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THECANNABISEXPERIMENTAs marijuana use becomes moreacceptable, researchers are scramblingto answer key questions about the drug.BY DANIEL CRESSEYIn 2013, Beau Kilmer took on a prettyaudacious head count. Citizens in thestate of Washington had just voted tolegalize marijuana for recreational use,and the state’s liquor control board, whichwould regulate the nascent industry, wasanxious to understand how many people wereusing the drug — and importantly, how muchthey were consuming.The task was never going to be straightforward.Users of an illicit substance, particularly heavy users, often under-report theamounts they take. So Kilmer, co-directorof the RAND Drug Policy Research Centerin Santa Monica, California, led a team todevelop a web-based survey that would askpeople how often they had used cannabis inthe past month and year. To help them gaugethe amounts, the surveys included scaledpictures showing different quantities ofweed. The survey, along with other data theteam had collected, revealed a rift between280 | NATURE | VOL 524 | 20 AUGUST 2015© 2015 Macmillan Publishers Limited. All rights reserved

FEATURENEWSOLIVIER DOULIERY/ABACA/PRESS ASSOCIATIONperception and reality. Based on prior data,state officials had estimated use at about85 tonnes per year; Kilmer’s research suggestedthat it was actually double that, about175 tonnes 1 . The take-home message, saysKilmer, was “we’re going to have to startcollecting more data”.Scientists around the world would echothat statement. Laws designed to legalizecannabis or lessen the penalties associatedwith it are taking effect around the world.They are sweeping the sale of the drug out ofstairwells and shady alleys and into modernshopfronts under full view of the authorities.In 2013, Uruguay became the first nation tolegalize marijuana trade. And several countriesin Europe — Spain and Italy amongthem — have moved away from tough penaltiesfor use and possession. Thirty-nine USstates plus Washington DC have at least someprovisions for medicinal use of the drug.Washington, Colorado, Alaska and OregonRetailers in Coloradocan now sell cannabisto the public.have gone further,legalizing the drugfor recreational consumption.A handfulof other states including California andMassa chusetts are expected to vote on similarrecreational-use measures by the end of 2016.But the rapid shift has caught researcherson the back foot. “Broadly speaking, there’sabout 100 times as many studies on tobaccoor alcohol as there are on illegal substances,”says Christian Hopfer, a psychiatry researcherat the University of Colorado School of Medicinein Aurora. “I don’t think it’s the priorityit should be.”Despite claims that range from its being atreatment for seizures to a cause of schizophrenia,the evidence for marijuana’s effectson health and behaviour is limited and attimes conflicting. Researchers struggle toanswer even the most basic questions aboutcannabis use, its risks, its benefits and theeffect that legalization will have.The quick shifts in policies should providea plethora of natural experiments, but thewindow will not be open for long. “There’san opportunity here. Some of the mostinformative research we can do is right at themoment the market changes,” says RobertMacCoun, a social psychologist and publicpolicyresearcher at Stanford Law School inCalifornia who worked with Kilmer on theresearch done in Washington.WHAT ARE THE NEGATIVE EFFECTS?For years, the debate over the drug’s safetyhas been polarized. Those seeking legalizationclaim that it is basically harmless. Yetgovernments around the world have placedcannabis among the most-dangerous illegaldrugs, running hard-hitting campaigns warningof the threats that it poses to mental healthand social well-being.Scientists are fairly sure about some things,particularly when it comes to the shorttermeffects. They know, for instance, thatit impairs memory and coordination, andcan cause paranoia and psychosis 2 . These aresome of the classic symptoms of being ‘high’and can have major health effects in and ofthemselves. Studies have found, for example,that drivers are between twice and seventimes as likely to crash if they have recentlysmoked the drug 3,4 .In the longer term, effects are less clear, butthere are a few that most scientists agree on.Contrary to many popular arguments, thereis evidence that cannabis is addictive. Around9% of users become dependent on the drug,showing signs of addiction such as developingtolerance or experiencing withdrawalsymptoms when they stop using. Beyond that,however, long-term effects have been difficultto pin down.Cannabis is often smoked, and this canraise the risk of respiratory problems andpossibly lung cancer. A 2008 study in NewZealand found that smoking pot increasedthe risk of lung cancer by 8% for each ‘jointyear’(the equivalent of smoking a joint perday for one year), even after taking tobaccouse into account 5 . But other studies havefound little to no correlation with lung cancer,even for heavy users 6 .Other health outcomes are even more difficultto disentangle from confounding factors.Some researchers have found links to pooreducational performance, low social attainment— such as job status — and altered braindevelopment. For example, the ChristchurchHealth and Development Study — whichfollowed almost 1,300 children born in NewZealand in 1977 — found that people whoused cannabis daily are around 50% morelikely to have psychotic symptoms 7 than arenon-users and are at greater risk of not finishingschool 8 .And another study from New Zealand,which followed 1,000 people in Dunedinfrom birth to age 38, shows that persistentcannabis use, especially if started young,correlates with steeper declines in IQ in later“Marijuanaresearch islike tobaccoresearch in the’60s. Any studyabout harms ischallenged.”life and with problems with memory andreasoning compared with people who havenever used the drug 9 .Hall says that the association with negativesocial and mental-health outcomes hasbeen consistently observed, but the debate“is how we explain that association”, whichhe says will probably involve a combinationof factors.The difficulty, says Valerie Curran, apsycho pharmacologist at University CollegeLondon, lies in teasing apart correlation andcausation, because “there are so many confounders”.For example, adolescents who usecannabis are probably also drinking excessiveamounts of alcohol and engaging in otherrisky activities. Attributing the effects to oneparticular substance or behaviour is thereforevery difficult.Similar problems abound in the hotlycontested link between cannabis and schizophrenia.Multiple studies have shown anincreased risk of this mental-health disorderCORRECTED 24 AUGUST 2015 | 20 AUGUST 2015 | VOL 524 | NATURE | 281© 2015 Macmillan Publishers Limited. All rights reserved

NEWSFEATUREin people who use cannabis versus peoplewho do not. A study of 50,000 Swedish menaged 18–20 found that heavy users werearound three times more likely to developschizophrenia than those who had neverused the drug 10 . Although the increase inrisk was significant, the overall risk is stilllow — just 1.4% of men who reported usingcannabis developed the disorder, comparedwith 0.6% of those who said they had nevertried the drug. Some cannabis advocates suggestthat the link may be down to people withsuch problems ‘self-medicating’, but this isdifficult to prove.Many of the negative health outcomesseem to be exacerbated if the drug is usedin adolescence, leading to suggestions thatcannabis is adversely affecting developingbrains. And effects may also be linked to thedrug’s potency, which in itself is hard to pindown.As cannabis use becomes legal, the datamay become easier to collect. But the drug’suse is still low compared with alcohol andtobacco, says Wayne Hall, an addictionresearcher at the University of Queenslandin Brisbane, Australia, so it is hard to drawfirm conclusions. Marijuana may be themost popular illegal drug, he says — about44% of US adults have used it at some pointin their lives according to one source — butonly about one in ten have used it in the pastyear. By contrast, around 70% drank alcoholin that time. “The number of people who useit with any regularity for a long time is prettysmall. The longer-term consequences arereally understudied,” says Hall.Reefer madnessAfter more than a century of fairly lenientlaws surrounding cannabis, public attitudesin the United States and elsewhere shiftedagainst the drug in the early 1900s.Anti-marijuana propaganda escalated in the1930s, with films depicting the horrors thatbefell users (see right).1976The Netherlands decriminalizes possession,use and sale of small quantities of marijuana.1996California becomes the first state to legalizemedical cannabis, through Proposition 215.2012Washington and Colorado vote to legalizerecreational marijuana for adults aged 21 orolder, although the drug does not becomeavailable for sale until 2015.Survey data have revealed a dramatic shift in attitudes towards marijuana in the United States.Adults saying marijuana shouldbe made legal (%)504030201001969 1975 1980 1985 1990 1995 2000 200520102015IMAGE: MOVIE POSTER IMAGE ART/GETTY; DATA SOURCE: PEW RESEARCH CENTERHOW STRONG IS IT?A major question for researchers — anda complication in interpreting the evidence— is dosing. There are more than 85cannabinoid chemicals in pot. The one ofmost interest to researchers — and users — istetrahydrocannabinol (THC). Growers havebeen able to breed high concentrations of thechemical into strains of the plant meant forrecreational and medicinal use. A potencymonitoringprogramme run by the Universityof Mississippi for the US National Institute onDrug Abuse (NIDA) found that THC levelshave steadily increased in the United States 11 ,from 2–3% in 1985–95 to 4.9% in 2010. Theincrease is even starker for imported cannabisseized by law-enforcement officials. For thesedrugs, potency has gone from less than 4% inthe late 1980s and early 1990s to more than12% in 2013.But it is hard to determine the amounts ofTHC being consumed by the average customer.It is unclear, for example, whetherusers ‘titrate’ their doses, adjusting theirintake according to the potency. Nicotineusers are known to do this with cigarettes,but nicotine does not impair judgement inthe same way that cannabis does. And theeffects of THC are less immediate, especiallyfor edible forms.The escalating potency raises questionsabout previous research because users inolder studies may have been consuminglower-potency cannabis, and the effectsmay be different (see ‘Research gaps’). Astudy published earlier this year, for example,linked high-potency cannabis to athreefold-increased risk of psychosis versusnon-use but found no association withlower-potency forms 12 . And many researchershave complained that the pot approvedfor study in experiments funded by NIDA isa poor match for what is used recreationallyor medicinally.In tandem with changing laws, the ColoradoDepartment of Public Health and Environment(CDPHE) is establishing reference labsto check the potency of what is sold. And theUS government is expanding the varieties ofmarijuana that researchers with federal fundingcan obtain.In places where the drug is legal, existinglabelling standards may also be inadequate. Asurvey done between August and October lastyear found that only 17% of edible cannabisproducts in San Francisco, Los Angeles andSeattle had accurate labels. More than halfhad less THC than claimed, and some containedsignificantly more 13 . “A lot of peopleget a rude surprise,” says MacCoun.ARE THERE MEDICAL BENEFITS?Although states are starting to ease restrictionson recreational use of marijuana, whatgot the ball rolling in changing public perceptionsand the legal landscape for pot were thearguments for its medical use.Colorado introduced its rules allowingmedical marijuana more than a decade beforeit allowed recreational use. The amendmentto the state’s constitution listed eight conditionsfor which marijuana was approved:cancer, glaucoma, HIV/AIDS, cachexia (aprogressive wasting syndrome), persistentmuscle spasms, seizures, severe nausea andsevere pain. But, says Larry Wolk, executivedirector and chief medical officer of theCDPHE, “those are dictated by the constitutionand not necessarily by medical research”.Although there is a huge amount ofanecdotal evidence — and well-organizedadvocacy groups that campaign for easieraccess to medical marijuana — there is littleconclusive scientific evidence for many of the282 | NATURE | VOL 524 | 20 AUGUST 2015© 2015 Macmillan Publishers Limited. All rights reserved

FEATURENEWSSOURCES: SCOPUS; REF. 11claimed medical benefits. One of the reasonsfor this dearth of evidence is that money generallyhas been obtainable only for researchon the negative effects of cannabis. That isbeginning to change.When Colorado first legalized the drug,its public-health department began collectingfees from patients who applied topurchase pot at medical dispensaries. By 2014,the state had amassed more than US$9 million,most of which was ploughed back intoa medical marijuana research programmeselected by the CDPHE. Among the projectsfunded by the Colorado millions, there aretwo investigating whether cannabinoidscan help to mitigate seizures in childhoodepilepsy. Similar research is being pursuedin the United Kingdom and elsewhere in theUnited States.Another, more-established use is for peoplewith multiple sclerosis. A cannabis-basedspray has been approved in 27 countries fortreatment of muscle problems associated withthe disease, such as spasms.Other claimed benefits of marijuana, suchas boosting appetite in people with AIDS,are supported by more-limited evidence. Ifpositive effects can be clearly demonstrated,it would be a huge vindication for marijuanaadvocates. It might also go some way towardsjustifying medical-marijuana legislation.In the meantime, however, scientists arewatching the emerging cannabis frontier withwary eyes. “I think it’s an experiment,” saysRobert Booth, a psychiatry researcher at theUniversity of Colorado. “When this study isall said and done, we’ll know a whole lot aboutthe effects of marijuana.”WHAT HAPPENS WHEN YOU MAKE IT LEGAL?One of the biggest questions is how legalizationwill change usage patterns. One place inwhich researchers are looking for answersis Europe, where cannabis regulation tendsto be much lighter than it is in the UnitedStates (see ‘Reefer madness’). In the UnitedKingdom, some police forces overlook cannabisuse and small-scale growing operations.Spain allows private consumption, but stillhas restrictions on sales.The most extreme and long-standingexample is the Netherlands, which decriminalizedthe possession and sale of small quantitiesof cannabis in 1976. But although somestreets of Amsterdam have been transformedinto pungent tourism hotspots, the countryas a whole has not changed its habits much.Although hard data on cannabis use inEurope is patchy, the Netherlands does nothave hugely more users than other nations.Data aggregated by the United Nations Officeon Drugs and Crime put use in the Netherlandsat about 7%. That is more than in Germany(5%) and Norway (5%), about the sameas in the United Kingdom and less than in theUnited States (15%). Nor has the NetherlandsResearch gapsPublished research on marijuana lags behind that ofother drugs, such as alcohol and cocaine, accordingto a search of the bibliographic database Scopus.Studies in Scopus mentioningkeywords (thousands)201510501960 1969 1978 1987 1996 20052014The amount of tetrahydrocannabinol (THC) incannabis has risen sharply in the past three decades,raising concerns about the relevance of older researchand studies using less-potent varieties of the drug.THC component in imported marijuanaseized by US officials (%)12108642AlcoholCocaineMarijuana01985 1989 1993 1997 2001 2005 20092013seen a huge spike in use of harder drugs,dampening fears that marijuana serves as agateway to more-dangerous substances suchas heroin and cocaine. The message from theNetherlands, says Franz Trautmann, a drugspolicyresearcher at the Trimbos Institute inUtrecht, the Netherlands, is that “a very liberalpolicy doesn’t lead to a skyrocketing prevalence”.Rather, cannabis is endemic, he says.“We can’t control this through prohibition.This is something which more and more isrecognized.”But the lesson from the Netherlands maybe limited because the drug is still illegal,and growing and selling large quantities isstill punishable by law. Colorado has gonefurther by legalizing not merely the drug’suse, but the whole production chain, and thatcould have fundamentally different effectson the economics of pot. “Legalized productionreally raises the prospect of a dramaticdrop in price,” says MacCoun. “It’s conceivablemarijuana prices could drop 75–80% ina fully legalized model.” (Although Uruguaylegalized the drug in 2013, it reportedly hasstruggled to regulate production and to set upworking dispensaries.)The effects of a sharp drop in cost areunknown. Taxation may also have unintendedconsequences. If states tax by weight, usersmight look to higher-potency strains to savemoney. And once cannabis is a business, itgains a business lobby. Cannabis researchersalready talk of being bombarded with e-mailsfrom pro-cannabis groups if they make negativecomments about the drug. “Marijuanaresearch is like tobacco research in the ’60s,”says Hopfer. “Any study about harms is challenged.It’s really something.” Many fear thatthe big money now to be found in cannabiswill drive attempts to obfuscate the risks.“If the commercial interests are too big, thenthe profit interest is prevailing above thehealth interest. This is what I’m afraid of,” saysTrautmann.Legalization provides an opportunity toanswer some important questions. In a fewyears, Colorado, Washington and otherswill know (if only roughly) how legalizationaffects usage patterns, the number ofcar crashes and the number of people seekinghelp for drug dependency. The CDPHEfundedprogrammes will have added to theknowledge of beneficial effects. And continuinglong-term studies of large groups of userswill provide more evidence for statisticianswho are attempting to disentangle correlationand causation on the negative impacts.“When a jurisdiction changes its marijuanalaws, that provides an opportunity forgreater leverage on the questions of cause andeffect,” says MacCoun. But, he adds, the signalswill only really be clear if the laws resultin a dramatic increase in use — somethingthat is neither a given, nor necessarily desirable.“Obviously, we don’t want marijuanause to rise just to allow us to answer ourquestions, but if it does, we’ll be poring overall the data.” ■Daniel Cressey writes for Nature from London.1. Kilmer, B. et al. Before the Grand Opening: MeasuringWashington State’s Marijuana Market in the Last YearBefore Legalized Commercial Sales (RAND Corp.,2013); available at Volkow, N. D., Baler, R. D., Compton, W. M. &Weiss, S. R. B. N. Engl. J. Med. 370, 2219–2227 (2014).3. Hall, W. Addiction 110, 19–35 (2014).4. Ramaekers, J. G., Berghaus, G., van Laar, M. &Drummer, O. H. Drug Alcohol Depend. 73, 109–119(2004).5. Aldington, S. et al. Eur. Respir. J. 31, 280–286 (2008).6. Hashibe, M. et al. Cancer Epidemiol. Biomarkers Prev.15, 1829–1834 (2006).7. Fergusson, D. M., Horwood, L. J. & Ridder, E. M.Addiction 100, 354–366 (2005).8. Fergusson, D. M., Horwood, L. J. & Beautrais, A. L.Addiction 98, 1681–1692 (2003).9. Meier, M. H. et al. Proc. Natl Acad. Sci. USA 109,E2657–E2664 (2012).10. Zammit, S., Allebeck, P., Andreasson, S., Lundberg, I.& Lewis, G. Br. Med. J. 325, 1199 (2002).11. Office of National Drug Control Policy National DrugControl Strategy: Data Supplement 2014 (WhiteHouse, 2014); available at Di Forti, M. et al. Lancet Psychiatry 2, 233–238(2015).13. Vandrey, R. et al. J. Am. Med. Assoc. 313, 2491–2493 (2015).20 AUGUST 2015 | VOL 524 | NATURE | 283© 2015 Macmillan Publishers Limited. All rights reserved

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