THE CLIN­I­CAL EV­I­DENCE

Cosmos - - Cover Story -

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.

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