12 December 2002

No evidence for cannabis 'gateway' causation of hard drug use.

Reassessing the marijuana gateway effect. Morral AR, McCaffrey DF, Paddock SM. Addiction (2002) 97;1493-1504

Dear Colleagues,

These authors use a meticulously designed formula for detecting whether household survey figures of drug use can be explained without using the a proposed effect that previous cannabis use makes an individual more likely to use other illicit drugs (the 'gateway' theory). The authors make a simple assumption about drug use behaviour and then look to see if the comprehensive age-group, annual data available can be made to fit without a 'gateway' or 'enhancing' factor involving prior cannabis use. This exercise reminds me of the elegant mathematical demonstration that the square root of two is an irrational number and cannot be represented by a fraction such as p/q where p and q are integers.

For the exercise, the authors assumed that each individual has a given propensity to try drugs to which they are exposed at a given age (this survey only looked at "ever tried" criteria). Thus some were quite vulnerable to drugs they came across while others would be less likely to use them. They assumed further that such individuals would be equally likely to use any drug they came across (ie. that there was no such thing as the 'gateway' theory) and then compared their calculations with the comprehensive drug prevalence figures together for each age 12 to 22 years from the US National Household Survey of Drug Abuse (NHSDA).

After complex statistical computations for both cannabis and 'hard' drugs, the authors conclude that the drug use prevalence figures are consistent with their assumptions, needing no 'priming' or 'gateway' effect for the increases seen in drug use prevalence from the household surveys. Rather than claiming that this disproves the 'gateway' theory (which remains to be supported by any specific evidence to my knowledge), the authors are very modest in their conclusions. They state that a gateway 'priming' effect may still exist but that their figures do not support it. It would appear that if such a gateway effect did in fact exist, that there would have to be an equal and opposite effect keeping the numbers using hard drugs constant. This latter would require some subjects to have a decreased propensity or 'immunity' to drug use. Such an interpretation would be curious or even spurious and thus, the reader is left to seriously question the gateway theory based on these data and the original assumption.

In this study, perhaps for the first time, the 'gateway' theory of enhanced vulnerability has been put to scientific scrutiny and found wanting.

Starting a series of commentaries by selected experts James Anthony writes a long yet rather unconvincing plea that we not abandon the gateway theory, in spite of these results. Rather than giving cogent reasons, he calls on an odd comparison with the shared viral causes of chickenpox and shingles. This seems a weak analogy, as behavioural problems such as drug use do not have a single origin like a virus (although there are occasionally similarities between drug epidemics and those caused by infectious disease, see Frischer M).

Kenkel and Mathios call for economic examinations of the supply and demand situations for drugs, forgetting that this has been done 'de facto' in Holland and South Australia for 20 years. But the trove of interesting evidence from decriminalised areas, including independent statistics is once again ignored, even by serious commentators on drug policy.

Lynskey claims that Morral et al's work is inconsistent with other findings but the two studies he quotes do not seem to address causation of 'progressive' drug use, merely its existence (including alcohol and tobacco). He then states that his own and other work shows that there is a strong genetic component (~50%) to drug use and/or dependence, and that such a common factor may explain Morral's findings. But such a propensity to all drug use is precisely what Morral's group assumed ... and then deduced that this fitted the detailed serial drug prevalence findings without the need for an additional 'priming' or gateway effect. Indeed, a gateway effect would have produced very different prevalence figures from those found by the household surveys.

The study authors reply with the only really robust statements of the otherwise bland 'debate' regarding the existence of the 'gateway' or stepping-stone theory of drug use. Although they say their work does not disprove the gateway theory they are "sceptical about the prospects for any [future] definitive tests [of the validity of the marijuana gateway effect]". They go on to say that US prohibition policies result in 'an enormous black market and over 600,000 arrests annually with associated economic, personal and social consequences. Evaluation of prohibition policies should balance the known and possible harms of legal access to marijuana against the known and possible harms associated with marijuana prohibition." An American president propounded the same sentiment 20 years ago, but without any moves on the official, lignified American stance on strict cannabis prohibition. It is interesting that cannabis for medical treatment is now gaining popular interest again. It was widely used in the first half of the twentieth century (eg. 'cannabis tincture').

There have been claims that a new study by Lynskey et al. in JAMA 'proves' the gateway theory, however this is not the claim of the authors. They state of their study of adolescent drug use in twins who 'used' or 'did not use' cannabis by age 17 that: "While the findings of this study indicate that early cannabis use is associated with increased risks of progression to other illicit drug use and drug abuse/dependence, it is not possible to draw strong causal conclusions solely on the basis of the associations shown in this study." There are serious limitations in this study which was a cross sectional retrospective study using phone interviews from the twins up to 15 years after the exposure.

Regardless of the existance of a gateway theory and other possible serious dangers of cannabis, our current laws seem not to protect young people. None of the many subjects in these trials was prevented from using cannabis under the current system. As in Holland, it would seem more logical for the authorities to regulate the drug as occurs with alcohol and tobacco, two drugs which are also often called 'gateway' drugs (with some justification). Prohibition may indeed be the main common factor linking cannabis, heroin, cocaine and other illicit drug use. Lynskey et al. support this by writing: ".. access to cannabis use may provide individuals with access to other drugs as they come into contact with drug dealers. ... [Dutch decriminalization of cannabis] may have been partially successful as rates of cocaine use among those who have used cannabis are lower in the Netherlands than in the United States."

comments by Andrew Byrne ..

Administration of a lighter-coloured methadone liquid with unexpected outcomes.

Administration of a lighter-coloured methadone liquid. Byrne A, Hallinan R, Love A. D&A Review [letter] 2002 21;4:405

We report a naturalistic experiment whereby 88 dependent patients were administered a lighter coloured methadone preparation for 2 weeks with unexpected outcomes.

The methadone liquid was supplied as new batch which was much lighter in colour than usual. Its appearance was consistent with a 1:1 dilution with water. Being a pure solution, free of sugars, flavouring or preservatives, the taste was reported to be not substantially different although some patients felt it was less bitter.

In this medical practice, over a 2 week period, 88 patients were given 1200 doses of the lighter coloured medicine. Of these, 686 were 'take-away' or dispensed doses (56%, mean 3.9 doses per patient per week). Patients had been in treatment an average of 6.3 years and 69 (78%) had consistently clear supervised urine tests for heroin, cocaine and amphetamine. There were 11 who were also prescribed supervised diazepam due to dual dependency.

Approximately 30 of the patients reported withdrawal symptoms from the medicine and two made telephoned reports to the NSW Methadone Advice and Complaint Service. Symptoms included insomnia, cravings, sweating and 'hanging out'. No patient reported using heroin as a result of the new medication but several requested a return to the previous (darker) medicine or the alternative sugar-based syrup, each of which was still available individually on request. One patient became acutely agitated over the change and ultimately moved to another dispensary.
The strength of methadone in both samples was found to be identical on pathology testing. On request, the drug company restored the usual supply after two weeks.

These observations would seem to indicate that minor symptoms may be interpreted incorrectly as a lack of opioid. Thus much of what patients experience from small changes in opiate doses may be psychologically mediated. Illicit drug users often report variable strengths of street drugs. In this case, a batch of medicine with less dye in it caused serious and credible complaints from a large proportion of long-term stable patients despite reassurance at the time. In two cases the feelings were so strong that outside assistance was sought over the matter.

Yours faithfully,

*Andrew Byrne (dependency specialist)
*Richard Hallinan (associate general practitioner)
*Anne Love (registered nurse)

*The Medical Practice, 75 Redfern St, Redfern, NSW, 2016
email for correspondence: ajbyrne@ozemail.com.au

Our thanks for Mr David Ruxton of Sydney Diagnostic Services who performed the drug assays.

Adolescent cannabis use addressed in 'Addiction' supplement December 2002

'Addiction' supplement December 2002. "Treatment of marijuana disorders". Edited by Michael L. Dennis and Thomas F. Babor.

Dear Colleagues,

This edition of Addiction on cannabis is most unusual in several respects, for a scientific journal. Least controversial is that 'cannabis', the normal scientific term, is used interchangeably with the American intrusive term 'marijuana' which should probably now be avoided in serious research writing. Further, some authors appear to assume that cannabis use automatically warrants the term 'disorder' and still further that this is requires treatment in a high proportion of cases. This Addiction 'special issue' was 'made possible by the Center for Substance Abuse Treatment (CSAT) ... US Department of Health and Human Services'. This sort of patronage of a scientific journal is unusual in my experience. I do not know whether 'special editions' or 'supplements' as such are peer reviewed in the normal way.

The two introductory pieces, each including the contributing 'guest editors' (one being a regular Addiction regional editor), repeatedly emphasise the importance and prevalence of cannabis problems and thus the crucial place of good research and translating this into clinical practice. One can only agree. It is only in the third last paragraph of these 15 pages that they concede that existing treatment for cannabis dependence is associated with smaller reductions in drug use than with other drugs, and, especially in adolescents and young adults "in some cases actually increase their [cannabis] use". This important latter statement is written in parentheses for no syntactical reason that I could detect.

Quite rightly, emphasis is given by the authors to the age of first use of cannabis and the likelihood of problems in later life. They state rather cumbersomely: "The likelihood of having tobacco or alcohol problems is highest (39% and 45% respectively) for adolescents who first tried these substances prior to age 15 and the rates decline with later onset. ... For cannabis and other drugs there is a very different pattern: the rate of problems is more than 60% among people who first used prior to age 15. Although the rates decline in the older onset age cohorts, they never fall below 50% for a given substance. (The two exceptions to this pattern are cocaine and heroin, which have a high risk of problems regardless of the age of first use)."

These authors make a bold statement, then contradict it parenthetically for two of the most troublesome drugs in that country. "Never" usually means 'never'. But not, evidently, when followed by a sentence put in parentheses. This subject is too important to use less-than-accurate unscientific or ill defined language. We should use clear, correct and importantly, unemotional language when addressing one of the major problems facing modern society, being drug use in young people. We know that a scientific approach to any subject is more likely to result in optimal outcomes ... be it drug treatment, population control, HIV/AIDS, malaria programs or other endeavours. There are a number of important inconsistencies in this issue of Addiction.

There appear to be unwritten assumptions about cannabis use and its dangers in a section entitled "Beyond Benign Neglect". Referring to those in whom treatment was 'mandated', the authors state: "Even those who are not cannabis-dependent demonstrate a wide range of functional impairment (eg. missing work, school, fighting, arrests, injuries) that varies with their frequency of using cannabis use." Apart from awkward English, this would seem to imply that cannabis use is often associated with delinquency and perhaps (but without any references) in a *causative* manner.

These authors detail the widespread availability, relative cheapness and strength of cannabis in America, but there is only passing reference to the failure of legal sanctions to keep the drug out of the reaches of young people. It is a serious oversight to ignore good research from Holland, a comparable western country which has had virtually legal availability of cannabis for adults for over a generation. I cannot imagine any reason why serious, experienced researchers and commentators would choose to neglect such a major source of evidence on cannabis harms.

There is still a major problem with terminology when some authors consider cannabis use needful of treatment may consist of only weekly drug use episodes. True cannabis dependence is a problem and certainly needs all of our efforts as professionals in the field. But some would consider a program which sought to address once weekly cannabis use in teenagers as rather 'low-priority' in the scheme of drug related harms, and when compared against the major problems of hepatitis C, overdose, depression and dependence (not to mention bush fires and terrorism).

Dennis and colleagues describe the Cannabis Youth Treatment (CYT) experiment in the first research report in this Addiction supplement. They randomly assigned young people referred from a variety of agencies to be treated with one of five behavioural therapies including CBT and family therapy. But when describing 'existing practice' for 150,000 adolescents treated in 1998, it is stated that half used the drug only weekly. It is hard to take the rest of their work seriously when they are 'treating' a large proportion of young people who may not qualify for a DSM IV category for either abuse or dependence.

Dennis and co-authors stress that they were anxious to be able to generalise their results to the American community. It is disappointing, therefore, that they excluded 44% of 1250 referrals on a number of criteria. These included those who (i) had used other drugs/alcohol to a significant degree (ii) had a substantial medical or psychological diagnosis, (iii) were intellectually impaired, (iv) had a severe conduct disorder or impending incarceration, (v) lacked an available English speaking parent. Another 15% declined to be involved while over half of those accepted felt that they did not need treatment for cannabis use. About two thirds were coerced by the American judicial system making the results less meaningful scientifically in other jurisdictions such as Canada, UK or Australia. Fully 80% did not view their cannabis use as 'a problem'. Only 45% were classified as cannabis dependent, yet we are given the intriguing information that this figure rises to 76% if the parents' opinions are included (!).

Self report of cannabis use in the previous month at intake, three and six months was 83%, 59% and 58%. On-site urine testing performed at the same intervals was positive for 76%, 68% and 71%. These hardly give rise to great optimism for the five programs being trialed. Nor is any statistical significance given for these modest and seemingly unimpressive, if downward, trends. No explanation is given for the remarkable finding that up to a quarter of the enrolled subjects were not actually using cannabis at or near the start of 'treatment' by either self report or urine test.

Therapy sessions were taped and reviewed with which some may find a fundamental ethical discomfort. Retention is incompletely reported, eg. 81% completed 2 months or more of a 3 month program (mean 80 days). The average stay in a 5-6 week treatment was 43 days which seems unlikely if not impossible unless there were 'overstayers'. To the credit of these researchers, it appears that over 90% of subjects were interviewed at 3, 6, 9 and 12 months using various extensive means of contact.

With high expectations I read on to find that these researchers, who repeatedly stressed the importance of their work, give no outcome results despite their comparative 'manual' intervention 'treatment phase' ending over two years ago. They whet our appetite by stating that after some preliminary results reported here, "more will be forthcoming in the coming years". Of the copious references fully 37 are from these authors themselves and their own institutions, showing their publishing prowess and perhaps also just how small the cannabis 'treatment' field actually is.

In this special issue of Addiction there follows a series of 6 "research reports", mostly from the same stable of authors as the initial report and involving one or both guest editors. These mostly document various aspect of the conduct of the same study of 600 American teenagers who chose to use cannabis and came to attention of the treatment fraternity. Once again, the wider field is not always considered in most of these, notably the item on costs which omits to compare the cost of legal sanctions which are the primary option used in some countries for drug control amongst their citizenry. The second part of this Supplement is devoted to the Marijuana Treatment Project looking at long term cannabis users and three treatment interventions. Sadly, this is just a description of the trial (including an interesting 'delayed treatment control') but again, no outcome results!

Considering the widespread use of cannabis and its propensity to cause problems in some users, especially young people, research of this nature is very important. However it is most unusual to publish details and proposals in peer reviewed journals before results are collated. Surely it is putting the cart before the horse - especially when some such programs have shown little, or even negative impact on drug use in the past. Some of the subjects are probably normal adolescents and the chance of 'treatment' improving their outcomes is simply not a consideration. The decision to omit the "no treatment" or 'control' option for treatment interventions was taken for stated reason that "past studies have shown consistently that untreated or minimally treated adolescents become worse or fail to improve". Many would disagree with this deduction and some may even find it spurious. Without controls the rigour of any study is reduced, which is very disappointing for a large, prospective intervention such as this.

comments by Andrew Byrne ..


Dennis M, Titus JC, Diamond G, Donaldson J, Godley SH, Tims FM, Webb C, Kaminer Y, Babor T, Roebuck MC, Godley MD, Hamilton N, Liddle H, Scott CK & CYT Steering Committee. The Cannabis Youth Treatment (CYT) experiment: rationale, study design and analysis plans. Addiction (2002) 97 (Suppl )1 16-34

Stephens RS, Babor TF, Kadden R, Miller M. Marijuana Treatment Project (MTP). Addiction (2002) 97 (Supp )1 109-124