the AIDS epidemic had put medical cannabis on the radar.mirroring the experience of Donald Abrams, immunologist Zvi Bentwich also witnessed the antinausea and pain-relieving effects that smoking cannabis had on his AIDS patients. While anti-retroviral drugs would mercifully bring the raging AIDS epidemic in both countries under control, the clamour for the palliative use of cannabis by cancer patients grew, aided by the internet.
Israel’s government obliged but with strict regulation. Patients, supported by a letter from a physician, could obtain a medical cannabis permit from the ministry of health. Growers needed a licence. One of the first companies to gain one, in 2007, was Tikun Olam . As patient numbers grew, it began to collect information about their responses. In 2015 Bentwich, who also heads the Centre for Emerging Tropical Diseases and AIDS at Ben Gurion University, joined Tikin Olam to lead a formal clinical trials program. “If the medical community is to accept cannabis, that depends on carrying out large reliable clinical trials,” he says. “In the US, as well as in most European countries, that is still extremely difficult.”
So far Israel is leading the pack. It is the only country, for instance, to have published the results of a randomised double blind study on the use of cannabis by Crohn’s disease patients. Timna Naftali, a gastroenterologist at Meir Medical Centre, carried out the trial after discovering several patients were self-medicating with cannabis. “They had reduced their medication and not suffered flare ups,” she says. “It was very intriguing.”
In her trial, 21 patients were assigned randomly to a group that smoked Thc-rich cannabis cigarettes twice a day for eight weeks or to a group that smoked cannabis free of THC and other cannabinoids. The results, published in Clinical Gastroenterology and Hepatology, showed that in in 10 of 11 patients with Crohn’s disease smoking the Thc-rich cigarettes, there were “significant clinical benefits”. One criticism was that perhaps patients merely felt better due to the euphoric effects of cannabis, so Naftali is repeating the trial, leaving it to an endoscopist to decide. This time 50 patients are receiving an oil, containing a 4:1 ratio of
cannabidiol to THC. “As a doctor, I’m not happy about telling patients to smoke,” Naftali says.
Another trial that tested a pure extract of cannabidiol was ineffective. “Perhaps it was the low dose,” Naftali muses. “There’s also a claim you have to have it in combination.” Perhaps it is a case of what Mechoulam has dubbed the “entourage effect” – the consequence of a mysterious biological synergy between cannabis compounds.
Another world-first trial under way in Israel is testing the effects of cannabis on youngsters with autism. Given cannabis can trigger psychotic behaviour, it is surprising to think it would be a candidate for a condition where psychotic behaviour is often part of the problem. But a third of autistic children also suffer from seizures.
When paediatric neurologist Adi Aran, at Jerusalem’s Shaare Zedek Medical Centre, prescribed cannabis for the seizures of autistic children, their parents reported dramatic results. Children who never spoke began speaking, and even writing for the first time. To verify these anecdotal results, he is running a trial on 120 youngsters, aged 5 to 21 years . Some receive whole cannabis oil containing a 20:1 ratio of cannabidiol to THC; others receive a purified extract containing only cannabidiol and THC; a final group receive a placebo, an identically flavoured oil. All will undergo a ‘washout’ period, where they are gradually weaned off their oil.
In principle, most doctors would like to see the results of numerous such trials before prescribing cannabis. However, parents like Abigail Dar disagree with this approach. “A parent like me with a complicated child doesn’t have the luxury of principles,” she says. Her son, Yuval, now in his early twenties, is severely autistic, and was once so prone to violent outbreaks she could not be alone with him . “Yuval tried over a dozen anti-psychotic medications since he was 12 years old to treat symptoms like endless anxiety, restlessness, violent outbreaks or, as we call it, ‘life in the shadow of hell’. They only made him more agitated and aggressive.”
Dar managed to get Yuval prescribed cannabis in 2015. Though autism did not count as one of Israel’s qualifying conditions for medical cannabis, the health ministry finally granted permission as a ‘mercy treatment’. “It was a life-changer from the very first day,” according to Dar. “He hasn’t exhibited a single self-injurious behaviour or outburst in the last 14 months. He is calmer, more attentive and communicative. He smiles more.”
Dar has carried out her own careful experimentation for what works for her son, using chemovars that vary in their CBD-TO-THC ratio. As far as she is concerned, placing Yuval in a randomised, placebo-controlled, washout trial would be immoral. “With suffering kids you don’t take it away,” she says. “I tell parents to stay away; it’s not in favour of kids.”
Instead, through a collaboration with Meiri’s lab, she is pushing to more effectively gather the data already being generated. “We have 200 kids and adults with severe autism we are guiding through strains and dosages to find out what works. We track them with questionnaires: we look at things like violent outbreaks, sleep and appetite. The idea eventually is to go global. It will give us some small amount of knowledge on how to treat autism.”
It’s not just desperate cases like Dar that make cannabis a poor fit for the box of a RCT. Abrams sees no need for more trials when it comes to treating pain or nausea in patients with cancer. Nor is he alarmed by the range of products sold in dispensaries. “I don’t consider it to be that dangerous, compared to the pharmaceutical agents we already prescribe,” he says. “I have many patients that were weaned off opiates thanks to cannabis.” He points out that in the US, 90 people die each day from overdoses of opiates, in many cases prescribed to treat chronic pain .
MEIRI NEVER IMAGINED his CV would one day include heading a laboratory for cannabis research. In early 2015, after four years at the Ontario Cancer Institute, he was all set to return to cancer research. Then he noticed a curious publication from a Japanese research group that reported a cannabis extract blocked the ability of human breast cancer cells to spread in a culture dish. What pricked Meiri’s interest was that the extracts appeared to be scrambling the cell’s internal scaffolding – his particular area of expertise.
Meiri repeated the experiment on different types of cancer cells. He found the cannabis extract was just as potent as some chemotherapy drugs. But it was another finding that really captured his interest: the effectiveness of the extract depended on the cannabis variety and the grower. As the son of a strawberry farmer, he understood exactly what he was seeing. “Strawberries taste different in the morning and afternoon,” he explains. He was seeing the effects of a cocktail of different chemicals.
Which of these chemicals were responsible for the anti-cancer effect? To find out, Meiri bought a machine for high-performance liquid chromatography, a technique to separate and identify parts of a mixture. Soon he was a de facto guru. A grant from a philanthropist in 2016 marked a point of no return.
‘The plural of anecdote is not data’ is an oft-quoted medical aphorism. But anecdotes can’t be ignored either. Meiri is acquiring quite a collection. On one occasion, he was contacted by the father of a sevenyear-old whose seizures had returned after being free of them for nearly a year. The father, wanting to know why the oil had stopped working, sent samples to Meiri. When the scientist analysed them, he found they were just olive oil. “It was a data point,” he says, “showing that the effects of cannabis extract were real.”
Then there was the disastrous day he learned that several autistic kids taking cannabis oil had gone berserk. “Tali, we have a situation,” he recalls telling the head of the data project. All the extracts the children were taking had the same 20:1 ratio of CBD to THC. But looking at the chemical profiles, it was clear the offending extracts carried at least five different compounds. “It doesn’t provide the answers,” he says. “It shows where to begin searching.”
THERE IS NO SIMPLE WAY out of the cannabis mess. With much of the world clamouring to use cannabis as a cure for all manner of ailments, and an exploding cannabis industry that is happy to push that demand along, it is crucial to establish just how real its clinical benefits and harms are – especially for children.
The medical establishment ideally needs randomised clinical trials, such as those Israel is admirably pushing ahead with. “I would say the Israelis have taken the lead,” Abrams says.
But 30,000 users in Israel and millions in the US aren’t waiting for such results. Some, like Abigail Dar, are too desperate. Others are wedded to their own trialand-error experiments with different chemovars.
Another complicating factor is that the diabolically complex chemistry of the cannabis plant is too overwhelming to sort out through individual RCTS. Researchers are still scratching at the surface of a potential treasure trove of medicines that appear to act synergistically. The list of conditions to try them against appears never-ending. The number of trials needed to test each combination against each condition seems mindboggling.
The database collated by Meiri and his clinical collaborators is now being prepared for publication. It should help link the pot-pourri of chemicals inside cannabis to clinical effects. It may be second-tier science, but it appears to be one of the best strategies for navigating a path out of the haze that still envelops medical cannabis. ELIZABETH FINKEL is editor-in-chief of Cosmos. Conflict of Interest statement. Elizabeth Finkel is a member of the scientific advisory board of AUSIMED, which raises funds to support scientific collaborations between Australia and Israel. IMAGES 01 Voisin / Getty Images 02 Dan Herrick / Getty Images
Medieval medicine: dispensaries sell a wide variety of cannabis products, exact chemical compositions unknown.