Appendix 14 - Supplementary memoranda from the Advisory Council on the Misuse of Drugs (ACMD)
Drug misuse is one of the major social, legal and public health challenges in the modern world. In the UK, the total burden of drug misuse, in terms of health, social and crime-related costs, has recently been estimated to be somewhere between £10 billion and £16 billion per year (Ref 1).
The main current approaches to drug misuse are interdiction of supply (via policing and customs control), education and treatments. All three demand clarity in terms of the relative risks and harms that drugs engender. At present, attitudes to policing and the punishments for possession and supply of drugs are scaled according to their classification under the Misuse of Drugs Act (MDAct), while education and health care provision are nominally tailored to the known actions and harms of specific drugs.
In the current MDAct, the three Classes — A, B or C — are intended to reflect the dangers of the drug, Class A being the most harmful and C the least. The classification of a drug determines several factors, in particular the legal penalties for importation, supply and possession, as well as the degree of police effort targeted at limiting its use. As well as being given a Class, all drugs are also placed in one of five Schedules depending on whether they have clinical utility and, if so, their safe-keeping and prescribing requirements. Drugs with no present clinical use are in Schedule 1 (e.g. MDMA, LSD), the most abusable clinically useful drugs (e.g. diamorphine [heroin], morphine) are in Schedule 2 and the less risky drugs are in lower Schedules. The current classification system has evolved in an unsystematic way from somewhat arbitrary foundations with seemingly little scientific basis. In this paper we suggest a new system for evaluating the risks of individual drugs that is based as far as possible on facts and scientific knowledge. We suggest it could form the basis of a new classification system for the MDAct. It provides a rational means to rank the relative threat from any new street drug, as well as to respond to evolving evidence about the potential harm of current drugs.
Beginning from first principles, we suggest that there are three main factors that together determine the harm associated with any drug of potential abuse. These are:
The MDAct classification refers only to drugs that are currently illegal in the UK. The system we propose is intended to be of more general value. We intend this to be flexible and of broad utility. It is applicable to different cultures and traditions, and to changing social attitudes. It applies to all drugs, legal or illegal, when used for other than medicinal purposes.
Assessing the propensity of a drug to cause physical harm, i.e. damage to organs, involves a systematic consideration of the safety margin of the drug in terms of its acute toxicity, as well as its likelihood to produce health problems in the long term. The impact of a drug on physiological functions, such as respiration and the heart, are major determinants of physical harm. The route of administration is relevant to the assessment of harm. Drugs such as heroin, especially taken intravenously, carry a high risk of causing sudden death from respiratory depression, and they therefore score highly on acute harm. Tobacco and alcohol have a high propensity to cause illness and death on chronic administration. Recently published evidence shows that long-term cigarette smoking reduces life expectancy, on average, by 10 years (Ref 2). Tobacco and alcohol together account for about 90% of all drug-related deaths in the UK.
The Medicines and Healthcare Regulatory Authority [MHRA], through the Committee on the Safety of Medicines (CSM), has well-established methods of assessing the safety of medicinal drugs that can be used as the basis of this aspect of risk appraisal. Indeed a number of drugs of abuse have licensed indications in medicine and will therefore have had such appraisals, albeit, in most cases, determined many years ago. Three separate aspects of physical harm can be identified:
The route of administration is relevant not only to acute toxicity but also to "secondary" harms. For instance, administration of drugs by the iv route can lead to the spread of blood-borne viruses such as hepatitis and HIV, which have huge health implications for the individual and society. The potential for iv use is currently taken into account in the MDAct classification and was treated as a separate parameter in our exercise.
This dimension of harm involves interdependent elements — the pleasurable effects the drug produces and its propensity to produce dependent behaviour. Highly pleasurable drugs such as opiates and cocaine are frequently abused and the "street value" of drugs is generally determined by their pleasurable potential. Drug-induced pleasure has two components — the initial, rapid effect (colloquially known as the "rush") and the euphoria that follows this, often extending over several hours (the "high"). The faster the drug enters the brain the stronger the "rush", which is why there is a drive to formulate drugs in ways that allow them to be injected intravenously or smoked: in both cases, effects on the brain can occur within 30 sec. Heroin, crack cocaine, tobacco (nicotine) and cannabis (tetrahydrocannabinol) are all taken by one or other of these rapid routes. Absorption through the nasal mucosa, as with powdered cocaine, is also surprisingly rapid. Taking the same drugs by mouth, so that they are only slowly absorbed into the body, generally has a less powerful pleasurable effect, although it can be longer-lasting.
An essential feature of drugs of abuse is that they encourage repeated use. This tendency is driven by a variety of factors and mechanisms. The special nature of drug experiences certainly plays a part. Indeed, in the case of hallucinogens (LSD, mescaline, etc) it might be the only factor that drives regular use, and such drugs are usually rather infrequently used. At the other extreme are drugs such as crack cocaine and nicotine, which, for most users, induce powerful dependence. Physical dependence or addiction involves increasing tolerance (progressively higher doses being needed for the same effect), intense craving, and withdrawal reactions, such as tremors, diarrhoea, sweating and sleeplessness, when drug use is stopped. These indicate that adaptive changes occur as a result of drug use. Addictive drugs are repeatedly used, partly because of the power of the craving and partly to avoid withdrawal.
"Psychological" dependence is also characterised by repeated use of a drug but without tolerance and without physical symptoms directly related to drug withdrawal. Some drugs, such as cannabis, can lead to habitual use that seems to rest only on craving without obvious physical withdrawal symptoms. But some other drugs, such as the benzodiazepines, can induce psychological dependence without tolerance, in which physical withdrawal symptoms occur through fear of stopping. This form of dependence is less well studied and understood than addiction but is a robust phenomenon, in the sense that withdrawal symptoms can be induced simply by persuading a drug user that the drug dose is being progressively reduced while it is, in fact, being maintained constant (Ref 3).
The features of drugs that lead to dependence and withdrawal reactions have been reasonably well characterised and include:
For many drugs there is a good correlation between the phenomena seen in humans and those observed in studies on animals. Also, drugs that share molecular specificity (having similar tendencies to bind with or interact with the same target molecules in the brain) tend to have similar pharmacological effects. Hence, some sensible predictions can be made about new compounds before they are used by humans.
Drugs harm society in a number of ways. The main ones are through the various effects of intoxication, through damaging family and social life, and through the costs to the healthcare, social care and policing systems. Drugs that lead to intense intoxication are associated with huge costs in terms of accidental damage to the user, to others and to property. Alcohol intoxication, for instance, often leads to violent behaviour and is a frequent cause of car and other accidents. Many drugs cause major damage to the family, either because of the impact of intoxication or because they distort the motivations of users, taking them away from their families and into drug-related activities including crime.
Societal damage also occurs through the immense healthcare costs of some drugs. Tobacco is estimated to cause up to 40% of all hospital illness and 60% of drug-related fatalities. Alcohol is involved in over half of all A&E visits and orthopaedic admissions (Ref 4). Intravenous drug delivery brings particular problems in terms of blood-borne virus infections, especially HIV and hepatitis, leading to the infection of sexual partners as well as needle-sharers.
Table 1 shows the assessment matrix that we designed, which includes all nine parameters of risk, created by dividing each of the three major categories of harm into three sub-groups described above.
|Category of harm||Parameter|
|Dependence||4||Intensity of pleasure|
|8||Other social harms|
Participants were asked to score each substance for each of these nine parameters, using a four-point scale, with 0 being no risk, 1 some, 2 moderate and 3 extreme risk. For some analyses [e.g. Table 3], the scores for the three parameters for each category were averaged to give a mean score for that category. An overall harm rating was obtained by taking the mean of all nine scores.
The scoring procedure was piloted by members of the panel of the Independent Inquiry into the MDAct (the Runciman Committee 2000; Ref 5). Once refined through this piloting, an assessment form based on Table 1, with additional guidance notes, was used. Two independent groups of experts were asked to perform the ratings. The first was the national group of consultant psychiatrists who were on the Royal College of Psychiatrists' register as specialists in addiction. Replies were received and analysed from 29 of the 77 registered doctors canvassed on 14 compounds (those listed in legend to fig 2). Tobacco (cigarettes) and alcohol were also included because their extensive use has provided reliable data on their risks and harms: hence, they provide familiar benchmarks against which the absolute harms of other drugs can be judged.
Following this assessment a second group was convened that also assessed these 14 substances and for completeness an additional six abused compounds (khat, 4MTA, GHB, ketamine, methylphenidate, alky nitrites (Table 2)). This group was made up of individuals with a wide range of expertise in addiction — ranging from the forensic science service through to general practitioners and epidemiologists and included law enforcement officers. Scoring was done independently and individual scores were then presented to the whole group for a "Delphic" type discussion. Individuals were allowed to revise their score on any of the parameters in the light of this discussion, after which a final mean score was calculated. The number of members taking part in the scoring varied from eight to 16 over the course of several meetings.
|Substance||Class in Act||Schedule in Regulations||Comments|
|Cocaine||A||2||includes crack cocaine|
|Barbiturates||B||most in 3|
|Buprenorphine||C||3||Pending move to Class B|
|Benzodiazepines||C||most in 4(1)|
|Alkyl Nitrites||-||-||Not controlled|
|Ketamine||-||-||Not controlled, but moving to class C in 2006|
Use of this risk assessment system proved straightforward and practicable. The overall mean scores by the independent group averaged across all scorers, are plotted in rank order for all 20 substances in Figure 1. The classification of each substance under the MDAct is also shown by the shading of the bars of the histogram. Although the two substances with the highest harm ratings (heroin and cocaine) are Class A drugs, overall there is a surprisingly poor correlation between MDAct Class and harm score. Of both the 8 highest and the 8 lowest substances in the ranking of harm, three are Class A and two are unclassified. Alcohol, ketamine, tobacco and solvents (all unclassified) were ranked as more harmful than LSD, ecstasy and its variant 4-MTA (all Class A). Indeed, the correlation between MDAct classification and harm rating was not statistically significant (Kendall's rank-correlation = -0.18; 2P = 0.25. Spearman's rank-correlation = -0.26; 2P = 0.26). Interestingly, of the unclassified drugs, alcohol and ketamine were rated particularly high, and the Advisory Council on the Misuse of Drugs has recently recommended that ketamine should be added to the MDAct (as Class C) [Ref 5A].
Figure 2 compares the overall mean scores (averaged across all nine parameters) for the psychiatrists with those of the independent group for the 14 substances that were ranked by both groups (see legend to Fig. 2). The average scores for the two groups were remarkably well correlated (r = 0.892; t = 6.8; P < 0.001) which suggests the scores and process have validity.
The respective classification, where appropriate, under the Misuse of Drugs Act is shown above each bar. Class A drugs are indicated by red bars, B by blue, and C by green. Unclassified substances are shown as yellow bars.
Table 3 lists the independent group results for each of the three sub-categories of harm. The scores in each category were averaged across all scorers and the substances are listed in rank order of harm, based on their overall score. Many of the drugs were consistent in their ranking across the three categories. Heroin, cocaine, barbiturates and street methadone were in the top five places for all categories of harm, whereas khat, alkyl nitrites and ecstasy were in the bottom five places for all. On the other hand, some drugs differed considerably in their harm rating across the three categories. For instance, cannabis was ranked low for physical harm but somewhat higher for dependence and harm to family and community. Anabolic steroids were ranked high for physical harm but low for dependence. Tobacco was high for dependence but distinctly lower for social harms (because it scored low on intoxication) and physical harm (since the ratings for acute harm and potential for iv use were low). There was also good agreement between the independent group and the psychiatrists in their scores for the individual categories of harm.
|Substance||Group 1 Physical harm||Group 2 Dependence||Group 3 Social harms||Average|
Drugs that can be administered by the iv route were ranked relatively high, and this was not caused solely by exceptionally high scores for parameter three (propensity for iv use) and nine (healthcare costs). Even if the scores for these two parameters were excluded from the analysis, the high ranking for such drugs persisted. In other words, drugs that can be administered intravenously were also judged to be substantially harmful in many other respects.
The correlation coefficient is r = 0.892 (P < 0.001).
The straight line shows the least squares fit.
The results of this study do not provide justification for the sharp A/B/C divisions of the MDAct classification. Distinct categorisation is, of course, convenient for setting the priorities for policing, education and social support, as well as for determining sentencing for possession or dealing. But, first, the rank ordering of drugs in the MDAct classification is not confirmed by the more complete assessment of harm described here. Second, sharp divisions in any ranking system are essentially arbitrary unless there are obvious discontinuities in the set of scores. There is only a hint of a discontinuity in the spectrum of harm in Figure 1 is the small step in the very middle of the distribution, between buprenorphine and cannabis. Interestingly, alcohol and tobacco both appear in the top 10, higher-harm group. There is a rapidly accelerating harm value for drugs higher than alcohol. So, one possible interpretation of our findings is that drugs more dangerous than alcohol might be Class A, cannabis and those below might be Class C, and drugs in between might be B. In that case, it is salutary to see that alcohol and tobacco — the most widely used unclassified substances — would have harm ratings comparable to Class B illegal drugs.
The participants in this study were asked to assess the harm of drugs in the form that they are normally used. In a few cases, it was clear that the harms caused by a particular drug could not be completely isolated from interfering factors associated with the particular style of use. For example, cannabis is commonly smoked mixed with tobacco, which might have elevated its scores for physical harm, dependence, etc. There is a further level of uncertainty resulting from polydrug use, particularly in the so-called recreational group of drugs including GHB, ketamine, ecstasy and alcohol, where adverse effects may be attributed mainly to one of the components of common mixtures. Crack cocaine is generally considered to be more dangerous than powdered cocaine, but here they were considered together. Similarly the scores for the benzodiazepines might have been biased in the direction of the most abused drugs, especially temazepam. Individual scoring of particular benzodiazepines and of other drugs that can be used in different forms might be more appropriate.
With such relatively small numbers of independent scores, we did not think that it was legitimate to estimates correlations between the nine parameters. It is quite likely that there is some redundancy: that is to say, they might not represent nine independent measures of risk. Similarly, the principal components of the parameters were not extracted, partly because it was felt that there were insufficient data and partly because it might not be appropriate to reduce the number of parameters to a core group, at least until further assessment panels have independently validated the entire system.
Our analysis gave equal weight to each parameter of harm: individual scores have simply been averaged. Such a procedure would not give a valid indication of harm for a drug that has extreme acute toxicity, such as the "designer" drug contaminant MPTP, a single dose of which damages the substantia nigra of the basal ganglia and induces an extreme form of Parkinson's disease. Indeed, this simple form of the system of scoring might not deal adequately with any substance that is extremely harmful in only one respect. Take tobacco, for instance. Smoking tobacco beyond the age of 30 reduces life expectancy by an average of up to 10 years (A1) (Ref 2). It is the commonest cause of drug-related deaths, and it is a huge burden on the Health Service. But its short-term consequences and social effects are modest. Of course, the weighting of individual parameters could easily be changed, to emphasize one aspect of risk or another, depending on the importance attached to each. And other procedural mechanisms could be introduced to take account of extremely high values for single parameters of harm.
Despite these qualifications, we were impressed by the consistency of the scores between different groups of scorers and the correlation between scores across the categories of harm, for most drugs. Our findings raise questions about the validity of the current MDAct classification, despite the fact that this is nominally based on an assessment of risk to users and society. This is especially true in relation to psychedelic type drugs. They also emphasise that the exclusion of alcohol and tobacco from the MDAct is, from a scientific perspective, arbitrary. The fact that these two legal and widely used drugs lie in the upper half of the ranking of harm is surely important information to be taken into account in public debate on the impact of illegal drug use.
We believe that a system of classification like ours, based on the scoring of harms by experts, on the basis of scientific evidence, has much to commend it. It is rigorous, and involves a formal, quantitative evaluation of several aspects of harm. And it can easily be reapplied, as knowledge advances. We note that a numerical system has also been described by MacDonald et al. (Ref 6) for assessing the overall harm of drug use: an approach that is complementary to the scheme described here.
The approach to harm estimation that we propose provides a comprehensive and transparent process for the evaluation of the danger of drugs. It could be developed to aid in decision-making by regulatory bodies such as the UK's Advisory Council on the Misuse of Drugs and the European Medicines Evaluation Agency. Moreover, our findings reveal no clear distinction between socially accepted and illicit substances. We note that other organisations [e.g. the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (Ref 7) and the CAM committee of the Dutch government (Ref 8) are currently exploring other risk assessment systems, some of which are also numerically based. Such approaches might help society to engage in a more rational debate about the relative risks and harms of drugs, by basing discussion on a formal assessment of harm rather than on prejudice and assumptions.
Some of the ideas developed in this paper arose out of discussion at workshops organised by the Beckley Foundation (Beckley Park, Oxford OX3 9SY), to whom we are grateful. We thank Dr David Spiegelhalter of the MRC Biostatistics Unit for advice on statistics.