Categories of harm
There are three main factors that together determine the harm associated with any drug of potential abuse: the physical harm to the individual user caused by the drug; the tendency of the drug to induce dependence; and the effect of drug use on families, communities, and society.[5], [6], [7] and [8]
Physical
Assessment of the propensity of a drug to cause physical harm—ie, damage to organs or systems—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 effect of a drug on physiological functions—eg, respiratory and cardiac—is a major determinant of physical harm. The route of administration is also relevant to the assessment of harm. Drugs that can be taken intravenously—eg, heroin—carry a high risk of causing sudden death from respiratory depression, and therefore score highly on any metric of acute harm. Tobacco and alcohol have a high propensity to cause illness and death as a result of chronic use. Recently published evidence shows that long-term cigarette smoking reduces life expectancy, on average, by 10 years.9 Tobacco and alcohol together account for about 90% of all drug-related deaths in the UK.
The UK Medicines and Healthcare Regulatory Authority, in common with similar bodies in Europe, the USA, and elsewhere, has well-established methods to assess the safety of medicinal drugs, which can be used as the basis of this element of risk appraisal. Indeed several drugs of abuse have licensed indications in medicine and will therefore have had such appraisals, albeit, in most cases, many years ago.
Three separate facets of physical harm can be identified. First, acute physical harm—ie, the immediate effects (eg, respiratory depression with opioids, acute cardiac crises with cocaine, and fatal poisonings). The acute toxicity of drugs is often measured by assessing the ratio of lethal dose to usual or therapeutic dose. Such data are available for many of the drugs we assess here.[5], [6] and [7] Second, chronic physical harm—ie, the health consequences of repeated use (eg, psychosis with stimulants, possible lung disease with cannabis). Finally, there are specific problems associated with intravenous drug use.
The route of administration is relevant not only to acute toxicity but also to so-called secondary harms. For instance, administration of drugs by the intravenous route can lead to the spread of blood-borne viruses such as hepatitis viruses and HIV, which have huge health implications for the individual and society. The potential for intravenous use is currently taken into account in the Misuse of Drugs Act classification and was treated as a separate parameter in our exercise.
Dependence
This dimension of harm involves interdependent elements—the pleasurable effects of the drug and its propensity to produce dependent behaviour. Highly pleasurable drugs such as opioids and cocaine are commonly 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 street drugs in ways that allow them to be injected intravenously or smoked: in both cases, effects on the brain can occur within 30 seconds. 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 various factors and mechanisms. The special nature of drug experiences certainly has a role. Indeed, in the case of hallucinogens (eg, lysergic acid diethylamide [LSD], mescaline, etc) it might be the only factor that drives regular use, and such drugs are mostly used infrequently. 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 (ie, progressively higher doses being needed for the same effect), intense craving, and withdrawal reactions—eg, tremors, diarrhoea, sweating, and sleeplessness—when drug use is stopped. These effects indicate that adaptive changes occur as a result of drug use. Addictive drugs are generally used repeatedly and frequently, 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 or physical symptoms directly related to drug withdrawal. Some drugs can lead to habitual use that seems to rest more on craving than physical withdrawal symptoms. For instance, cannabis use can lead to measurable withdrawal symptoms, but only several days after stopping long-standing use. Some drugs—eg, the benzodiazepines—can induce psychological dependence without tolerance, and physical withdrawal symptoms occur through fear of stopping. This form of dependence is less well studied and understood than is addiction but it is a genuine experience, in the sense that withdrawal symptoms can be induced simply by persuading a drug user that the drug dose is being progressively reduced although it is, in fact, being maintained at a constant level.10
The features of drugs that lead to dependence and withdrawal reactions have been reasonably well characterised. The half-life of the drug has an effect—those drugs that are cleared rapidly from the body tend to provoke more extreme reactions. The pharmacodynamic efficacy of the drug also has a role; the more efficacious it is, the greater the dependence. Finally, the degree of tolerance that develops on repeated use is also a factor: the greater the tolerance, the greater the dependence and withdrawal.
For many drugs there is a good correlation between events that occur in human beings and those observed in studies on animals. Also, drugs that share molecular specificity (ie, that 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 human beings. Experimental studies of the dependence potential of old and new drugs are possible only in individuals who are already using drugs, so more population-based estimates of addictiveness (ie, capture rates) have been developed for the more commonly used drugs.11 These estimates suggest that smoked tobacco is the most addictive commonly used drug, with heroin and alcohol somewhat less so; psychedelics have a low addictive propensity.
Social
Drugs harm society in several ways—eg, through the various effects of intoxication, through damaging family and social life, and through the costs to systems of health care, social care, and police. 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 common cause of car and other accidents. Many drugs cause major damage to the family, either because of the effect 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 health-care 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 visits to accident and emergency departments and orthopaedic admissions.12 However, these drugs also generate tax revenue that can offset their health costs to some extent. 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. For drugs that have only recently become popular—eg, 3,4-methylenedioxy-N-methylamphetamine, better known as ecstasy or MDMA—the longer-term health and social consequences can be estimated only from animal toxicology at present. Of course, the overall use of a drug has a substantial bearing on the extent of social harm.
Assessment of harm
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 subgroups, as described above. 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, the scores for the three parameters for each category were averaged to give a mean score for that category. For the sake of discussion, an overall harm rating was obtained by taking the mean of all nine scores.
Table 1.
Assessment parameters
Parameter
Physical harm One Acute
Two Chronic
Three Intravenous harm
Dependence Four Intensity of pleasure
Five Psychological dependence
Six Physical dependence
Social harms Seven Intoxication
Eight Other social harms
Nine Health-care costs
Full-size table
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The scoring procedure was piloted by members of the panel of the Independent Inquiry into the Misuse of Drugs Act.13 Once refined through this piloting, an assessment questionnaire based on table 1, with additional guidance notes, was used. Two independent groups of experts were asked to do 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 who were asked to assess 14 compounds—heroin, cocaine, alcohol, barbiturates, amphetamine, methadone, benzodiazepines, solvents, buprenorphine, tobacco, ecstasy, cannabis, LSD, and steroids. Tobacco and alcohol were included because their extensive use has provided reliable data on their risks and harms, providing familiar benchmarks against which the absolute harms of other drugs can be judged. However, direct comparison of the scores for tobacco and alcohol with those of the other drugs is not possible since the fact that they are legal could affect their harms in various ways, especially through easier availability.
Having established that this nine-parameter matrix worked well, we convened meetings of a second group of experts with a wider spread of expertise. These experts had experience in one of the many areas of addiction, ranging from chemistry, pharmacology, and forensic science, through psychiatry and other medical specialties, including epidemiology, as well as the legal and police services. The second set of assessments was done in a series of meetings run along delphic principles, a new approach that is being used widely to optimise knowledge in areas where issues and effects are very broad and not amenable to precise measurements or experimental testing,14 and which is becoming the standard method by which to develop consensus in medical matters. Since delphic analysis incorporates the best knowledge of experts in diverse disciplines, it is ideally applicable to a complex variable such as drug misuse and addiction. Initial scoring was done independently by each participant, and the scores for each individual parameter were then presented to the whole group for discussion, with a particular emphasis on elucidating the reasoning behind outlier scores. Individuals were then invited to revise their scores, if they wished, on any of the parameters, in the light of this discussion, after which a final mean score was calculated. The complexity of the process means that only a few drugs can be assessed in a single meeting, and four meetings were needed to complete the process. The number of members taking part in the scoring varied from eight to 16. However, the full range of expertise was maintained in each assessment.
This second set of assessments covered the 14 substances considered by the psychiatrists plus, for completeness, six other compounds (khat, 4-methylthioamphetamine [4-MTA], gamma 4-hydroxybutyric acid [GHB], ketamine, methylphenidate, and alkyl nitrites), some of which are not illegal, but for each of which there have been reports of abuse (table 2). Participants were told in advance which drugs were being covered at each meeting to allow them to update their knowledge and consider their opinion. Recent review articles[5], [6], [7], [15], [16], [17] and [18] were provided.
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Table 2.
The 20 substances assessed, showing their current status under the Misuse of Drugs Act
Class in Misuse of Drugs Act Comments
Ecstasy A Essentially 3,4-methylenedioxy-N-methylamphetamine (MDMA)
4-MTA A 4-methylthioamphetamine
LSD A Lysergic acid diethylamide
Cocaine A Includes crack cocaine
Heroin A Crude diamorphine
Street methadone A Diverted prescribed methadone
Amphetamine B ..
Methylphenidate B eg, Ritalin (methylphenidate)
Barbiturates B ..
Buprenorphine C eg, Temgesic, Subutex
Benzodiazepines C eg, Valium (diazepam), Librium (chlordiazepoxide)
GHB C Gamma 4-hydroxybutyric acid
Anabolic steroids C ..
Cannabis C ..
Alcohol .. Not controlled if over 18 years in UK
Alkyl nitrites .. Not controlled
Ketamine .. Not controlled at the time of assessment; controlled as class C since January, 2007
Khat .. Not controlled
Solvents .. Not controlled; sales restricted
Tobacco .. Not controlled if over 16 years in UK
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Occasionally, individual experts were unable to give a score for a particular parameter for a particular drug and these missing values were ignored in the analysis—ie, they were neither treated as zero nor given some interpolated value. Data were analysed with the statistical functions in Microsoft Excel and S-plus.
