This study tested the impact of a long-acting form of amphetamine as medication to help control dependent use of the closely allied stimulant, methamphetamine. Prescribed usually for the treatment of pathological sleepiness or attention deficit/hyperactivity disorder, effects of the amphetamine tablets prescribed in the study take several hours longer to emerge than normal amphetamine and last three to six hours longer, giving it a 'smoothing' profile similar to methadone for heroin users; non-rapid onset make it less intensely pleasurable, and longer duration suits it to once-daily administration.

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Doses in the study averaged 80mg per day and were capped at 110mg. To ensure as far as possible that the medication was the active ingredient in the outcomes of the trial, a randomly allocated control group was prescribed an identical placebo tablet and patients, staff and researchers gathering the data did not know who had been prescribed which. Also the requirement to attend daily for supervised tablet-takingmeant researchers knew how much of the medication had actually been consumed, and all patients were offered the same psychosocial supportand treatment contact. The trial started with up to a fortnight during which doses of the active tablets (with a mirror procedure for the placebos) were titrated upwards, followed by an intended 12 weeks on the stabilised dose and then four weeks when it was tapered to zero and the trial treatments ended. For about the first month patients had to go daily to the clinic pharmacy to have their tablet-swallowing supervised by staff; after this supervision was continued but at community pharmacies.

Patients were recruited from the South Australia state addiction treatment service. Among other criteria, to be included in the trial they had to be dependent only on methamphetamine and not on any other drug except tobacco, to have recently used methamphetamine regularly, and to be free of serious physical or mental illness. Of 313 screened initially over the phone, 49 started the trial, of whom 23 were allocated to amphetamine and 26 to placebo. Nearly 9 in 10 were injecting their methamphetamine, usage averaged five days a week, patients averaged 32 years of age and had been using for over ten years, half were unemployed, and half too had previously been treated for their use of the drug. Patients were assessed by researchers at the start of the trial, during the treatment period, and two months after this period ended, a follow-up giving some indication of whether impacts might persist once patients were no longer taking medication. Though many patients dropped out of treatment, at the final follow-up researchers managed to re-assess nearly 8 in 10 methamphetamine patients and nearly two thirds of the placebo patients. Patients were included in the outcome analyses regardless of whether they were able to be reassessed.

Main findings

The most clear-cut and statistically significant result was greater retention among patients prescribed the active medication. Two thirds completed the trial compared to just under third prescribed placebo, they stayed in treatment for an average 86 days (out of a possible 104) compared to just 49, and placebo patients dropped out earlier.

The other statistically significant differences related to signs of dependence rather than use levels. In both groups, patients' responses to the Leeds Dependence Questionnaire revealed an easing of their dependence from the start to the end of treatment. Two months later this easing had been sustained among those prescribed methamphetamine while dependence rose (but not to pre-treatment levels) among those prescribed placebos. The gap this created at the final follow-up was statistically significant. Withdrawal symptoms too were suppressed more effectively by methamphetamine than placebo throughout the treatment period, a greater reduction which was statistically significant during the initial two weeks of treatment.

During treatment estimated consumption of methamphetamine (an amalgam of times used and amount used on each occasion over the past month) fell dramatically in both groups, a drop largely sustained at the final follow-up. However, these reductions were only slightly and non-significantly steeper among the methamphetamine patients. These results based on the patients' own accounts were broadly confirmed by testing hair samples.

Of the 23 patients prescribed amphetamine, one experienced a serious side effect – high blood pressure requiring a dose reduction. On average systolic blood pressures actually fell during amphetamine prescribing, while other measures of circulatory health were stable. No serious mental health problems were recorded, and in particular there were no reports of psychotic symptoms, though some patients did experience mild irritability, mood swings and headaches. There was an appreciable weight loss among the prescribed patients not seen in the controls.

The authors' conclusions

The primary objectives of this study were to engage users in treatment and reduce methamphetamine use and dependence. The results showed that a maintenance pharmacotherapy programme of daily sustained-release amphetamine dispensing under pharmacist supervision is both feasible and safe and improves engagement with treatment as assessed by retention. Also dependence was moderated more by methamphetamine than placebo. Together with the general decreases in methamphetamine use, dependence and withdrawal symptom severity, these outcomes provide preliminary evidence that sustained-release amphetamine may be an efficacious treatment for methamphetamine dependence.

The fact that (except for retention) methamphetamine's advantages over placebo were minor and/or not statistically significant may have been due to the relatively intensive support both groups were offered including psychotherapy, medical and research appointments, and daily monitoring by pharmacy staff. Patients said this structure greatly helped reduce their methamphetamine use. However, 43% of the sample did not attend any psychotherapy sessions, suggesting that counselling alone may not be enough to engage a high proportion of methamphetamine injectors in treatment.

Methamphetamine is a potent and for predisposed individuals, highly addictive variant of the stimulant amphetamine, known in its smokable form as 'ice' or 'crystal' among other names. While blood levels of the active metabolites of cocaine fall to half their peak level in 90 minutes, methamphetamine's 'half-life' is 10 hours or more. Users tend to take the drug in 'binges' or 'runs' over one to three days, followed by abstinence, then repeated use. Because of its lengthy half-life, this pattern results in increasing concentrations of the drug which can be toxic, particularly because the body does not 'get used' to its effects as readily as with other drugs. When experts met to rank drugs in terms of their harms in the British context, they placed methamphetamine fourth after alcohol, heroin and crack cocaine, though in terms of harms to the actual user it came third, closely behind heroin and crack. On this sub-scale, amphetamine and cocaine came next after alcohol.

In England and Wales it has been estimated that 319,000 adults used amphetamines in 2009/10 and of whom 110,000 used in the past month, and in Scotland, about 3805 and 1268. Across the UK in 2009/10 or 2010, at least 12,128 people using amphetamines (including methamphetamine) were in or referred for treatment for problems with illegal drugs, just over 5% of the total of 226,302. These totals are an amalgam of differently defined statistics in the different nations. Details in background notes. How many of these patients were prescribed amphetamine is not recorded, but from the featured study and the studies summarised below it would seem a minority would both be suitable and benefit from this prescribing more than they would have done from psychosocial therapy alone.

But without prescribing on offer, many fewer patients see treatment as 'for them', so fewer put themselves in a position to benefit from psychosocial therapy. They also miss an opportunity for harm reduction advice and professional monitoring of physical and mental health, both important for amphetamine users. Prescribing also helps retain patients long enough and stabilise them sufficiently for them to gain the most from these other inputs, and has important direct harm reduction benefits associated with reduced injecting.

Controlled trials have tested stabilisation rather than maintenance programmes. Typically amphetamine prescribing programmes are likely to be shorter than those for opiate dependent patients, partly because stimulants can more easily be withdrawn; a typical untreated pattern of stimulant use includes periods when users are able (or feel they have to) stop using for a while. However, British services have prescribed long-term and observed beneficial results in terms of client stability and reduction in injecting. Concerns over cardiovascular risks from heavy stimulant use and the risk of precipitating a psychotic episode cannot be dismissed, but from the studies to date these risks are largely confined to patients who top up their prescribed doses with large amounts of illegal supplies, the risks are probably less than in untreated stimulant dependence, they can be minimised by careful monitoring, and patients' health is improved in other ways by a stabilised lifestyle, reduced injecting, and the regular medical contact associated with attending for prescribing and dispensing.

These impressions from clinical experience and studies which have observed the progress of patients have yet to be confirmed in rigorous trials which have as far as possible equalised everything (including randomising patients and the taking of 'dummy' tablets) except the prescribed amphetamine. In the three randomised trials to date including the featured study, substantial and statistically significant benefits were generally not found, but all three were as justifiably seen as stabilisation-withdrawal trials as maintenance, and probably none was representative of the usual patients and usual practice observed by less rigorous studies.