Getting the Cannabis Withdrawal Question into Proper Perspective: Comments on Smith

© 2002 Society for the Study of Addiction to Alcohol and Other Drugs Addiction, 97, 754–758

GETTING THE CANNABISWITHDRAWAL QUESTION INTO PROPER PERSPECTIVE:COMMENTS ON SMITH

Sir—The debate about whether there is a cannabis with-drawal syndrome or not is often a proxy for the relateddebate about whether cannabis use should continue to be prohibited. The implicit assumption often is that our policy towards cannabis depends upon whether acannabis withdrawal syndrome exists: if cannabis has awithdrawal syndrome, then it is ‘addictive’, and hence itsuse should continue to be prohibited; or if there is nocannabis withdrawal syndrome, then cannabis is not anaddictive drug, and hence prohibition should be repealed.This is a false antithesis, because one can accept thatthere is cannabis withdrawal syndrome and advocate a relaxation of prohibition without self-contradiction. Itis an understandable assumption, however, because thepresumed absence of a withdrawal syndrome has been astrong argument for cannabis repeal.

As Neil Smith (2002) argues, it is of some theoreticalinterest to decide whether: (1) cannabis ‘withdrawalsymptoms’ are like those of the alcohol or opioid with-drawal syndromes; (2) they are ‘rebound’ symptoms; or(3) they are non-specific symptoms that people experi-ence when they stop doing something that they enjoydoing. The limited animal and human evidence is unableto distinguish between them and Smith makes sensiblesuggestions about how further research may addressthese questions.

It would be unfortunate, however, if we allowed thedebate about cannabis withdrawal symptoms to preventus recognizing that cannabis is a drug of dependence inthe following ways that it shares with other psychoactivesubstances. For a substantial minority of cannabis users(perhaps 10%) their lives revolve around using cannabis:they spend most of their waking time intoxicated; theycontinue to use it despite personal and social problemsthat their use causes; they find it difficult to stop or cutdown when they try to do so; some report ‘withdrawalsymptoms’ on cessation; and some say that these ‘with-drawal symptoms’ are one reason why they find it hard

to stop using cannabis. These dependence symptomscohere in the same way that dependence symptoms do for other drugs (Swift, Hall & Teesson 2001) and the more of these symptoms users report the more psycho-logical distress they report (Degenhardt, Hall & Teesson2001).

WAYNE HALL

Professorial Research FellowDirector, Office of Public Policy and EthicsInstitute for Molecular BioscienceUniversity of QueenslandAustralia

References

Degenhardt, L., Hall, W. & Lynskey, M. (2001) The relation-ship between cannabis use, depression and anxiety amongAustralian adults: findings from the National Survey ofMental Health and Well-being. Social Psychiatry andPsychiatric Epidemiology, 36, 219–227.

Smith, N. T. (2002) A review of the published literature intocannabis withdrawal symptoms in human users. Addiction,97, 621–632.

Swift, W., Hall, W. & Teesson, M. (2001) Characteristics of DSM-IV and ICD-10 cannabis dependence among Australianadults: results from the National Survey of Mental Health andWell-being. Drug and Alcohol Dependence, 63, 147–153.

CANNABIS PRODUCES DEPENDENCE:A COMMENT ON SMITH

Sir—In recent times, there has been renewed interest incannabis research due to a resurgence in the medicalmarijuana debate, heightened attention to polydrug useand the recent characterization of the endogenouscannabinoid system through which cannabis producesits effects. The review by Smith (Smith 2002), entitled ‘Areview of the published literature into cannabis with-drawal symptoms in human users’, is particularly timely.Smith summarizes the epidemiological and clinical literature and concludes that cannabis tolerance anddependence in humans is not in doubt. This conclusionis important because the fundamental argument has

Letters to the Editor

Letters to the Editor 755


always centered on whether or not cannabis use can lead to dependence. However, the question that Smithaddresses is whether the dependence syndrome alsoinvolves a physical withdrawal syndrome.

Many dependence studies with both marijuana and itspsychoactive constituent THC have been carried out, andthe results have not always been consistent. As waspointed out in the review, these studies varied regardingstudy material (THC versus marijuana), route of admin-istration, dose, duration of exposure, experimental conditions, measured parameters, etc. Despite Smith’sconclusion that no definitive conclusions can be drawnfrom these studies regarding a cannabis withdrawal syn-drome, it is remarkable that there is as much consensusas there is. It is difficult to ignore that many studies reportsimilar characteristics of the cannabis abstinence syn-drome despite the vagaries of the experimental protocols.Some of the most common symptoms include irritability,restlessness and nervousness, frequently appetite andsleep disturbances and, in some instances, aggression(Jones et al. 1976;Kouri et al. 1999; Haney et al. 1999a;1999b).

While the preponderance of data supports an asso-ciation of a withdrawal syndrome upon cessation ofcannabis use in some individuals, the extent to which this syndrome varies among individuals remains to bedetermined. Furthermore, the relationship between theextent and pattern of cannabis use and the severity ofwithdrawal needs to be established. A final question iswhether the cannabis withdrawal syndrome is suffi-ciently robust to contribute significantly to cannabisdependence. It may be that the rewarding properties ofcannabis or the relief cannabis provides from a pre-existing pathological conditions are sufficient to main-tain dependence.

Finally, basic scientists have always relied upon rewardand physical dependence models and biochemical corre-lates to assess dependence liability of drugs. In this regard,cannabinoids are self-administered by animals (Martel-lotta et al. 1998; Tanda et al. 2000), produce a physicalwithdrawal syndrome upon either cessation of drug treatment (Aceto et al. 2001) or by challenge with anantagonist (Aceto et al. 1995; Tsou et al. 1995). Further-more, chronic administration of cannabinoids produces aprofound down regulation of cannabinoid receptors(Oviedo et al. 1993; Fan et al. 1996; Breivogel et al. 1999).While none of these studies alone produces definitive evidence for a biological basis for a cannabinoid with-drawal syndrome, collectively they support the notionthat cannabinoids, as well as cannabis, produce toleranceand dependence, a portion of which has a physical mani-festation. There is no question that future basic and clini-cal research will be required before we can fully appreciatethe consequences of chronic cannabis use.

BILLY R. MARTIN

Department of Pharmacology and ToxicologyMedical College of Virginia CampusVirginia Commonwealth UniversityPO Box 980613Richmond, VA 23298–0613USAE-mail: [email protected]

References

Aceto, M., Scates, S., Lowe, J. & Martin, B. (1995) Cannabinoidprecipitated withdrawal by the selective cannabinoid receptorantagonist, SR 141716A. European Journal of Pharmacology,282, R1–R2.

Aceto, M. D., Scates, S. M. & Martin, B. R. (2001) Spontaneousand precipitated withdrawal with a synthetic cannabinoid,WIN 55212–2. European Journal of Pharmacology, 416,75–81.

Breivogel, C., Childers, S., Deadwyler, S., Hampson, R., Vogt, L. &Sim-Selley, L. (1999) Chronic9-tetrahydrocannabinol treat-ment produces a time-dependent loss of cannabinoid receptorsand cannabinoid receptor-activated G proteins in rat brain.Journal of Neurochemistry, 73, 2447–2459.

Fan, F., Tao, Q., Abood, M. & Martin, B. R. (1996) Cannabinoidreceptor down-regulation without alteration of the inhibitoryeffect of CP 55,940 on adenylyl cyclase in the cerebellum ofCP 55,940-tolerant mice. Brain Research, 706, 13–20.

Haney, M., Ward, A. S., Comer, S. D., Foltin, R. W. & Fischman,M. W. (1999a) Abstinence symptoms following smoked marijuana in humans. Psychopharmacology (Berlin), 141,395–404.

Haney, M., Ward, A. S., Comer, S. D., Foltin, R. W. & Fischman,M. W. (1999b) Abstinence symptoms following oral THCadministration to humans. Psychopharmacology (Berlin), 141,385–394.

Jones, R. T., Benowitz, N. & Bachman, J. (1976) Clinical studiesof cannabis tolerance and dependence. Annals of the New YorkAcademy of Science, 282, 221–239.

Kouri, E. M., Pope, H. G. Jr & Lukas, S. E. (1999) Changes inaggressive behavior during withdrawal from long-term mari-juana use. Psychopharmacology (Berlin), 143, 302–308.

Martellotta, M. C., Cossu, G., Fattore, L., Gessa, G. L. & Fratta, W.(1998) Self-administration of the cannabinoid receptoragonist WIN 55,212-2 in drug-naive mice. Neuroscience, 85,327–330.

Oviedo, A., Glowa, J. & Herkenham, M. (1993) Chronic cannabi-noid administration alters cannabinoid receptor binding in ratbrain: a quantitative autoradiographic study. Brain Research,616, 293–302.

Smith, N. (2002) A review of the published literature intocannabis withdrawal symptoms in human users. Addiction,97, 621–632.

Tanda, G., Munzar, P. & Goldberg, S. R. (2000) Self-administration behavior is maintained by the psychoactiveingredient of marijuana in squirrel monkeys. Nature Neu-roscience, 3, 1073–1074.

Tsou, K., Patrick, S. & Walker, J. M. (1995) Physical withdrawalin rats tolerant to 9-tetrahydrocannabinol precipated by a cannabinoid receptor antagonist. European Journal ofPharmacology, 280, R13–R15.

756 Letters to the Editor


DEFINING THE INDEFINABLE:COMMENTS ON SMITH

Sir—Neil Smith (Smith 2001) pleads for a precise defini-tion of a cannabis withdrawal syndrome in humans. Hesuggests that research should seek to distinguish this syn-drome from that of other drugs, to separate rebound fromwithdrawal, and personality characteristics from symp-toms due directly to drug elimination. He may be chasinga chimera. Drug dependence, tolerance, rebound andwithdrawal are interrelated processes merging into aspectrum. Precise definitions may not be any more possi-ble than separating the colours in a rainbow. Nor canwithdrawal symptoms of one drug be clearly differenti-ated from those of others with similar pharmaclogicalactions.

Withdrawal reactions are the consequence of homeo-static adaptations to the presence of a drug in the body,often resulting in tolerance. Such adaptations includemodulation of receptor density, sensitivity or couplingmechanisms. They affect both postsynaptic effectorreceptors and autoreceptors and influence intercon-nected neurotransmitter systems, each of which mayelicit modifications in other receptors downstream.Added to this may be behavioural tolerance involvingalterations in learning and memory synapses. Thesechanges are unevenly distributed in different brainsystems and depend upon individual characteristicsdetermined by genetic and environmental factors.

Cessation of drug use exposes all these adaptations,releasing unopposed activity in many neurotransmittersystems. This state is manifested as a withdrawal (‘dis-continuation’) syndrome. The same mechanisms under-lie both rebound and withdrawal. The character, severityand duration of symptoms depend on the particularsystems that have undergone modulation, the degree andrate of reversal of adaptive changes, and the pharmaco-kinetics, dosage and duration of use of the drug—all ofwhich vary between individuals (Ashton 1991, 1999).

Drugs with similar pharmacological effects producesimilar withdrawal reactions. Cannabinoids, like opiates,benzodiazepines and alcohol, cause receptor changes onchronic administration and alter release and/or turnoverof acetylcholine, noradrenaline, dopamine, serotonin,opioids, GABA and glutamate. Thus it is not surprisingthat they have withdrawal reactions in common, includ-ing sleep disturbance, tremor, autonomic symptoms anda host of others, resulting from similar mechanisms.Clinical definitions of supposedly drug-specific with-drawal syndromes can only be arbitrary (Ashton 1991).For example, the appearance of two or more new symptoms and/or an increase in symptoms to > 50%above baseline were suggested for benzodiazepines, basedon placebo-controlled trials (Tyrer et al. 1981, 1983).

However, new symptoms varied between studies and the50% limit does not account for a 49% or lower increase.Furthermore, any specific cannabis withdrawal featuresare unlikely to be recognized until the many physiologi-cal functions of the endocannabinoid systems that areperturbed by cannabis are understood.

Nevertheless, closer study of the variables whichmake it difficult for cannabis users to quit may resolvedoubts that this drug can cause dependence and also lead to rational methods of management, at presententirely lacking, for those who seek medical help in withdrawal.

HEATHER ASHTON

University of NewcastleSchool of NeurosciencesDivision of PsychiatryThe Royal Victoria InfirmaryQueen Victoria RoadNewcastle-upon-Tyne, NE1 4LPUK

References

Ashton, H. (1991) Protracted withdrawal syndromes from ben-zodiazepines. Journal of Substance Abuse Treatment, 8, 19–28.

Ashton, H., Young, A. H. & Ferrier, N. (1999) Psycho-phamacology revisited. Journal of Psychopharmacology, 13,296–297.

Smith, N. (2002) A review of the published literature intocannabis withdrawal symptoms in human users. Addiction,97, 621–632.

Tyrer, P., Owen, R. & Dawling, S. (1983) Gradual withdrawal ofdiazepam after long-term therapy. Lancet, 1, 1402–1406.

Tyrer, P., Rutherford, D. & Higgett, T. (1981) Benzodiazepinewithdrawal symptoms and propranolol. Lancet, 1, 520–522.

ADDICTION ’S DECISION TO WITHDRAWA PUBLISHED PAPER FROM CITATIONON THE GROUNDS OF UNDISCLOSEDCONFLICT OF INTEREST

In 1991, the then British Journal of Addiction (BJA) pub-lished a paper by Peter Ellemann-Jensen, a Danish econ-omist, on the social costs of smoking (Ellemann-Jensen1991). The paper had been submitted in August 1990 (asconfirmed by the entry in the accession book). Sadly, theauthor had died before the submission was made. Thepaper was refereed, minor points were met, and it waspublished with a note that ‘a few more extensive sugges-tions, which would have required rewriting portions ofthe original text, could not be taken fully into account’.That, in uniquely difficult circumstances, seemed to me the way to proceed. I do not have the original file, but am now told that Dr Terkel Christiansen assisted

Letters to the Editor 757


with the finalization, and accept that fact (Pedersen &Christiansen 2002).

Last year, I was contacted by a Danish journalist whotold me that he had been exploring a possible relationshipbetween Philip Morris (the tobacco multinational) andthe late Dr Ellemann-Jensen. The call came as an unwel-come surprise, but I had a duty to check out the facts—it would have been wrong to turn a blind eye. I obtainedthe following tobacco industry documentation:

15/10/89: Memo re. Philip Morris InternationalCorporate Affairs Action Plan. A passage read: ‘we areseriously addressing the social cost of smoking issue,which is being used to underpin penal taxation, particu-larly in the Nordic countries . . . Furthermore, PeterEllemann-Jensen, a Danish economist . . . has beenrecruited to publish a critique of an unfavourable socialcost study published in Sweden. We have initiated aproject with aims to recruit additional welfare econo-mists, statisticians and econometricians’.

08/08/90: Internal memo, Covington and Burling,lawyers acting for Philip Morris. ‘We are pursuing appro-priate publication of Peter Ellemann-Jensen’s article,preferably in the British Journal of Addiction, and will alertyou and Johan so that, in turn [a public figure] may bealerted, for whatever publicity he can give it.’

Faced with those documents, I now had to interpretthem. I felt that in so doing I would do well to err on theside of caution given their provenance, but the followinginferences appeared to me fairly drawn:1 Philip Morris’s lawyers were claiming that they had‘recruited’ Dr Ellemann-Jensen. That word has no pre-cisely agreed meaning in English usage. A conservativeinterpretation might perhaps be ‘have established ahelpful relationship with’.2 Specifically, they wanted Dr Ellemann-Jensen to‘publish a critique of an unfavourable social cost studypublished in Sweden’.3 At the time that Dr Ellemann-Jensen’s paper was beingsubmitted to BJA, Philip Morris had foreknowledge of thepaper’s existence.4 The lawyers saw BJA as the preferred journal for pub-lication of the article and were seemingly aware of thedirection in which the author was likely to send it.5 Ahead of publication, the lawyers were declaring theirintention to use this paper for publicity purposes—themention of a public figure in this context may be indus-try bravado, but the fact that the paper was seen by thelawyers as having publicity value is established.6 Dr Ellemann-Jensen’s paper had developed a critique ofwhat from the tobacco industry’s point of view was an‘unfavourable’ study. His paper stated that previouslypublished estimates were ‘too high’.

With those documented facts to my mind evident, thenext question had to be what weight to give to them. I

believed that, taken conjointly, they suggested that in1990 Dr Ellemann-Jensen had a relationship with thetobacco industry. On the evidence it was not a trivial orequivocal relationship, but a working relationship. If anauthor in 1990 had known that a paper on tobacco wasalready within the cognizance of the tobacco industry ator around the time of its submission, that the industrywas appraised of the journal to which that paper was tobe submitted and that the industry was intending to usethe paper for publicity purposes, the editor should havebeen told. Furthermore, if the facts had been declared aneditor would have been within their rights if they hadviewed the submission as compromised and rejected it. Iam not suggesting that every journal would have takenthat view, but that this would have been a legitimateresponse.

With the facts determined and their significanceassessed, there was then the third-level question: whatshould the editor of Addiction do 10 years later about thisunwelcome problem? It could be argued that I shouldhave made further enquiries from previous colleagues ofDr Ellemann-Jensen—I do not think that was, in the cir-cumstances, incumbent on me; I did not have contactnames, but the suggestion deserves to be heard. What Isaw here was a case of conflict of such extent that, afterdue deliberation, I decided to publish a notice saying thatthe paper should no longer be cited (Edwards 2001). The acid test to determine the legitimacy of that decisionwas my belief that this paper would not have been pub-lished in BJA had its context been declared at the time ofsubmission, together with my feeling that any author in1990 submitting to this journal should have been openon a tobacco industry relationship. Let me again empha-size my belief that not every editor would have acted thus,but this was a journal that was already well known totake a campaigning position on public health aspects oftobacco (Raw 1991), I would have expected an author tohave known the journal’s likely negative response to apre-publication industry link and to have seen the needfor transparency. Raw cited no less than 12 BJA publica-tions for 1989 and 1990 dealing with tobacco. Most ofthese were scientific reports, but some were intentionallycampaigning—Crofton (1989) and Ball (1990) comeinto the latter category.

My action did not imply criticism of the paper’s scien-tific worth, nor am I suggesting that the research leadingto the paper’s publication was funded by tobacco inter-ests. I am sorry for the hurt caused to the feelings of DrEllemann-Jensen’s friends, family and colleagues thatmay result from my decision, but I hope they will acceptthat in seeking to meet my editorial responsibilities I amnot casting aspersions on Dr Elleman-Jensen’s integrity,but focusing strictly on the conflict of interest question.The sad fact of his death means of course that the actual

758 Letters to the Editor


submission, although intended by him, was not made byhim, so the question of who failed to make the declara-tion is complex.

Dr Kjeld Moller Pedersen and Dr Terkel Christiansen,in their recent letter to Addiction (Pedersen & Christiansen2002), take me to task on several counts. I have studiedtheir criticisms respectfully and my colleagues and I willtake note of their views when we discuss procedures thatwill be put in place ahead of any further event of thiskind. This letter tries openly to meet the criticisms madeof my editorial action. Others must form their own opin-ions as to whether my judgement was sound and I readilyacknowledge that there is unlikely to be only one view onsuch an unusual and difficult case.

I am aware that what I say above will not necessarilysatisfy Dr Pedersen and Dr Christiansen, and they wouldprobably still like to see my decision reversed. Their chal-lenge is well made out, but on reflection I do not feel ableto meet their wishes. My reasons for holding firm areessentially three-fold.

Firstly, I believe that the editorial note of August 2001was a response from this particular journal that accordswith a reasonable acid test. Our correspondents, despitetheir robust criticisms, have not given me reason torescind that judgement.

Secondly, after the editorial note was published,further significant information has come to hand on DrElleman-Jensen’s involvement with the tobacco industry.Dr Pedersen revealed in an earlier draft of the jointly pub-lished letter that Dr Ellemann-Jensen’s expenses for atten-dance in December 1989 at a meeting of the AmericanEconomic Association had been paid by Philip Morris. Inaddition, according to a recent article in a Danish news-paper (Jyllands-Posten, 29 December 2001), Dr Ellemann-Jensen had at some time received research money fromPhilip Morris and his original doctoral dissertation waspublished by Philip Morris. That the relationship betweenDr Ellemann-Jensen and the tobacco industry was morethan ‘trivial’ is confirmed.

Thirdly, I am persuaded that the tobacco industry sets unusual problems for the integrity of science. Thatindustry’s activities must be laid bare (Chapman 2002;

Edwards et al. 2002). One of the most unhappy outcomesof its often covert activities is that good researchers ofirreproachable personal integrity have at times beencaught in the industry’s net.

GRIFFITH EDWARDS

Editor-in-Chief, Addiction

Conflict of interest

In 1978, G.E. had contact with the tobacco industryabout possible funding for a research centre initiative:nothing came of the discussions. In 1992, he publishedwith colleagues an alcohol research article where a staffstatistician had received 2 year support from the HealthPromotion Research Trust (a tobacco-industry-fundedbody): the sources of funding were declared in the publi-cation (Edwards et al. 1992).

References

Ball, K. (1990) Exporting death. Britain’s malignant epidemicspreads to the developing world. British Journal of Addiction,85, 313–314.

Chapman, S. (2002) Denying nicotine’s addiction potential:comments on Frenk & Dar. Addiction, 97, 99–100.

Crofton, J. (1989) Tobacco: world action on the pandemic.British Journal of Addiction, 84, 1397–1400.

Edwards, G. (2001) A paper that must be withdrawn from pub-lication. Addiction, 96, 1099.

Edwards, G., Babor, T. F., Hall, W. & West, R. (2002) Anothermirror shattered? Tobacco industry involvement suspected ina book which claims that nicotine is not addictive. Addiction,97, 1–5.

Edwards, G., Oppenheimer, E. & Taylor, C. (1992) Hearing the noise in the system. Exploration of textual analysis as amethod of studying change in drinking behaviour. BritishJournal of Addiction, 87, 73–81.

Ellemann-Jensen, P. (1991) The social costs of smoking revis-ited. British Journal of Addiction, 86, 957–966.

Jyllands-Posten (2001) Strid om tobaks-artikel [Dispute overtobacco article]. Jyllands-Posten, 29 December 2001.

Pedersen, K. M. & Christiansen, T. (2002) A fair hearing or academic kangaroo court? Addiction, 97, 227–229.

Raw, M. (1991) The British journal of not just alcohol anddrugs. British Journal of Addiction, 86, 361–363.

Documents

Getting the Cannabis Withdrawal Question into Proper Perspective: Comments on Smith