A procedure is outlined for comparing dependence potential and acute toxicity across a broad range of abused psychoactive substances. Tentative results, based on an extensive literature review of 20 substances, suggested that the margin of safety (“therapeutic index”) varied dramatically between substances. Intravenous heroin appeared to have the greatest risk of dependence and acute lethality; oral psilocybin appeared to have the least. Hazards duc to behavioral deficits, perceptual distortion, or chronic illness were not factored into the assessments.
INTRODUCTION
Drugs differ in their potential adverse health effects. Although individual health impairment is only one aspect of widespread drug abuse costs (e.g., accidents involving others, family dysfunction, lost productivity), it is probably the most direct and prominent indicator of risk. This paper will present a preliminary comparative overview of the dependence potential and the acute physical toxicity of 20 psychoactive substances used nonmedically in North America.
Despite the fact that researchers are characteristically cautious and skeptical about the validity of broad-based comparisons, legislators and administrators are often forced – in the light of publicized abuses of some substances – to take decisive action regardless of the amount or quality of scientific information available. In order to provide empirical data for policy decisions, the Committee on Problems of Drug Dependence and the National Institute of Mental Health initiated in 1948 an on-going series of research studies on the abuse liability of psychoactive substances[1]. In the last decade the scope of work has broadened from the original focus on narcotic analgesics to an extensive range of stimulants and sedative-hypnotic compounds[2].
When comparisons are made among substances, they typically include only substances that fall within a similar chemical structures or action prototype category [e.g., stimulants[3, 4], sedative-hypnotics[5-7]]. Studies that attempt to rank-order or make numerical comparisons across pharmacological categories are much less common, although a respectable number of such studies have been published [e.g., Refs. 8-17]. One obvious reason for the relative infrequency of such broad comparative studies is the formidable complexity of controlling for the host of biological, biochemical, learning, and environmental factors that influence the subjective and behavioral effects of even a single substance.
MEASUREMENT OF DEPENDENCE
A comparison of dependence potentials cannot be estimated without first establishing an effective dose. Operational definitions of an effective dose typically employ drug self-administration or drug discrimination paradigms[18]. A variety of sophisticated laboratory procedures with both human and nonhuman animals has been developed in recent years [cf. Refs. 2, 19-23]. In self-administration studies, the effective dose may be determined by observing the amount of drug required to maintain stable responding by the animal under different experimental conditions (e.g., continuous free access to the substance, substitution of the substance for a placebo or a standard reinforcing substance). By permitting an organism to choose one of two drugs or allowing it to substitute a particular substance for a range of other substances, the relative reinforcing strength of the experimental drug can be measured. Human verbal reports of subjective effects[13, 24] and of drug-seeking behavior in natural settings[25, 26] have been used to supplement laboratory observations.
Physical dependence is often (but not always) characterized by development of physiological tolerance to the drug and by withdrawal symptoms upon removal of the drug. A measurable abstinence syndrome has been the traditional sine qua non for “addiction”[27]. When withdrawal symptoms appear minimal or nonexistent, psychological dependence has been employed as a theoretical construct to explain drug-seeking behavior. Cocaine, for example, can act as strong positive reinforcer by producing self-reported positive mood states[4, 10], but its absence has less potential to serve as a negative reinforcing situation because the drug produces comparatively modest physical withdrawal symptoms[28-30]. Conversely, nicotine has weak positive consequences (e.g., increased alertness or improved motor skills) compared to more salient negative consequences (e.g., withdrawal symptoms of drowsiness and headaches)[31]. Thus, if dependence is measured by a desire to repeat a positive experience, cocaine and methaqualone would likely be reported as most addictive[7, 32, 33]. If dependence is measured by relief of physical craving or by unsuccessful attempts to stop use, nicotine and opioids probably would be ranked as most addictive[8, 11, 14].
An individual user’s withdrawal symptoms have social or public significance primarily to the extent that they act as negative reinforcers for drug-seeking behavior already in the person’s repertoire. And because the avoidance of such withdrawal symptoms cannot explain the initial drug-taking episode, the combining of physical and psychological factors into a single “dependence potential” category would seem to be a tolerable loss of information. This is a tentative and debatable decision, but it appears consonant with the rationale of DSM-III-R that shifted the focus of definitions of drug dependence away from aversive experiences in the absence of substances to behaviors exhibited in relation to the presence or potential presence of substances[34].
MEASUREMENT OF TOXICITY
“Toxicity” customarily refers to the extent to which a chemical has adverse effects on a living organism. The most traditional laboratory measure of physiological risk has been the “therapeutic index”[35], although the term may be inappropriate when referring to substances that have no established medicinal value. The number of animals that show a specified reaction, and the number of animals that die, can be plotted at various dosage levels and time intervals in order to generate dose-response curves characterizing the substance of interest. The ratio of the median lethal dose ([LD.sub.50]) to the median effective dose ([ED.sub.50]) provides a one-point estimate of how selective or nontoxic a substance is in producing the specified reaction.
A general functional similarity between animal species has been well-documented for some substances[18, 36], but other substances show considerable interspecies and interstrain variability. For example, the [LD.sub.50] of parenterally administered MDMA in mice is apparently twice the [LD.sub.50] in rats[37, 38]; the [LD.sub.50] of intravenous mescaline is about twice as much for mice as for dogs, but less than for monkeys[39]. The desire to use less invasive laboratory procedures[40, 41], and to verify the applicability of nonhuman animal studies to humans, has focused attention on data sources that come “naturally.” Unfortunately, information received from sources such as hospital emergency rooms and coroner offices is problematic at best and misleading at worst. For an illustration of potential misinterpretation, consider the raw numbers of a 4-year study[42] of toxic accidents in one county in Arizona. Coroner records showed that carbon monoxide deaths outnumbered cocaine deaths, and that caffeine was more often involved in fatalities than amphetamines. These seemingly anomalous statistics are easily explained: the number of people exposed to a substance, as well as its inherent toxicity, influences the number of deaths. Yet exposure is seldom factored into the drug fatality statistics cited in the popular media or in U.S. Government publications (e.g., Drug Enforcement Statistical Report, National Intelligence Consumers Report).
Nonetheless, even death rates among users prove difficult to interpret. Fatalities from intentional suicide[43-45] and from misadventures with law enforcement[46, 47] should probably be discounted when using morbidity rates to compare pharmacological toxicity. Furthermore, the initial health status of the deceased is often unknown, and when the purported cause of death or illness is an illicit substance, the trauma may not be due to the putative substance at all, but rather, extenders or contaminates which often go undetected in postmortem examinations[48-50]. Most decedents ingest more than one psychoactive substance (typically alcohol).
The most comprehensive epidemiological data collection system relevant to drug abuse is the Drug Abuse Warning Network (DAWN). It collects information from approximately 740 emergency rooms and 90 medical examiner’s offices in 27 metropolitan areas of the United States[51]. The problematic nature of using DAWN data to estimate toxicity has been illustrated by Anthony and Trinkoff[52]. They computed the number of emergency room episodes and deaths per one million prescriptions for 10 different benzodiazepines. Because benzodiazepines compose a relatively narrow subclass of sedative/hypnotic drugs, we might reasonably expect a positive correlation between the number of prescriptions written, emergency room episodes, and deaths. Surprisingly, there was no correlation between these three variables for any of the drugs except diazepam (Valium). Even then, we cannot justifiably conclude that diazepam is the most toxic of the 10 benzodiazepines until we control for possible confounding variables (e.g., diazepam users may use the drug for a longer period of time or may be heavier users of alcohol). DAWN reports do not include such information.
In summary, neither nonhuman experimental studies nor clinical statistics yield unambiguous results with respect to acute lethal dosages. The best guess lethal dose” for an average adult human who has not developed tolerance to the substance is probably the [LD.sub.50] extrapolated from a broad range of laboratory animal studies that falls within the range of lethality cited in clinical or forensic reports.
RATING PROCEDURE
As a means of exploring the feasibility of broad-based comparative rating, a literature review was conducted that focused on 20 psychoactive substances. Six major drug classes were represented: anesthetics (ketamine, PCP, nitrous oxide), cannabis (marijuana), depressants/sedative-hypnotics (diazepam, ethanol, methaqualone, secobarbital), hallucinogens/psychedelics (LSD, MDMA, mescaline, psilocybin), opiates (heroin, morphine, opium), and stimulants (amphetamine, caffeine, cocaine carbonate, cocaine hydrochloride, nicotine).
In contrast to conventional deductive inquiries (e.g., meta-analyses) in which a sampling frame and statistical parameters are specified in advance, this preliminary investigation used an inductive procedure[53]. No hypotheses were proposed in advance regarding the relative dependence potential or acute lethaiity/toxicity of the substances.
The initial step of the review process was simply to compile literature references cited in standard psychopharmacology texts[54-57] and published bibliographies[58-61] that appeared likely to give a quantitative estimate of dependence potential or toxicity. Sources cited in these materials were scanned for additional relevant books, book chapters, and articles. Next, seven on-line computer databases were interrogated: Biosis Previews (1969-1992), Current Contents (1989-1992), Embase (1982-1992), Health Periodicals Database (1976-1992), Medline (1986-1992), PsychInfo (1966-1992), and Toxline (1965-1992). The database descriptors included each of the 20 target substances, cross-indexed with the terms “toxicity,” “dependence,” “dependency,” “dose,” “dosage,” “reinforcement,” and “therapeutic index.” This procedure yielded approximately 12,800 English language citations. Many of these citation were redundant because the same serial publication was indexed in more than one database. Research reports which appeared, on the basis of their title or abstract, to focus primarily on pharmacokinetics, medicinal biochemistry, drug design, anatomy, therapy, or legislation were excluded from the domain of eligible citations. These restrictions limited the review to about 950 potentially relevant articles. Approximately 70% of these articles were accessed and read. Of these, about 350 articles were found to give a quantitative estimate of lethality or an empirically derived comparison of dependence potential, and were not obviously duplicative of a similar study published by the same authors in a different book or journal. These 350 articles constitute die database of findings reported here. This procedure undoubtedly missed some relevant studies both in books and journals, as well as in sources not searched (e.g., technical reports, conference presentations, and dissertations).
Simply in terms of the quantity of published research, there was a substantial difference between substances. The one substance that far exceeded all others as a topic of investigation was ethyl alcohol. Caffeine ran a distant second; nicotine came in third, followed by benzodiazepines and amphetamine derivatives. These five substances are not the most consciousness-altering or habit-forming, but their legitimate legal status and widespread use make them the most accessible to researchers. Of the 20 target substances, opium had the fewest published reports, followed by mescaline. “Crack” cocaine also had very few reports of experimental studies, reportedly due, in part, to technical problems caused by cocaine smoke particles being too large to pass beyond the upper respiratory tract of small laboratory animals (62, 63).
In an effort to mitigate gross interpretative errors and personal bias, drafts of several versions of a summary data table were sent, over a 2-year period, to an ad hoc panel of 35 toxicologists and psychopharmacologists, selected on the basis of their having published significant research in the area of abusable substances. These researchers were asked to correct and comment on the findings. Twenty-four written or telephone replies were received. Most of the comments were brief and related only to the particular substance or class of substances about which the researcher had published. Where an apparent error occurred in the data table or where an apparent discrepancy existed between reviewers, a second request for comment was made. Four such requests were mailed, two replies were received.
RESULTS
A summary of acute lethality and dependence potential estimates is presented in Table 1.
The acute lethal dose is die presumed [LD.sub.50] for a 70-kg nontolerant adult human. Both the lethal doses and the effective doses listed in Table 1 are point estimates of the median of an unspecified range of values. The effective dose of a drug was defined as the median amount of the substance capable of serving as a reinforcer for self-administration or of eliciting a verbal self-report of a generally desired subjective state (e.g., alertness, sociability, visionary dreaming, euphoria) in a 70-kg nontolerant adult human. Because the route of administration is such a critical factor in bioavailability [e.g., oral morphine sulfate being about 1/6 as potent as subcutaneous morphine sulfate (56)], the data in Table 1 are specifically limited to the route indicated for each substance. It should be noted that a substance may be used for several different therapeutic or recreational purposes, and therefore may have several ED curves. A 200-400-mg dose of meprobamate would probably be effective in producing euphoria or relief from anxiety, but a higher dose would be needed to produce sleep. Therefore the margin of safety changes as the purpose changes. The ED level for recreational or psychotherapeutic uses tends to be lower than for generally accepted medical uses (cf. Refs. 109, 116).
Dose response curves could not be generated, and no confidence intervals for the medians can be specified. Therefore, rather than present the resultant LD/ED ratio (“safety margin”) in numeric terms in Table 1, a qualitative scale was used (ranging from “very large” to “very small”) in order to emphasize the uncertain nature of the median estimates.
The number of literature references was limited to five reports or articles for any one substance. Citation preference was given to review articles, with second preference for original experimental studies. Therefore, in some cases the size of an effective or lethal dose appears in a study referenced in the review article rather than in the review itself; also, numerous relevant clinical or forensic case reports are not cited.
As a means of facilitating comparison of the substances, the information in Table 1 is presented in matrix form in Fig. 1. Opiates, as a group, have the most narrow margin of safety and the greatest dependence potential. Conversely, cannabis and hallucinogens/psychedelics have the widest margins of safety and the lowest dependence potential. The extreme positions are occupied by oral psilocybin and by intravenous heroin. The apparent safety margin of psilocybin appears to be several hundred times greater than that of heroin.
Despite troublesome limitations of the data sources, the magnitude of the difference between many of the substances suggests that they can be reliably and meaningfully ordered with respect to their dependence potential and acute lethality.
FUTURE HEALTH RISK ASSESSMENTS
The study reported here is merely a prototype of a more in-depth review that would be needed for a policy-relevant comparison of health risks. First, with respect to acute health hazards, an index of “general toxicity” should be devised that would include nonfatal trauma and behavior/perceptual decrements. Death is a very gross indicator of adverse health impact, and indeed, acute lethality may be almost irrelevant for a few substances that have a relatively large therapeutic index or safety margin (e.g., LSD, psilocybin). Several researchers (153, 154) have proposed a “reinforcement/toxicity” ratio as a metric, similar to the therapeutic index, that would permit a rank-ordering of psychophysiological toxicity of psychoactive substances. Reaction time, sensory thresholds, and anorectic effects were used by these researchers as criteria of acute toxicity. Potentially traumatic psychological disturbances are not limited to hallucinogens, but include all opiates, many depressants, and some stimulants at high doses (42, 123). Safety margins should also be adjusted to reflect the probability of chronic disease and long-term complications from particular types of substance use (e.g., emphysema, needle-transmitted hepatitis).
Second, estimates of dependence potential need to be better documented with respect to their ecological validity. Generalizing the results of an experiment across a given population (e.g., alcoholics in treatment) must be distinguished from generalizing results to a larger population (e.g., to all young people who have used an alcoholic beverage). Reportedly, one-half to two-thirds of adults in the United States use alcohol, yet only 8 to 10% are believed to be dependent on alcohol (155). Similarly, several longitudinal studies of young adult drug users (e.g., Refs. 156, 157) have claimed that as many as 75% of these people had experimented with cocaine, but 9 to 20% reported subsequent daily or compulsive cocaine use. We would be very hesitant to predict the potential negative impact of a state lottery on the average citizen if we studied only compulsive gamblers. Addicts or postaddicts may be unusually sensitive (or insensitive) to certain compounds. Oversampling these individuals increases the probability of observing false positives (84). Yet virtually no published studies have randomly selected human participants from a nonaddict population in order to compare self-administration rates across different classes of psychoactive substances as these are used in normal social settings. There are obvious ethical reasons for not exposing naive volunteers – even if informed and willing – to some substances. Nonetheless, this legitimate reason does not diminish the fact that most experimental studies of dependence potential lack demographic representativeness.
Estimating the magnitude of dependence and the incidence of severe toxicity in exposed populations would require consideration of variables such as age, gender, life-style, and patterns of exposure, as well as dosage levels. How such projected health hazards should be managed (in contrast to how they are assessed) involves political, social, and economic factors well beyond the scope of scientific risk assessment (cf. Ref. 158). Indeed, the priority ratings made for purposes of public health promotion or law enforcement – now often based on a “worst case” or “media visability” approach – would not necessarily coincide with the ratings of dependence potential and toxicity.
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