A.3 AMPHETAMINES AND AMPHETAMINE-LIKE DRUGS

INTRODUCTION

Amphetamines are synthetic amines which are in some ways similar to the body's own adrenalin (epinephrine). These drugs generally evoke an arousal or activating response not unlike one's normal reaction to emergency or stress. Naturally occurring stimulants, such as khat, ephedrine, strychnine, cathine, caffeine and cocaine, have been used in various cultures for centuries.18. 189 Amphetamines were first synthesized in the latter part of the 19th century, although their major pharmacological properties were not discovered until
1928.2, 42

A variety of amphetamine-related drugs currently exist. The most common amphetamine substances are amphetamine (Benzedrine®), dextroamphetamine (Dexedrine®), and methamphetamine (Methedrine® or Desoxyn®), with Benzedrine® being the least potent. Pharmacologically similar ("amphetamine-like") drugs with different chemical structures include benzphetamine (Didrex®), phenmetrazine (Preludin®), phendimetrazine (Dietrol® or Plegine®), methylphenidate (Ritalin®), pipradrol (Meratran®), diethylpropion (Tenuate®, also called amfepramone), and chlorphenteramine (Pre-sate®). Although various distinctions can be drawn among these drugs, many of their effects are similar if the dose is adjusted, and, consequently, they will be discussed as a group, with amphetamine as the prototype. Two amphetamine-related drugs, MDA (methylenedioxyamphetamine) and STP (DOM or dimethoxymethylamphetamine), with potent psychedelic-hallucinogenic properties are discussed in A.5 Hallucinogens. Cocaine is dealt with separately below. (See A.4 Cocaine.) Caffeine is not discussed in detail in this report, but the reader is referred to several recent reviews of the effects of this popular drug.[b] Common slang terms for the various amphetamines and amphetamine-like drugs include: 'speed', 'crystal', `meth', 'bennies', `dexies', 'A', 'uppers', `go fast', 'pep pills', 'diet pills', 'jolly beans', 'truck drivers', 'co-pilots', 'eye openers', 'wake-ups', 'hearts' and `footballs'.

Amphetamines were introduced in medicine in the 1930s, and their stimulating properties were widely used by both Allied and Axis soldiers during World War II to counteract fatigue. Since then, amphetamines have been commonly employed in medical practice and often used non-medically by vehicle drivers on long trips, night-shift workers, fatigued housewives, students studying for exams and others who must meet deadlines, athletes attempting to increase performance, and others desiring general stimulation, pleasure or fun.
In the late 1940s much of the war-time drug stockpile became available on the world market, and in many countries amphetamines were avalable on a non-prescription, over-the-counter basis. Widespread use followed in most industrialized areas with numerous unpleasant consequences. Use reached epidemic proportions, for example, in the 1950s in Japan—a country which had never previously had a serious drug problem except alcoholims.20, loo Since this time, amphetamines and related thugs have generally been put under governmental control, and in some countries, such as Sweden, they are highly restricted in both medical and non-medical applications. Additional controls on the medical use of amphetamines and some related drugs have recently been imposed in Canada as well.23

The popularity of medical and non-medical use of these drugs spread rapidly in all age groups and social classes in North America after W.W. II. The drugs were usually taken orally or sniffed, and, more rarely, injected. Oral use was made of 'dismantled' Benzedrine® inhalers, which were on the unrestricted legal market at that time.

Popular oral use of amphetamines has continued, and in the mid-1960s a phenomenon new to North America developed and has caused major concern—the intravenous use of massive doses by persons commonly referred to as 'speeders' or 'speed freaks'. In North America, methamphetamine has been the most popular substance for such use, but in other countries, such as Sweden,12 phenmetrazine is preferred. Although this practice has been most frequently noted among youthful multi-drug-taking individuals, considerable opposition to such use of amphetamines has developed with the 'hip' community. The 'speed trip' is in many respects the antithesis of the experience sought with psychedelic drugs. Instead of the orientation towards the 'consciousness expansion', personal insight, and aesthetic and religious awareness often attributed to the psychedelic drug experience by hallucinogen users, the 'speed' phenomenon is usually characterized by action, power, arrogance and physical pleasure, and regularly leads to suspicion, paranoia, hostility and, often, aggression and violence. In addition to these undesirable personal characteristics, which often render 'speed freaks' highly unpopular, even amongst their peers, 'speeders' generally present a picture of chronic ill health unparalleled among other youthful users.

The message received by the Commission at public and private hearings, and in written communication with youthful drug users has been mostly negative towards 'speed'. Many experienced illicit drug users consider amphetamines extremely dangerous and undesirable, and have expressed surprisingly hostile attitudes toward these drugs in no uncertain terms. Numerous persons well known to youth, who have had considerable influence on drug attitudes during the past decade (e.g., John Lennon and the Beatles, Frank Zappa and the Mothers of Invention, Timothy Leary, Allen Ginsberg, and Donovan) have made public statements against the use of 'speed'.

Amphetamines are legally available in a variety of tablets, capsules (both in immediate and delayed release forms), elixirs, liquid injections and, until recently, inhalers.121 Methamphetamine generally appears in powder or `crystal' form on the illicit market. Amphetamines have been available for medical use in North America in combination with such drugs as barbiturates (e.g., Dexamyl®) and other sedatives, atropine, caffeine, vitamins and minerals, and thyroid extract. One of the most exotic pharmaceutical combinations has been described as follows:

This is a multi-coated tablet of pentobarbital on the outside to induce sleep rapidly, phenobarbital under a delayed dissolving coating to extend the sleep, and under another coating, an amphetamine to awaken the patient in the morning."

As with other prescription drugs which are widely used, such as the barbiturates, minor tranquilizers and related sedatives, the distinction between medical and non-medical use of amphetamines is not always easily made.

MEDICAL USE

As early as 1935, amphetamines (in oral doses from 20-200 mg per day) were found to be a specific treatment for narcolepsy, an uncommon illness which is characterized by sudden attacks of weakness and sleep. These drugs remain the most effective treatment for this disorder.

Since the 1940s amphetamines (generally in doses of 10-50 mg per day) have been used in the treatment of overactive children who showed disorders of attention and impairment of learning capacity. In the last few years, a number of investigators have published results of controlled studies which revealed that amphetamines and methylphenidate were among the most effective treatments for hyperkinetic disorders. There has been a considerable amount of controversy surrounding the use of stimulants in the management of overactive children. Some opponents claim that the drugs are frequently used for social rather than medical reasons to make unruly children conform to the standards of an overly discipline-conscious school system.40, 70, 91, 117

Psychiatrists have occasionally used intravenous injections of methedrine (in doses of 15-30 mg) for diagnostic purposes. Administered in this fashion, the drug induces a state of excitation, elation and increased talkativeness, during which a previously inhibited patient may reveal information and symptoms which might be considered important for the understanding of his disorder. He may also express, more freely, previously suppressed emotions. It has been observed that some patients with a border-line psychosis show typical psychotic symptoms more clearly following an injection of amphetamines.

At one time, these drugs were tried in the treatment of alcoholism and opiate narcotic dependence, but this practice was not successful and was abandoned. Since drug dependence is often a chronic condition, some patients who took this treatment became dependent on amphetamines instead of, or in addition to, their original drug.

Early hopes that amphetamines would prove to be an effective general treatment for severe depression were soon disappointed. Although these drugs are powerful stimulants and increase a depressed person's activity, they may also make him more anxious and agitated, deprive him of sleep, and may fail to elevate his mood or to reverse the fundamental depressive process. In some well-selected individuals, amphetamines have been effective in relieving mild depression and chronic fatigue. Other drugs which do not have significant stimulant-euphoric properties, such as phenelzine (Nardil®), amitriptyline (Elavil®) and imipramine (Tofranil®) are generally recommended for the chemotherapy of severe depression.

Amphetamines have a strong anorectic or appetite-suppressing effect. Most so-called 'diet pills' contain amphetamines or similar preparations. However, the appetite-suppressing action together with the pleasant stimulating effects of these drugs usually declines after about two weeks of regular use, unless the dose is continuously increased. Weight loss so produced has often been only temporary, and amphetamines are no longer generally recommended for the treatment of obesity. Fenfluramine (an amphetamine analog) suppresses appetite without producing general stimulation effects and has recently been approved for medical use in Canada. (The potential for nonmedical use of fenfluramine has not been extensively studied.)

Recent regulations in Canada restrict the regular medical use of amphetamines, phenmetrazine and phendimetrazine (but not other amphetamine-like drugs) to the treatment of narcolepsy, hyperkinesis, mental retardation, epilepsy, parkinsonism, and hypotensive states associated with anesthesia.23 Amphetamines have also been used, with varying degrees of success, in the treatment of pregnancy nausea, asthma, nasal congestion, nocturnal enuresis (bet wetting), pain and sedative overdose.m. 92, 98

CHEMICAL ANALYSIS OF ILLICIT SAMPLES IN CANADA

Methamphetamine is the most common of the stimulant drugs noted in reports of police seizures and 'street drug' analyses in Canada. Other amphetamines and amphetamine-like drugs are occasionally noted, but relatively few such samples have been identified chemically. When found, these latter drugs are typically of high quality and generally were originally produced by legitimate manufacturers. The methamphetamine available on the illicit market is usually prepared in clandestine laboratories and is apparently often misrepresented or of poor quality, contaminated by products of faulty and incomplete synthesis, and may be mixed with other drugs. As with other drugs, alleged amphetamine samples submitted to Canadian laboratories for analysis are often those suspected of being adulterated, some unknown drug, or the cause of adverse reactions. Consequently, the samples reviewed in the following section cannot be considered a representative selection of illicit Canadian amphetamines.

In the Marshman and Gibbins 1970 study of illicit drugs collected in Ontario, 70 samples were presented to the researchers as methamphetamine. Of these, 61.4% actually contained the drug.99 In addition, methamphetamine was detected in five samples which were alleged to be other substances. Amphetamines were found mixed with other drugs in only two instances.

Gibbins found that methamphetamine samples sold as grams (i.e., 'street grams') on the illicit market in Toronto typically contained less than one-tenth the specified quantity of the drug."

The Commission's national survey of 'street drug' analysis facilities covering 1971-72 and our own collection of drug samples provide data on 86 items alleged to be primarily methamphetamine.106, [c] Of these samples:

35% were methamphetamine
38% contained methamphetamine and other drug(s) 20% were some other drug(s)
7% contained no drug

Of nine additional samples presented as methamphetamine mixtures, only five contained the drug and none of the combinations were as alleged. Of a total of 111 methamphetamine-containing samples found in the study, 62 (56%) were relatively pure and free of adulteration. The most common mixtures found contained other amphetamines, barbiturates, LSD or PCP, but no one combination occurred more than a few times. In addition, 22 samples containing other amphetamines and 2 of phenmetrazine were found. Approximately one-half of these were mixed with other drugs. Most had been represented as methamphetamine. Methylphenidate was not detected in any samples.

The Health Protection Branch has reported to the Commission the quantitative analysis of 286 samples containing methamphetamine which were seized by the police during the period of June 1971—October 1972.63, [b] Many of these samples had been selected for special analysis because of previously detected impurities and consequently cannot be considered representative of either the forms of the drug on the street or of police seizures in general. These samples were almost exclusively in bulk powder or 'crystal' form (as opposed to capsules or tablets) and ranged from 0.6% to 97.2% pure methamphetamine with a median of 39.2%. Products of faulty or incomplete synthesis were often found, as were other amphetamines. No other impurities or specific mixtures occurred more than a few times each in this collection.

ADMINISTRATION, ABSORPTION, DISTRIBUTION, AND PHYSIOLOGICAL FATE

Amphetamines are usually administered orally and are readily absorbed from the gastrointestinal tract. Occasionally, intramuscular or intravenous injections are used medically. In the past, an amphetamine base inhaler was also available. Amphetamine can be smoked if it is burned with some combustible material such as tobacco. Non-medical users may employ any of these administration routes, including sniffing 'crystal'. Chronic 'speed freaks' generally prefer intravenous injections.

The various amphetamine-related drugs differ to a certain extent in the rate of metabolism and elimination, but the general processes are similar. About half of the amphetamine which enters the body is excreted unchanged in the urine; the remainder is metabolized or chemically altered in the liver prior to elimination. Excretion of the bulk of the dose is rapid, but traces of the drug may be found in the urine up to a week after the last administration.14. 75. 92, 98 Because of the considerable proportion excreted unchanged, certain persons have been reported to extract and re-use crystals from the urine when fresh supplies were scarce. (This general practice of 'reclaiming' excreted drugs is not new, and such procedures have been recorded for centuries.)

Amphetamines and metabolites can be readily identified in blood and urine using standard techniques. Most other popular stimulants are also detectible in body tissue and fluids s. 29, 8°' 107, 187 Extremely sensitive and rapid immunoassay techniques have recently been developed for the analysis of amphetamines."

MODERATE DOSE EFFECTS31, 75, 92, 98

Both the psychological and physiological responses to amphetamines vary profoundly with dose, and the acute effects of intravenous injection may differ significantly from oral doses. The general effects vary continuously over the full dosage range, but for clarification in the following discussion, the oral use of moderate quantities of amphetamines will be separated from high-dose oral and intravenous use.

At typical therapeutic doses (e.g., 5-30 mg) amphetamines produce electrophysiological (EEG) signs of central nervous system (CNS) activation, along with a variety of adrenalin-like peripheral (sympathomimetic) effects such as increased blood pressure, pulse rate and blood sugar; slight dilation of some blood vessels and constriction of others; widening of the pupils; increased respiration rate; depression of appetite; and some relaxation of smooth muscle. Such effects might last three to four hours.

The psychological response varies among individuals, but might typically include increased wakefulness, alertness, and vigilance, improvement in concentration and a feeling of clearer thinking, decreased fatigue and boredom, elevation of mood, a feeling of sociability, increased initiative and energy, and increased verbal and other behavioural activity. There may be an improvement in some simple mental tasks, in reaction time and muscular coordination, and in athletic performance. In general, improved functioning is most likely to occur when prior performance was at a sub-normal state due to drowsiness, fatigue or boredom.39,147

On the other hand, a moderate dose of amphetamine in other individuals (or perhaps even in the same individual at different times) might produce irritation, inability to concentrate, restlessness, anxiety, confusion, depersonalization, insomnia, blurred vision, tremor, nausea, headache, dizziness, heart palpitation, drowsiness, chest pains, chilliness, urinary retention, diarrhea or constipation, and other adverse symptoms. With higher doses, hypersensitivity, delirium, panic, aggression, hallucinations, psychosis, and cardiovascular abnormalities may occur in some individuals. There does not appear to be any evidence of irreversible physiological damage associated with longterm use of moderate doses of amphetamines, although temporary disorders do occur. Although deaths are rare, some fatalities have been reported in the literature in unusually sensitive individuals.82

After continued administration of even moderate doses, withdrawal may be associated with fatigue, drowsiness and, not infrequently, emotional depression. The increased energy and alertness elicited by the drug merely postpone the need for rest and clearly provide no long-term substitute for it. Many regular users of stimulants rely on these drugs for energy when fatigued and often do not get proper rest for long periods of time.

It has frequently been said that amphetamines have a "paradoxical effect" on children, especially in cases of hyperkinesis. These drugs reportedly calm hyperactivity and improve school performance in some unruly youngsters, but are considered CNS stimulants in adults. However, the reports are not necessarily contradictory since amphetamines are often noted to enhance concentration and directed attention and to reduce boredom in adults, as well as children, and may not necessarily lead to increased general motor activity in either case. The repetitive, obsessive-compulsive behaviour often seen with high-dose amphetamine use (to be discussed below) may involve pharmacological mechanisms analogous to those producing therapeutic effects on hyperkinetic children at lower doses.

HIGH-DOSE EFFECTS

There has been little direct experimental investigation on the effects of high doses of amphetamines in humans. The chronic, high-dose intravenous amphetamine syndrome has been described by numerous authors.27. 44, 90, 124 A similar picture may exist with high-dose oral or nasal use as wel1.82 The cycle or pattern of use usually begins with several days of repeated injections (usually of methamphetamine) gradually increasing in magnitude and frequency. Some users may 'shoot' or 'crank' up to several 'street grams' in a single day.55, 90, 131 (As noted earlier, however, the actual doses employed are uncertain, and it is unlikely that they exceed a few hundred milligrams.) Initially, the user may feel energetic, talkative, enthusiastic, happy, confident and powerful, and may initiate and complete highly ambitious tasks. He often becomes involved in behaviour of a repetitive, compulsive nature (called "punding" in Sweden). He does not sleep and usually eats very little. After the first few days, however, unpleasant toxic symptoms become stronger, especially as the dose is increased. These toxic effects may be similar to those described earlier for lower doses but appear in amplified and exaggerated form. Some symptoms commonly reported at this stage are: compulsive and stereo-typed repetition of meaningless acts, automatic jerking movements, irritability, self-consciousness, suspiciousness, fear, hallucinations and delusions which may take on the characteristics of a severe paranoid psychosis. Aggressive and antisocial behaviour may occur at this time. A number of homicides have been reported to result from such paranoia.43 Hallucinations often include tingling, itching and creeping sensations under the skin thought to be caused by insects or parasites. Intense scratching or digging at these imaginary 'crank bugs' may become so intense as to produce bleeding sores and permanent scars. Severe chest pains, abdominal pain mimicking appendicitis and unconsciousness lasting an hour or more have also been reported after `over-amping', or injecting too large a dose.83. 132

Towards the end of the 'run' (usually less than a week) the toxic symptoms dominate, the drug is discontinued, fatigue sets in, and prolonged sleep follows, sometimes lasting several days. Upon awakening, the user is usually lethargic, ravenously hungry and often emotionally depressed. The user may overcome these effects with another injection—thus initiating the cycle anew. In other instances, 'runs' may be separated by days or weeks. On certain occasions, 'down' drugs, such as barbiturates or minor tranquilizers, and more recently, opiate narcotics may be used to 'crash' or terminate a run which has become intolerable or otherwise unpleasant.

`Speed freaks' are generally unpopular within the multi-drug-using community and are often shunned. Consequently, these individuals may live together in 'flash houses' totally occupied by amphetamine users. Frequent `hassles', aggression and violence have been reported in such dwellings. Heavy users are generally unable to hold a steady job because of the drug use patterns and often develop a parasitic relationship with the rest of the illicit drug-using community. There are reports that many chronic users support themselves through petty crime.13. 113 There is significant evidence that much of the violence and criminal behaviour associated with 'speed' use may reflect social and pre-existing psychological conditions as much as the pharmacological effects of the drug.133

The immediate effect of the intravenous injection of amphetamines is a sudden, overwhelming pleasurable 'rush' or 'flash' which has been described by users in such terms as "an instant total body orgasm". This effect is reportedly quite different from the warm, drifting sensation associated with opiate narcotics injection, but may be initially similar to the 'splash' produced by intravenous cocaine.27. 9°,131 Some users claim that the immediate fantastic pleasure of the injection is their prime motivation for using 'speed', and that other aspects are secondary. There are also reports of 'needle freaks', for whom the use of the hypodermic syringe has acquired special rewarding connotations beyond the actual pharmacological effects of the drugs. On the other hand, since high-dose oral or sniffing use has been commonly reported in the literature for years, the injection 'rush' is clearly not a necessary component for all chronic users.82 In addition, it has been reported that some kind of initial (but delayed) 'rush' may be produced by large doses taken orally.

Some individuals report that sexual activity is prolonged by amphetamines, and may continue for hours. When orgasm finally comes it may be more pleasurable than normal; however, some users describe an inability to reach a climax. While only a minority of users report increased sexual activity, some people give this reason as a primary one for taking the drug.13. 36, 90, 124 Other users claim that they take the drug simply for euphoria or 'kicks', or because it enables them to be more confident and active.

The clinical picture of the chronic 'speed freak' is a distressing one indeed. Continued use of massive doses of amphetamines often leads to dehydration and considerable weight loss, sores and non-healing ulcers, brittle fingernails, tooth grinding, chronic chest infections, liver and cardiovascular diseases, a variety of hypertensive disorders, gastrointestinal dysfunction, psychiatric problems and, in rare cases, cerebral hemorrhage.30, 52, 89, 90, 130, 148 The extent to which these effects are the direct result of the drug or the secondary consequences of poor eating habits and malnutrition, unhygenic living conditions, over-exertion and improper rest is unclear, but evidence of direct damage due to high-dose use is accumulating. tizing angiitis, a progressive inflammatory disorder of the small arteries, has been reported in a group of intravenous amphetamine users, with fatal outcome in some. This disease may be linked to the drug and is often fatal if untreated.28 Further complications may be caused by unsterile and shared needles and injections, including tetanus, abcesses and ulcers of the skin, hepatitis, perhaps malaria, and a variety of other infections. Many problems associated with the injection of insoluble or colloidal particles often present in street 'speed' have been reported. Similar problems occur when tablets, legitimately produced for oral use only, are crushed, mixed with water and injected.8. 128 Although users may strain the drug solution through a wad of cotton or a cigarette filter as they draw it into the needle for injection, such measures are generally inadequate for this purpose and may, in fact, add impurities.

Although some users feel certain that their mental abilities have been impaired by heavy use, no clear picture of irreversible brain damage as a regular effect in human users has appeared in the literature. Several investigators have suggested that recovery from the major effects of chronic 'speed' use is slow but rather complete, requiring perhaps 6-12 months of abstinence and favourable living conditions.3. 89, 90 However, a recent study with monkeys, employing high doses within the range consumed by some chronic human users, revealed evidence of significant cardiovascular change and permanent neurological damage after only a few weeks of daily drug administration.'22 This is clearly a high priority area for further research.

The acute psychosis reportedly produced by heavy amphetamine use has received much attention recently. Many investigators contend that the condition is often indistinguishable from paranoid schizophrenia.32, 45 Prolonged lack of sleep, as occurs during a 'speed' run, by itself, has been shown to produce psychotic-like conditions.'" This led to the hypothesis that the entire amphetamine psychosis syndrome might be caused by general sleep deprivation or REM (rapid eye movement phase) sleep blockade. Although severe psychosis apparently occurs most often after heavy chronic use in previously unstable and perhaps pre-psychotic individuals,", 44, 45, 66, 69 symptoms of psychosis have been produced under controlled experimental conditions after less than two days of repeated administration in non-psychotic subjects.6, 57. 58' 59 Prolonged sleep deprivation, then, is not a necessary component of an amphetamine psychosis,46 although it probably plays a significant role in most instances. Phenothiazines seem to alleviate most of the signs of psychosis, and major symptoms generally clear up with proper rest after amphetamines are withdrawn. In some cases, however, residual symptoms may last for months after cessation of amphetamine use.45

The undoubtedly intricate causal relationships between prolonged psychiatric disturbances and chronic amphetamine use are not clear. While it is well established that high doses of amphetamines can reliably elicit or augment symptoms of psychiatric disorder as an acute effect, many investigators have stressed that a considerable degree of prior psychopathology often exists among regular 'speed' users—especially those who appear for psychiatric treatment.10, 36, 44, 45, 66, 89, 82, 97 Links between the acute symptoms of amphetamine toxicity and long-lasting psychiatric conditions in chronic users must be further explored. It is often not apparent whether existing psychopathology has predisposed certain persons to heavy amphetamine use or if the drug itself has produced the prolonged behavioural disturbances frequently observed in chronic users. Considerable interaction among these variables is to be expected. As well, we have little epidemiological information as to the proportion of even heavy users who actually develop severe psychotic or other pathological conditions. Most studies of the psychological characteristics of amphetamine users have obtained subjects as a result of their contact with treatment or law enforcement facilities and, consequently, have limited generality.

Various local surveys of physicians reported to the Commission as well as our own studies confirm the notion that medical and related services in areas with a high incidence of 'speed' use are frequently called upon to treat amphetamine-related problems—both physical and psychological. 64, 67, 104, 109, 111, 120 Generally, little is done beyond acute detoxification. Hospitalization is apparently not common. (The Federal Poison Control Program Statistics are discussed below.)

In the Commission's 1971 national survey of psychiatric hospitals, amphetamines were mentioned as a primary or secondary factor in the diagnostic records of 68 (0.3% ) of the 22,885 patients actually in residence at that time.", [6] In British Columbia, general hospitals with psychiatric wards were surveyed as well; amphetamines were noted in the diagnoses of 3 of the 293 psychiatric patients in the reporting institutions. In the national mental health data gathered by Statistics Canada, amphetamines were considered together with "other psycho-stimulants" (excluding cocaine) in a general category.26, 118, [e] Dependence on such drugs (ICD-304.6) was noted in the diagnoses of 176 (0.34%) of the first admissions and 95 (0.19%) of the readmissions to psychiatric hospitals and wards in Canada in 1970. Males outnumbered females by more than three-to-one in these data. It would appear that although various psychological and physical disorders are often noted in chronic amphetamine users, amphetamines are not presently a causal factor in a significant proportion of psychiatric hospital admissions in Canada. (See also Tables A.5, A.6 and A.7 in the Annex to this appendix.)

"SPEED KILLS"

In recent years, the slogan 'Speed Kills' has received much attention, and the idea appears to play a significant role in the attitude that some users and non-users have towards the drug. One commonly hears the view that once you're 'hooked on speed' you have only two to five years left to live. Some chronic 'speed freaks' incorporate this notion into the identity they present to others and the image they entertain of themselves. Many observers contend that the chronic use of intravenous amphetamines reflects a thinly disguised suicidal tendency, as well as an attention- and sympathy-gaining device. "Hello, I'm Philbert Desanex: I'm a speed freak and I'm going to be dead by fall," is only a slightly exaggerated caricature of the image purposefully projected by some of these individuals.

What is the evidence that 'Speed Kills' in the literal direct physical sense? Fatalities due to acute overdose are rarely documented.82. 89 We have no reliable knowledge of the extent of heavy amphetamine use, and, although we hear many dire predictions, there is no adequate information on the longterm prognosis or outcome of such use. It would certainly appear, however, that chronic adherence to this practice can be most detrimental to the individual and, often, to those with whom he interacts.

Although there is little evidence that the life expectancy of 'speed freaks' is lower than others living under similar circumstances, many investigators suspect this to be so.74 Suicide during the withdrawal phase has been cited as a risk.32 While there are few cases in the literature of death directly attributed to chronic amphetamine use, Clement, Solursh and Van Ast mention "... a number of cases of death on the street [in Toronto] apparently related to high-dose amphetamine abuse. At autopsy, however, pathological evidence of death directly due to amphetamines is rare in such cases."3° After a thorough review of the literature up to 1969, Cox and Smart of the Addiction Research Foundation reported: "Currently there is no evidence available on mortality rates among speed users and it is not certain that speed itself is a lethal drug. There is no evidence to support or deny that 'Speed Kills'."35

The Commission has investigated, in considerable detail, reports of amphetamine-related poisonings and deaths in Canada."• 105 The Federal Poison Control Program has records of approximately 600 toxic reaction or poisoning cases involving amphetamines or related stimulants in 1971.1", [f3 Of these, 296 cases were attributed to 'speed', 115 to phenmetrazine, 51 to amphetamine, 38 to dextroamphetamine and 20 to methamphetamine. Two reports of amphetamine fatalities were noted. The proportion of these cases associated with intravenous use was not indicated. Slightly more than half of the individuals were 10 to 24 years of age, and approximately one-quarter of the cases involved children under five. Overall, two-thirds of the patients were males.

Four deaths in the country were ascribed to amphetamines in the Statistics Canada Causes of death 1971 report—two were young people, and two cases involved persons over 45 years of age.25 After a search of records, the coroners of three provinces (Ontario, Alberta and British Columbia) provided the Commission with detailed reports of ten deaths thought to be related to the use of amphetamines during the years 19691971.68, [g] Only two cases were attributed directly to amphetamine poisoning or overdose. The remaining fatalities were due to hepatitis, gunshot wounds, and other accidents and suicides which were in some way associated with amphetamine use. All of these individuals were males, and eight were under 25 years of age. (Fatalities involving MDA are discussed in A.5 Hallucinogens.)

It would appear that even though large doses of amphetamines are physically toxic, these drugs rarely result in death as a direct acute overdose effect. Permanent consequences of chronic high-dose use on general physical condition, susceptibility to disease and overall longevity have yet to be fully clarified, but evidence is accumulating of detrimental effects in these areas.

DRIVING

As noted earlier, low doses of amphetamine typically result in a slight improvement in certain intellectual and perceptual abilities, reaction time and psychomotor performance. High or continuous doses likely result in detrimental effects on these functions, but there has been little direct experimentation in this regard. There is no available evidence that amphetamines have been a causal factor in a significant proportion of traffic accidents, although numerous anecdotes and case history reports have appeared in the literature. Evidence is accumulating, however, that under some conditions amphetamines may have detrimental effects on traffic safety, either through the direct effects of high doses or, indirectly, by preventing normal rest, facilitating overexertion and increasing driving exposure.87, 112, 129, 145 Further research is needed in this area, emphasizing the chemical detection of drugs in body fluids and tissues of persons involved in traffic accidents.

TOLERANCE AND DEPENDENCE

Tolerance to the various effects develops at different rates and to different degrees—some responses decline with chronic use sooner than others. The tendency to increase dose depends upon which of the potential drug effects is rewarding or reinforcing drug use. Many individuals, for instance, who use amphetamines to control narcolepsy may reach a stabilized dose and show very little need for increased quantity over a period of years. On the other hand, those using the drug to control appetite generally increase their dose since tolerance to the anorectic effect readily develops. Many psychological effects, such as the mood-elevating and stimulant response, may show a considerable sensitivity to tolerance, and individuals who either began using the drug to obtain these effects, or who acquired the taste for them after initially using amphetamines for other purposes, generally show a marked tendency to increase dose over time. Rapid tolerance reportedly occurs to the initial 'rush' following intravenous injection during a 'speed run'. Tolerance to some of the toxic properties occurs, and certain chronic users reportedly administer quantities which would be extremely toxic in a non-tolerant user. As with other drugs, the rate of tolerance development to the different pharmacological effects depends on the doses used, the frequency of administration, and various individual factors.41, 71, 81, 90

The question of physical dependence on amphetamines depends on the definition of the withdrawal symptoms necessary to meet the criterion. While it is clear that withdrawing amphetamine from chronic users does not produce as dramatic and physically distressing an abstinence syndrome as that associated with alcohol, barbiturates, or opiate narcotics, many investigators feel that the fatigue, prolonged sleep, brain wave (EEG) changes, voracious appetite, cardiovascular abnormalities, occasional gastrointestinal cramps, muscle aches and pains, lethargy and, often, severe emotional depression following the 'speed binge' constitute a physiological reaction analogous to the more dramatic withdrawal seen with depressant drugs.32, 41, 77, 93, 113, 130, 146 As one 'speeder' told the Commission, "As high as you get when you're speeding, that's how low you get when you crash."

The tendency for tolerance-producing drugs to manifest a rebound type of physiological and psychological pattern upon withdrawal has been given considerable attention: amphetamine abstinence in chronic users is generally characterized by profound sedation and depression of mood and physiological function, while drugs such as alcohol, barbiturates and the opiate narcotics (all of which produce sleep in high doses) generally exhibit a withdrawal syndrome of severe and toxic overstimulation, in some instances to the point of convulsions.

The fact that amphetamines have a physically less intense withdrawal syndrome than most other dependence-producing drugs, clearly indicates that a profound physical dependence is not a necessary component in an overall severe drug dependency situation. Subjective psychological factors seem to have considerably greater motivational importance in many instances—especially with chronic high-dose amphetamine use. While there is little evidence of any kind of physical dependence on moderate doses of amphetamines, psychological dependence on even low doses is frequently reported, and is considered by some to be a major hazard in both medical and nonmedical use.

AMPHETAMINES AND OTHER DRUGS

As noted earlier, amphetamines are sometimes used in conjunction or in alternation with a variety of depressant drugs such as barbiturates, tranquilizers, alcohol and opiate narcotics. The amphetamine and barbiturate `up-down cycle' has been described in both youthful and 'respectable' adult users at a variety of doses. Amphetamines may intensify, prolong or otherwise alter the effects of LSD, and it is reported that the two drugs are sometimes mixed. In addition, it would appear that the majority of youthful `speed' users have also had experience with marijuana and a variety of psychedelic and other illicit drugs, although many confirmed 'speed freaks' rarely consume hallucinogenic substances. Persons primarily dependent on opiate narcotics also frequently make use of stimulants such as amphetamine and, more rarely, cocaine—either as mixtures of the drugs or used separately on different occasions. In some instances, younger heroin users initially began opiate narcotics use secondarily as an aid or self-treatment for unpleasant aspects of chronic amphetamine use and subsequently went on to prefer heroin to 'speed'. (See also Appendix C Extent and Patterns of Drug Use.)

Interactions between opiate narcotics and amphetamine are complex. Physiological antagonism occurs with some responses, but not others.78 It has been reported that amphetamines may enhance the pain-relieving properties of opiate narcotics when the two are administered together." In addition, amphetamines and narcotics together may have significant antidepressant properties.°4 In rodent studies, cannabis has been shown to intensify amphetamine stimulant activity, but also to reduce acute amphetamine lethal toxicity.48' 141 Interactions between amphetamines and drugs of the alcohol-barbiturate type are complicated. Under certain circumstances amphetamine may antagonize some of the effects of sedative drugs, including their lethal toxicity. In other areas however, the drugs may have additive effects. Amphetamines can reduce some of the symptoms of alcohol hangover.7. 88, 183'116, 127, 149

Antagonists

Numerous compounds which antagonize various effects of amphetamine are currently being developed and investigated for possible use in the treatment of amphetamine dependence. Amphetamines produce a variety of central and peripheral effects and compounds which inhibit some responses may produce little change in others.

Alpha-methyl tryosine (« MT) has been shown to reduce the central stimulant and pleasurable subjective effects of intravenous amphetamine. 48, 62, 79, 135 In one recent series of studies employing intravenous doses of amphetamine (up to 200 mg), prior administration of 2 gm of a MT reduced self-rated amphetamine euphoria by 50%, and 4 gm almost eliminated the subjective effects entirely.", 61 The response to phenmetrazine was reduced as well. The duration of the amphetamine blockage was 24-48 hours. Tolerance to the antagonistic effects of a MT rapidly develops if it is administered daily, but significant tolerance does not occur (and amphetamine blockade is still maintained) if the drug is given in sufficient dose at two-day intervals. Other than some feelings of slight sedation, no major side effects with a MT were reported. There was no indication that the drug was interfering significantly with normal autonomic nervous system functioning. Further research on the effects of chronic high-dose a MT administration is needed. [+7

Other drugs which have been shown to block certain aspects of the amphetamine response include fenfluramine, methysergide and certain major tranquilizers such as chlorpromazine and pimozide (but not reserpine).15, 46, 62, 89, 140, 144 The recent development of immunoassay methods for the detection of amphetamines in body fluid raises the possibility of using similar antibodies to inhibit amphetamine effects in the living organism." However, immunization approaches to amphetamine antagonism could be complicated by the close chemical similarities between amphetamine and certain natural hormones in the body such as adrenalin.
Even if effective antagonists were found for the subjective effects of amphetamine that reinforce its use in humans, such compounds might well have no effect on the action of other readily available stimulants (such as methylphenidate), which have quite different chemical structures and possibly other mechanisms of action.125