Drug Abuse

Dealing with Drug Abuse

A Report to the Ford Foundation

THE DRUG ABUSE SURVEY PROJECT

STAFF PAPER I

The Drugs and Their Effects

by James V. DeLong

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A Primer on Psychopharmacology

Drugs of Abuse

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A PRIMER ON PSYCHOPHARMACOLOGY

Psychopharmacology, as the term is used here, refers to the study of the interactions of drugs with the central nervous system (CNS), including physical, behavioral, and subjective effects. The term is not always used so broadly; we have chosen a comprehensive definition because this brief paper is neither detailed enough nor sophisticated enough to require the fine divisions implied by more exact categorization into such subspecialties as neurophysiology, neurochemistry, neuropharmacology, psychopharmacology, neuropsychology, and so forth.

As will become obvious, there are many areas in which basic knowledge about the mechanisms of action of psychoactive drugs does not exist. Our purpose here is to describe for laymen the framework within which such knowledge must be sought, and the difficulties involved.*

* Since this paper was written by a layman for laymen, technical terms and discussion have been avoided as much as possible. In most cases where extended discussion would have to be highly technical, the conclusions of experts on the present state of knowledge are set forth with a citation to the discussion leading to these conclusions. Drs. Avram Goldstein, Norman Zinberg, Andrew Weil, Frederick DiCarlo, and Alan Green all read earlier drafts of this paper. They prevented some embarrassing errors, but they are not to blame for any that remain.

THE NERVOUS SYSTEM I

The nervous system is composed of millions of nerve cells (neurons) that are by no means homogeneous in structure. Some are very long, even up to several feet; some are bushy, with -many fibers reaching out to connect with other nerves; some are small and simple. The cells do not interlock with each other at the ends, where the impulse is transmitted from one to another. There are, instead, microscopic gaps, called synapses, between them, which must be bridged by the impulse.

There are several ways to categorize the parts of the nervous system, each useful for different purposes. One division is between the CNS-the brain and spinal cord-and the peripheral nervous system, which is everything else. The peripheral system is composed of nerve fibers extending out from cell bodies contained within the CNS and, to some extent, of cell bodies clumped outside of it but, of course, still connected. While the peripheral system has groups of fibers (nerves) and groups of cell bodies (ganglia), it is simple compared to the CNS, which consists of millions of tightly packed neurons, fiber groups (tracts), and clumps of cell bodies (nuclei) with billions of synapses.

The psychoactive component of the effect of drugs is due to their effects on the CNS rather than on the peripheral system, and it is the CNS with which we are concerned. The peripheral system is relevant only insofar as research into the mechanisms of peripheral action casts light on the workings of the CNS.

Another way of dividing the nervous system is by function. The somatic system includes both the central and the peripheral neurons that convey impulses from the sense organs, organize them in the brain, and deliver motor impulses to the skeletal muscles. The autonomic system governs the smooth muscles of the intestines, urogenital tract, and blood vessels; the heart muscles; and the endocrine glands. In short, the somatic system controls the body's response to the external environment; the autonomic system governs the internal environment.

The autonomic system is further subdivided into two parts. The sympathetic system generally mobilizes bodily resources for action-it constricts visceral blood vessels so that more blood is directed to muscles and brain, accelerates the heart beat, inhibits intestinal and gastric activity, widens the pupils of the eye, and secretes adrenaline The parasympathetic system is the antagonist of these effects. It acts to conserve bodily resources, usually by having effects that are the reverse of those of the sympathetic system. The parasympathetic system is more specific than the sympathetic, however. While the latter tends to act diffusely, causing all the effects at once, the parasympathetic system can act independently on different organs.

The differentiation between autonomic and somatic systems is clearest at the periphery of the nervous system. As one traces the systems toward the CNS, the distinction becomes more vague. In the main trunks of peripheral nerves, for example, the fibers of the different systems are bound together and can be separated only by tracing them to their terminations or on the basis of some differences in fiber types. Within the CNS centers, division of functions is always a matter of degree rather than of complete specialization. While some centers are concerned primarily with somatic or with autonomic functions, the two are always closely coordinated, and the separation is not complete.

The CNS itself is not, of course, a random melange of heterogeneous neurons. There are many different and identifiable parts to it-medulla, pons, cerebellum, midbrain, reticular formation, thalamus, optic tract, cerebral hemispheres, basal ganglia, and so forth. For some of these, the functions are fairly well established; for others, they are not. To try to describe these would be far beyond the scope of this appendix. For our purposes, it is enough to state the following propositions:

• There is much specialization within the CNS, in that a particular part will have a specific and identifiable function. (For example, the thalamus is a relay station, with impulses arriving from lower centers and being passed on to higher ones; the hypothalamus has the primary control over autonomic functions; the cerebral cortex contains the more complex psychological functions; and so on.)
• Each part consists of packed nerve cells with many connections to each other and to different parts of the brain.
• Many, if not all, functions involve more than one CNS center.
• It is easier to study motor or sensory functions, where CNS activity can be correlated with an output, than to study pure cognitive functions, where it cannot.

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PROBLEMS IN STUDYING THE CNS

The study of the CNS is extraordinarily difficult. As Kenneth Moore states, "The human brain contains a complex of millions of nerve cells that are anatomically independent but functionally interconnected. An impulse starting in one neuron can propagate throughout the nervous system over a variety of pathways. The route taken is determined by the inborn organization of the brain and by ongoing events that, because of neural plasticity, can establish new circuits."' Obviously, the number of permutations possible in such a system would make study difficult, even if no other problems existed. Moore, however, goes on to list some of the major impediments to research on the CNS:

• Many ideas about neural functioning derive from study of the peripheral system, where most synapses are well defined in that only one synapse exists at a particular point. In the CNS, the cell bodies are covered with synapses. They are also closely packed among other cells (the glia), which may perform some neural functions even though they are not neurons.
• In each peripheral synapse only one chemical transmitter is thought to act. Each CNS nerve cell may be affected by several different transmitters. [Transmitters are discussed on pp.67-68.]
• Neural reactions occur in milliseconds and are hard to find and measure.
• The biochemical processes involved in peripheral systems can be studied in test tubes (in vitro) where tissue slices can be made to react. This is not true for studies of the brain, because brain neurons in vitro are in a resting state, disconnected from the other neurons that ordinarily determine their activities. While artificial stimulation can be applied, there is no way of knowing whether this corresponds to actions in the body. In particular, it is difficult to relate any in vitro reactions to such higher functions as thought or emotion.
• Because the different units of the CNS have different functions and anatomies, the biochemical reactions of any particular part are probably not the same as those of any other part.
• There is a unique blood-brain barrier between the blood and the brain that makes chemical manipulation of the CNS via injection into the bloodstream more difficult than is manipulation of other tissues. [The capillaries in the brain are somewhat less permeable than the capillaries elsewhere in the body.]
• The synapses are so densely packed that chemical manipulation by administration directly to the brain is much more difficult.
• Some brain structures are not accessible in a live subject because they are surrounded by other structures. If it is not useful to study them in vitro, and one cannot study them in situ, it is rather difficult to study them at all.
• When experiments are carried out in a live subject it is often necessary to stop a chemical reaction quickly so as to preserve the tissue at a particular point in the process. This is usually done by rapid excision and immersion in a low-temperature liquid. Since the entire CNS is surrounded by bone, it is difficult to perform this operation quickly enough. Some chemicals present in vivo may never be identified because they are destroyed too quickly.'

This represents a formidable list of difficulties. And, since psychoactive drugs are usually fairly specific to the CNS-in that they affect the CNS without having much effect on other body systems-it is easy to see why knowledge of their sites and mechanisms of action is less than complete, despite intensive study during the past several decades.

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THEORIES OF PSYCHOACTIVE DRUGS

The present theory about the manner in which psychoactive drugs operate is that they affect the transmission of the nerve impulses across the synapses. This hypothesis is based upon more general theories concerning the chemical nature of this transmission. Researchers know that in a peripheral system certain chemical substances (acetylcholine in the somatic system and norepinephrine in the autonomic) are associated with the stimulation of nerve impulses. These substances can also be found in the CNS and appear to be correlated with activity levels there.

Because nerve impulses are thought to be electrical in nature, the theory of their effect is as follows: A nerve impulse that reaches the synapse of a particular neuron stimulates the release of a particular transmitter substance. This substance affects the receptors of the adjoining nerve cell (the postsynaptic neuron), changes its electrical potential, and triggers an impulse within it. Most of the transmitter substance is taken back into the neuron from which it came, although some of it is destroyed by enzymes or diffused by the blood. The postsynaptic nerve then returns to its original state.

Psychoactive drugs may affect this sequence by stimulating or inhibiting the production of the transmitter substance, by causing its release from storage, by affecting the process by which it is taken back into the neuron, or by stimulating or inhibiting its destruction. These processes have an effect on the level and type of activity in the CNS and a consequent effect on the perceptions and activities of the body.

Beyond this, it is difficult to say anything with much certainty. Some psychoactive drugs are associated with increased CNS levels of particular substances that are thought to be transmitters, but the causation is not firmly established. Mandell and Spooner have pointed out that the evidence for transmitter theory is in many ways startlingly indirect.' Their final comment is: "Even on a neurochernical level, we must talk about empirical correlates of behavioral states. Rigorous establishment of the transmitter or modulator role of brain substances appears to remain for the future."

The strongest evidence that a particular substance has transmitter functions concerns acetlycholine Wh). Neurons sensitive to this substance are distributed throughout the brain, so that it can have excitatory or inhibiting functions, depending on the region. ACh is difficult to study, because it does not pass the blood-brain barrier easily and is destroyed rapidly after artificial administration. Its effects on certain cells in the spinal cord have been studied, but not much is known about effects at other synapses in the CNS. There is also fairly good evidence that two catecholamines-norepinephrine (NE) and dopamine (D)-perform transmitter functions. Again, however, much of what is thought about their action is derived from research with the peripheral system, and conclusions must be approached warily. NE and D, together with their degrading enzymes, are also located in various regions of the brain.-'

Some researchers believe that 5-hydroxytryptamine (5-11T), often called serotonin, is also a transmitter, but the evidence is not as strong as for the substances already discussed. As Moore states, "Despite years of active investigation, the functional significance of this amine remains obscure."' The substance may excite, depress, or have no effect on neurons, but the reasons for the differences are not known. It has no functions in the peripheral system and is thus even more difficult to study than the other possibilities.

A number of other substances may be transmitters, but the evidence is ambiguous. For example, the brain contains a relatively high concentration of free amino acids, some of which may have transmitter functions. And there are a number of other possibilities, such as histamine, substance P, Prostaglandins, and ergothioneine.

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MECHANISMS OF DRUG ACTION

Even if the transmitter theory were certain and a connection between transmitters and psychoactive drugs proved, there would be the problem of understanding the mechanisms by which the drugs affect the transmitters. This problem relates to the more general pharmacological question of the manner in which drugs affect cells and to the basic pharmacological concept of receptor sites:

. . . most drugs are thought to produce their effects by combining with enzymes, cell membranes, or other specialized functional components of cells. Drug-cell interaction is presumed to alter the function of the cell component and thereby initiate the series of biochemical and physiological changes that are characteristic of the drug....

The cell component directly involved in the initial action of the drug is usually termed ... its receptor.,

In its simplest form, the receptor-site theory is that, at the basic site of action of any drug, there are cells or cell surfaces that form molecular bonds with the drug molecules. Current theory is that these sites are stereospecific-it is not only the chemical composition of the drug that determines whether the receptor can bond with it but its three-dimensional geometric shape as well. A cell surface might have, for example, three or four different points of contact where different molecular bonds could be formed. A drug molecule must have a geometric shape that allows proper subgroups of the molecule to come in contact with these points for the formation of a firm bond.

This theory of stereospecificity explains why drugs that are diverse in chemical structure may have similar effects (e.g., morphine, methadone, and meperidine). Even though chemical structures are different, geometric structures can be similar. In contrast, variations of the same substance with similar chemical structures but different geometric structures may not have similar effects.'

The classic assumptions of receptor-site theory are: (1) One molecule of drug combines with one receptor site, (2) a negligible fraction of the total drug is combined, and (3) the response of the body to the drug is directly related to the proportion of available receptor sites that are occupied.

The interaction between drugs and cells is governed by the law of mass action. The molecules of a drug are constantly associating with and dissociating from receptor sites. At some point, for any given drug concentration, an equilibrium is reached where association and dissociation balance. The drug-receptor interaction, therefore, is dynamic, not static. Since most drug-toreceptor bonds are thought to be relatively weak ionic bonds that are readily reversible, this concept of dynamic interaction becomes important in understanding the process of antagonistic effects, blockade, and reversibility of drug action. All are based on theories about differences in the strength of bonds formed by different drugs and on competition for receptor sites.

Since these basic assumptions do not, however, explain all the observed phenomena of drug action in many cases, including the action of narcotic analgesics, various departures from the basic occupancy assumption have been suggested. The most important are (1) that not only occupation of the receptor sites matters but also the intrinsic "efficacy" of the drug; (2) that it is not the occupancy of the site that matters but the act of occupying, and that drug effect depends on the relative rates of association and dissociation, and (3) that there are spare receptors that may be occupied, although at a lower level of efficiency, when the primary receptors are already occupied. These explain some of the otherwise unexplained phenomena, but they leave other, different mysteries of their own.' Nor are these questions likely to be settled soon.

There are two ways to gain information about a receptor. The first and only really satisfactory approach is to identify and isolate it. Then the investigation can follow established biochemical and physicochemical procedures. Sequence analysis can establish the primary structure of the macromolecules. Techniques like x-ray crystallography, high-resolution electron micrography, spectrophotometry, and analytical ultracentrifugation can yield data from which the secondary and tertiary structure may be deduced.

In the case of proteins, recent years have seen the elucidation of complete primary structures at an ever-increasing rate....

The second way of obtaining information about receptors is indirect. It has dominated pharmacologic research in the past. The approach is to draw inferences about a receptor from the biologic end results caused by drugs. A powerful tool employed toward this end has been the study of structure-activity relationships (abbreviated SAR). A suitable biologic effect of a drug is chosen for study. A prototype drug, which elicits the characteristic effect, is then modified systematically in its molecular structure. Substituents are added or subtracted at various positions and in different steric configurations. A series of such chemically related drugs is known as congeneric series. By testing the members of a series and observing how biologic potency is affected by each molecular modification, one may ultimately draw conclusions about the precise mode of combination of a drug with its receptor surface.10

Unfortunately, the study of psychoactive drugs belongs in the second category. No one has found the receptor sites or knows which cells might be involved. Concerning narcotic analgesics, Goldstein says, "It must be remembered . . . that the receptor, whose structural features are inferred from the SAR studies . . . is entirely hypothetical."11

Finally, theories of action at the receptor site say nothing about the biochemical events in the CNS that constitute the eventual product of the interaction of the drug and the receptor site. "Investigations of the mechanism of tolerance and of the mechanism of narcotic action have been hampered by the same difficulty-that the biochemical alterations produced by the drug in the whole brain are unlikely to have much to do with the specific biochemical changes that are responsible for the drug effects at the sites of drug action."12

Jaffe makes a similar point. After reviewing the various theories and experiments on the effect of opiates on cerebral neural action, cerebral metabolism, and neurotransmitters, he says:

... Unfortunately, knowledge of the functional role of the several postulated neurobumoral transmitter agents in the CNS is still so limited and controversial that the demonstration of an effect of morphine on them has not yet contributed significantly to an understanding of either the neurophysiological and behavioral effects of the drug or its mechanism of action .13

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DRUGS OF ABUSE

OPIATES

The Drugs." Opium is a natural substance derived from one variety of the poppy plant. It contains over twenty different alkaloids with varying properties, constituting 25 per cent of opium by weight. A few of these-primarily morphine and codeine are medically useful.

In discussing opiate abuse, the specific drugs of concern are the following:

Morphine is a natural alkaloid constituting 10 per cent by weight of the raw opium.

Heroin. Because heroin is produced by chemical treatment of morphine with acetic acid, the technical name for it is diacetylmorphine. In terms of analgesic effect, heroin is a little over three times as potent as morphine-for example, it takes three milligrams of heroin to produce the same analgesic effect as 10 milligrams of morphine.

Although heroin is the principal opiate of abuse in the United States, most research has been done with the more readily available morphine. In the opinion of experts, such research is applicable to heroin if the dosage difference is considered, because heroin rapidly breaks down into morphine in the body. Thus, its subsequent pharmacological action is the same.

Methadone is a synthetic opiate of approximately the same strength as morphine.

Meperidine is another synthetic opiate that is about 10 to 20 per cent as potent as morphine. It is better known under its trade name, Demerol.

While all four drugs are analgesic, euphorigenic, and in many ways fungible, there are some differences among them, particularly in maximal effect and duration of action. Throughout this paper, morphine is the primary subject. Important differences in the characteristics of the other opiates are discussed where relevant.

Because of lack of information, two topics are not discussed. First, it should not be assumed that the effects and characteristics of raw opium are the same as those of morphine. It has been suggested that the mixture of many different alkaloids in opium may have substantially modifying effects on the action of any individual alkaloid, such as morphine.15 This is unproved; but-since the medical use of crude opium ended in the Western world soon after 1850-there are no data either way. Secondly, it is possible to produce drugs from crude opium that are stronger than morphine. For example, some derivatives of thebaine, a nonanalgesic opium alkaloid, may be one thousand times more potent.16 The effects of such superpotent opiates have not been studied and might differ qualitatively from those of morphine.

Medical Uses. In the late nineteenth century, opium and morphine were sometimes referred to by physicians as "GOM," "God's Own Medicine." They were used for asthma, dysentery, alcoholism, and a wide variety of other diseases-including the simple cough." In fact, the opiates are effective cough suppressants, constipants, and tranquilizers, and, in an era lacking other drugs, their heavy use was natural.

Today, however, since there are drugs without the addictive potential of opiates that are equally, or nearly as, effective for most of these purposes, the medical use of opiates has become less common. Yet, the opiates are still the most effective pain-killing drugs known to medicine, and large quantities of morphine and meperidine are used as such every year. Although there is a continuing search for equally effective nonaddictive pain relievers, none has been found, and it may be that none will be. For a time, some of the narcotic antagonists were believed to have the desired properties; more recently, pentazocine was thought promising. But the latest evidence indicates that the analgesic qualities of these drugs are due to properties that also cause addiction.

Physical Effects and Toxicity. The exact method by which morphine blocks pain is unclear. It does not appear to block the transmission of the pain impulse through the nerves (as do local anesthetics), because sensation and feeling are not affected. For example, someone heavily dosed with morphine will still be able to feel a touch or other relatively slight sensations. In addition, experiments have shown that a patient, even after being given morphine as a pain reliever, can accurately determine the amount of pain he would be suffering without the drug. What seems to change is the relationship of the subject to the pain. Although he feels the pain and can tell how great it would be without the drug, he is not "bothered" by it. For these reasons, it is thought that the drug acts in the part of the brain that interprets the nerve message."

For a nontolerant individual, morphine is highly toxic. A dose of 100 to 200 mg. would be sufficient to cause a fatal respiratory depression. This, like the analgesic effect, is a consequence of the effects of the drug on the CNS rather than on other parts of the nervous system-morphine reduces the responsiveness of brainstem respiratory centers to concentrations of carbon dioxide."

Tolerance to the respiratory effect increases rapidly, and no researcher has yet found an absolute limit to the quantity of morphine that can be taken by a tolerant individual without causing death. Some persons have been known to take as much as four grams of morphine without adverse effect."

No one has discovered long-term organic damage caused by morphine. In autopsy, neither gross nor microscopic examination of tissues shows evidence of such effects." Various studies have followed the medical history of addicts over a substantial period of time, and, according to one of the studies, "while there is ample evidence that the aberrant way of life followed by most heroin abusers has both acute and chronic medical consequences . . . there is insufficient scientific basis for maintaining that long-term use of opiates-in and of itself-is related to any major medical condition.""

Addicts do, however, suffer from a variety of conditions ancillary to their general life-style and frequently die of viral hepatitis, bacterial infections, or other diseases. The death rate of the addict population is not known, but it is usually estimated as about 1.5 per cent to 2 per cent per year." Malaria used to be common among addicts, until dope sellers began using quinine to cut heroin. Other deaths are often attributed to an overdose of heroin sufficient to cause respiratory depression. The possibility of an overdose is always present, because the quality of street heroin so varies that an addict may not know how much pure heroin he is getting in any purchase or even how much he is used to taking.

Nevertheless, several experts have stated that overdose and disease do not explain all addict deaths." In many cases, the dead addict did not receive more heroin than he was used to or should have been able to take, given his pre-existing level of tolerance. It is possible that some people have a special sensitivity to heroin that takes the form of an idiosyncratic response to a single dose or that is analogous to an allergic reaction triggered by repeated use. However, there are no reports in medical annals of persons having this reaction after receiving morphine in a medical setting. Since morphine is used extensively in medicine, it would be expected that such a serious effect would have been observed by this time. But there are also some reports of an unusually high death rate in England, where addicts receive pure heroin. The English data on this are incomplete, however, and the causative factors have not been adequately analyzed.

Morphine does cause some physical effects, of uncertain significance. There are changes in excretion of epinephrine and norepinephrine. Rapid-eye-movement (REM) sleep is depressed. Stabilized addicts become hypochondriacal, apathetic, and bored with other people and have fitful sleep." Whether these responses signify permanent change or damage, however, is not clear.

In all animal species, including man, morphine has an excitatory effect as well as an analgesic one. This pattern is not unique to morphine; it is also true, for example, of barbiturates and alcohol. The reasons are not well understood. The effect could be due to be a difference in the speed with which the drug affects different CNS centers, with certain inhibiting centers being affected first. Or some CNS centers excited by the drug may react first, with the response subsequently suppressed by later-reacting centers. Various animal species, however, react to morphine in different fashions. The predominant effects in monkeys, dogs, rabbits, and rats, as well as in man, are sedative, while in horses, cats, and mice they are excitatory.

Man is considerably more sensitive to the effects of morphine than are most other animals. For example, the effective analgesic dose for a man is about 0.2 mg. of morphine per kilogram of body weight. In a dog it is at least ten times as high." This raises a number of questions about the meaning of animal experimentsspecifically, about the relative importance of direct physical (as opposed to psychological or psychoactive) consequences of taking the drug.

The opiates vary in several ways affecting consumer preferences, abuse potential, and the ability of an addict to stabilize his dosage and lead a relatively normal existence. The major elements of variance are as follows:

Peak effect. This is usually calculated as the maximum analgesic effect that can be obtained from a given dose of the drug as measured by the ability to relieve pain. Sometimes euphoric effect is measured directly through the observation of physical correlates of drug taking or through verbal responses to tests designed to determine the degree of euphoria. It is generally assumed, although not indisputably proved, that the peak of analgesic effect and the peak of euphoric effect are the same.

Duration of action. This is a more diffuse concept, because it could mean the duration of relief of a given amount of pain or the duration of the peak effect. Generally, as used in the sources, it seems to mean the length of time after administration before the drug user begins to feel withdrawal symptoms. Sometimes, however, the phrase "duration of analgesic action" is used. The exact meaning of this term is not clear, since it would seem to depend on the level of pain to be relieved. Empirically, it seems to be about the same as the generally accepted "duration of action" to withdrawal.

Method of administration. All opiates can be taken orally, subcutaneously (by injection under the skin), intravenously (by injection into the vein), intramuscularly (by injection into the muscle), or through the nasal passages. The effects will differ somewhat, depending on the method used. In addition, the effect of different methods of administration varies with the drugs. For example, when taken orally, methadone retains its efficacy more than morphine.

Potency and power. The power of a drug is defined by the upper limit of the absolute effects it can produce. The potency of a drug relates to the dosage that is necessary to produce a given effect. Thus, heroin is not more powerful than morphine, because both can produce the same effects; but it is more potent, because it produces equivalent effects at lower doses. Viewed narrowly, potency might seem of little significance medically, because one could always give more of the less potent drug. Few drugs, however, are so specific that they have only one effect, and the differences in potency may not be uniform for all effects. For example, morphine is an analgesic producing a side effect of nausea. Heroin is a more potent analgesic, but this does not mean, necessarily, that it would be more potent in causing nausea.

As stated above, potency of an opiate is measured in terms of analgesic effects, and this is thought-and only thought to equal euphoric effect. But, given the lack of knowledge about the mechanisms by which opiates work, it is not impossible that the various drugs affect different CNS centers in various ways, and that therefore qualitative variations occur in psychoactive experiences. Also, superpotent opiates, such as the thebaine derivatives, might have distinct effects that have not shown up in comparisons of existing drugs.

Although the basic facts about the opiates are not entirely clear, the following facts are known: "

Morphine, taken subcutaneously, has its peak effect in one half to one hour. Its duration of analgesic action is four to six hours, and the decline from the peak is rapid. When it is taken intravenously, the peak effect is reached sooner and is somewhat greater. Morphine is effective when taken orally, but the peak effect is much lower-perhaps only 20 per cent to 30 per cent of the subcutaneous peak. The duration of action of oral morphine is at least twelve hours and may be as long as twenty-four.

Heroin is generally thought to act about the same as morphine. Some animal experiments, however, indicate that heroin crosses the blood-brain barrier more quickly than morphine. If this is true for humans, its peak would come more rapidly than the morphine peak. Addicts sometimes cannot distinguish between heroin and morphine when they are injected subcutaneously; most are able to do so, however, when the drugs are taken intravenously.

Methadone, taken subcutaneously, has a peak effect in three hours and a duration of analgesic action of about twelve hours. When methadone is taken orally, the peak is about 70 per cent as great and occurs after four hours. Duration of action after oral administration is around twenty-four hours, and the decline from the peak is slow. Intravenously injected methadone peaks almost immediately, and the duration of action is lessened accordingly.

Subcutaneous meperidine has a duration of analgesic action of only two to four hours, and the peak is reached in less than an hour. With oral administration, the peak is about 50 per cent as high. Intravenous administration lessens the time needed to reach the peak effect. Addicted medical personnel, who have ready access to meperidine, tend to prefer that drug to the other opiates, possibly because of its fast action and relatively high potency when taken orally. The dosages of the different drugs required to produce the same peak effect when administered subcutaneously are: morphine-10 mg.; heroin-3 mg.; methadone-10 mg.; and meperidine-80 to 100 mg.

Addiction. Three aspects of opiate use are particularly important to an understanding of addiction and its consequences: (1) the nature of the euphoric psychoactive effect; (2) the development of tolerance to the drugs; and (3) the development of physical dependence, with physical withdrawal symptoms, when the drug is removed.

Psychoactive Eflects. Opiates cause a mental clouding characterized by drowsiness, an inability to concentrate, lethargy, and reduced visual acuity. As was mentioned before, stabilized addicts may be hypochondriacal, withdrawn, bored with other people, and less motivated. Opiates, however, do not cause slurred speech or significant motor incoordination." In some persons, they produce a very pleasant euphoria, but this reaction is not universal. Many people find that dysphoria, consisting of mild anxiety and fear, results instead and may be accompanied by such unpleasant effects as nausea and vomiting. Dysphoria is extremely common at first use, even among those who eventually become addicted; indeed, to attain euphoric effects at first may be an atypical response. In some subjects, the initial response is a desire to engage in increased activity."

Goldstein states:

It is well known . . . that most people react with extreme displeasure to an initial dose of an opiate narcotic, both nausea and dysphoria being common responses. It was once supposed that administration of opiates in legitimate medical practice might "create" addicts. There is no valid evidence of this claim, although it is true that the incidence of addiction is high in the health professions, where there is easy access to addicting drugs. It is quite obvious, however, that of the many millions of patients who receive morphine, an insignificantly small fraction ever seek to take the drug again. Likewise, in the population as a whole, very few of those who could obtain morphine or heroin illegally, if they wished, become addicts.30

Despite this, people start taking opiates because they like or expect to like the effect. It is not known whether those who become addicts have a different response to the initial use, experiencing some atypical internal metabolic change, or whether they simply have more persistence.

For those who find that they have an affinity for the drug, the euphoric effect is very powerful, although its exact nature is almost indescribable. This effect can be divided into two parts. The first part is the "rush"-the initial impact of the drug on the nervous system. This appears to occur only when the drug is taken intravenously, and not when it is taken orally or subcutaneously. Sexual images are frequently used to describe this effect: "It was like a huge orgasm"; "It was like coming from every pore." The second part is the follow-up sensation of being "high." Describing this is more difficult, however, for there is no common experience from which a pattern can be drawn. Basically, the effect appears to be that of an emotional analgesic, suppressing anxiety and care, although the analgesia is not a mere deadening of emotion. On the contrary, it can be a profoundly heightened sense of well-being. Whether everyone who persisted in opiate use would attain this euphoric state, or whether such a state is a selective reaction based on psychological factors, remains an unanswered question. There is no model of the addict personality as such that satisfactorily distinguishes between users and nonusers; nor is the psychic explanation the only one available. Some researchers believe that opiate addiction has a physiological basis, and that the attempt to find psychological variables is therefore pointless. The varying theories on this subject are discussed in the last part of this section.

Tolerance. A person can become accustomed to a drug's effects and thus require steadily larger doses to produce a constant effect. This phenomenon is common with many drugs in pharmacology, not just drugs of abuse. Tolerance is not the same as physical dependence and often occurs without it. It is an important aspect of opiate addiction, because the addict's need to take steadily larger doses to achieve a euphoric effect elevates the cost of his habit, causing increased criminal activity and presumably increasing any long-term toxic effects that may exist.

Tolerance does not always develop uniformly to all aspects of a drug's action. For example, while tolerance in time develops to the sedative effects of barbiturates, the amount needed for a lethal dose remains constant. On the other hand, tolerance seems to develop to all the major effects of narcotics. It "is characterized by a shortened duration and decreased intensity of the analgesic, sedative, and other CNS depressant effects as well as by a marked elevation in the average lethal dose."" As observed in the section on toxicity, limits on tolerance have not yet been determined.

Tolerance takes two forms. First, the body to some extent may increase its ability to metabolize or excrete the drug. While this has not been shown to be directly the case for the opiates, it has been shown that brain morphine levels become lower in tolerant than in nontolerant animals eight hours after drug administration. Secondly, constant brain levels of morphine will produce less effect in tolerant than in nontolerant animals, indicating that there must be some form of adaptation within the CNS at the cellular level. These two forms of tolerance are called "drug disposition" and "metabolic tolerance," respectively. Several theories have been developed to explain them-they are too complex to discuss here-only to come to the same conclusion, namely, that "the precise mechanisms underlying these two forms of tolerance to narcotics are not known.""

In a study of drug addiction as a social problem, an important issue is the speed with which tolerance develops. If, for example, tolerance develops rapidly, then whenever an addict increases his dose for a few days-or possibly even for a day-he will become tolerant to the increased dose and must therefore maintain at least that level of habit from then on to avoid withdrawal symptoms. Experimental evidence indicates that tolerance does develop rapidly. Human subjects have been brought to a level of 500 mg. of morphine within ten days. Tolerance to morphine begins with the first dose administered and builds rapidly; tolerance to heroin lags for a few days, then follows the same course. In animal experiments, it has been found that a dog, when given morphine continuously for eight hours, will begin to recover from behavioral depression by the end of that time, indicating a rapid development of tolerance to a given concentration of morphine in the body."

It is not clear whether tolerance increases arithmetically or geometrically. For example, although a nonaddict might find 100 mg. of morphine fatal, none of the sources indicates whether a dose of 200 mg. would be fatal to an addict who was already taking 100 mg. per day, or whether a dose of 600 mg. would be fatal to an addict on 500 mg.

Another important question is how long tolerance lasts after an individual has been abstinent for a time. Generally, it is believed that tolerance disappears when the drug taking stops. There are numerous street stories to the effect that addicts will voluntarily detoxify themselves to the point where their habit becomes such as to be economically supportable. Yet, in one classic experiment rats were found to retain substantial tolerance to morphine for almost a year after the last administration of the drug."

The final important aspect of tolerance is the phenomenon of cross@tolerance between drugs. Morphine, heroin, methadone, and meperidine are at least partial substitutes for one another, and tolerance to one confers tolerance to equipotent doses of the others.

Physical Dependence and Withdrawal. The term "physical dependence" or "physical addiction" means that an organism requires a drug for "normal" physical functioning. Abstinence will result in physical symptoms of varying types and severity until the body adapts to the new state. The term "addiction," however, is eschewed by experts in the drug-abuse field. Since drug abuse is dependent on an intermixture of physical and psychic variables, and since drugs of abuse are often used in such low doses that the degree of actual physical addiction is questionable, experts feel that it is more correct to use the terminology "drug dependence of the morphine type" or "drug dependence of the barbiturate type."" Even the withdrawal symptoms developed by abstinent users may be psychogenic in origin. In addition, users of drugs that are not powerfully addictive physically (e.g., tobacco) sometimes have a more difficult time in abstaining from use than do users of addictive drugs. For these reasons, it makes some sense to blur the distinction between physical and psychological dependence when discussing drug abuse as a social problem.

This should not induce the belief, however, that there is no such thing as physical addiction or physical dependence. Clearly, an opiate user becomes physically dependent in the sense that abstinence will cause severe and well-documented physical symptoms. These include restlessness and drug craving, followed by yawning, lacrimation, runny nose, perspiration, fever, chills, vomiting, panting respiration, loss of appetite, insomnia, hypertension, general aches and pains, and loss of weight. The intensity can be "nearly unbearable" if the dosage is high enough."

Several researchers have commented that withdrawal from opiates-as well as from barbiturates and other hypnotics-is characterized by rebound hyperexcitability; that is, during withdrawal, the physiological systems that were depressed by the drug are in a state of increased excitability. It is not clear, however, whether all withdrawal symptoms are rebound effects, or whether this is a general,rule applicable to other drugs as well."

Withdrawal from the various opiates has been studied scientifically. As a general rule, the intensity and duration of the withdrawal symptoms are related to the intensity and duration of the drug's action. Thus, morphine withdrawal starts within a few hours (four to ten, depending on the user's tolerance level), peaks rapidly (around the second day of abstinence), then declines sharply. Most of the obvious symptoms disappear within seven to ten days. Meperidine withdrawal reaches its peak in about twelve hours and lasts only four or five days. In some ways, however, its peak intensity is greater than that of morphine withdrawal. Withdrawal from methadone follows a slower course. No symptoms appear until about the third day. After this, they increase steadily until between the sixth and the ninth day, when they peak at a level less than two-thirds as intense as the peak for morphine withdrawal. Thereafter, they decline slowly, not disappearing until after about two weeks. The maximum intensity of methadone withdrawal is always tolerable, but its duration may be the factor that causes some addicts to regard the withdrawal from methadone as nastier than the withdrawal from morphine."

The disappearance of the gross symptoms does not mean, however, that the withdrawal is complete. Increasingly, researchers are finding some effects that persist for many weeks longer, and empirical observations show that the relapse vulnerability is greatest immediately after withdrawal. Dr. William Martin divides the abstinence syndrome into early and protracted abstinence. In human experiments, subjects were stabilized on 240 mg. of morphine, then withdrawn slowly over a period of three weeks. They showed the general withdrawal symptoms discussed above, although in milder degree than occurs after sudden withdrawal. The symptoms persisted to some extent for six to nine weeks. After this, the protracted abstinence syndrome emerged, characterized by minor physical differences that persisted through the twenty-sixth week of withdrawal. The clinical significance of this is not clear, for it has not been proved that protracted abstinence contributes to readdiction. But careful experiments with rats have shown that postaddict rats have a greater liking for narcotics than do rats that have never been addicted. This preference lasts four to six months after withdrawal."

While no limit on the development of tolerance to opiates has been found, there does seem to be a limit on the degree of physical dependence that can be developed, as measured by the intensity of the withdrawal symptoms. For morphine, this maximum is reached at dosages of around 400-500 mg. per day; higher doses do not result in more intense withdrawal symptoms."

This points up the fact that tolerance to, and physical dependence on, a drug are not the same thing. The body can even develop a tolerance to drugs on which it does not become physically dependent. But tolerance is always present when physical dependence develops.

In the case of the opiates, the speed with which physical dependence develops seems to lag only slightly behind the speed of the development of tolerance. A patient receiving therapeutic doses of morphine for a week or two will not have recognizable withdrawal symptoms spontaneously after discontinuance, but these can be precipitated by an antagonist after only two or three days on morphine. By similar means, withdrawal has been caused in a dog after an eight-hour infusion of morphine. Goldstein believes that physical dependence is probably initiated with the first dose of the drug." At that stage, of course, withdrawal would be so mild as to be unnoticeable, but it seems possible that a single dose could create a craving for the drug, even though the physical genesis of this feeling would be unknown to the user.

As might be expected, there are no definitive explanations for the phenomenon of physical dependence. Its existence is simply defined by the presence or absence of withdrawal symptoms. Jaffe states:

At present no single model is able to account for all the complex phenomena that are seen with the many classes of drugs producing tolerance and physical dependence. It is likely that multiple mechanisms are involved, and that each model may reflect a facet of the truth. For the present the most heuristic models are the best ones .42

Goldstein also observes that, although "the mechanism of the development of tolerance and physical dependence is still unknown.... there has been no dearth of theoretical speculation."" It appears that dependence is due to "drug-induced alterations at the cellular level, with the most prominent changes occurring in the CNS . . . these changes are not limited to any one part of the CNS but occur throughout the entire neuraxis.""

The sources are silent, however, on two important questions about physical dependence and tolerance. The first of these concerns stabilization dosages. It is well known, for example, that an addict can be stabilized on a drug, since taking a given amount will result in neither withdrawal nor euphoria. But there is little information on how much latitude there is in the stabilization dose. That is, if a morphine addict is used to 100 mg., can he take anywhere between 90 and 100 mg. without becoming aware of the difference; or is his tolerance of deviation from his normal dose less than this? Also, are there variations between the opiates, depending on peak intensity and duration of action? Generally, experts believe that it is harder to stabilize on such short-acting drugs as morphine and heroin than on methadone. The short, sharp peak and rapid decay characteristic of the morphine effect may mean that a dose insufficient to produce euphoria soon results in bodily concentrations too low to prevent withdrawal.

Another important question is whether the euphoric effect disappears at high levels of opiate tolerance. That is, will an addict who is used to 500 mg. of morphine achieve euphoria if he takes 550 or 600 mg.? The fact that the severity of withdrawal levels off at around this dose might indicate an upper limit on the ability to obtain a euphoric effect. None of the sources found, however, presents evidence to support either possibility.

Finally, it is well known that physical dependence on a given opiate can be satisfied by any other opiate. This is the pbenomenon of cross-dependence, described by Jaffe as follows:

Cross-dependence may be partial or complete, and the degree is more closely related to pharmacological effects than to chemical similarities. A broad-spectrum drug such as methadone, which depresses the entire range of functions that are similarly affected by morphine, can completely substitute for morphine or meperidine. However, meperidine, which has a narrower spectrum with less autonomic and sedative effects, does not entirely prevent the autonomic manifestations of withdrawal from morphine.

In general, any potent narcotic analgesic, regardless of chemical class, will show cross-dependence with other narcotic analgesics . . . . 45

METHADONE MAINTENANCE

A successful method of treating heroin addicts is to maintain them on daily doses of methadone. More detail about the programs using this technique is contained in Staff Paper 3.

The pharmacological basis of methadone maintenance has been covered in preceding sections, albeit implicitly. The significant characteristics are as follows:

• Methadone is a synthetic opiate. Its administration to a heroin addict will either prevent the withdrawal symptoms caused by abstinence from heroin or end them if they have already developed.
• Methadone and the other opiates exhibit cross-tolerance. A person tolerant to one of them is tolerant to equipotent doses of another.
• The action of oral methadone lasts about twenty-four hours. A methadone program can administer the drug once a day, rather than three or four times, as would be necessary if morphine or heroin were used.
• High doses of methadone (e.g., about 80 mg. or more) will prevent withdrawal, block the euphoric effect from an injection of heroin, and prevent the "drug hunger" (defined by Dr. Jerome Jaffe as "a felt sense of physical abnormality") felt by addicts who have become abstinent.
• Lower doses of methadone (e.g., 50 mg.) will prevent withdrawal and the drug hunger. They will not block the euphoric effect of an injection of heroin, although presumably some minimum quantity of heroin is required. The success rate for programs using low doses is approximately the same as the rate for those using high doses for addicts in treatment six months. Experts believe that blocking the euphoria is not so important as preventing the drug hunger.
• No significantly harmful side effects of methadone have been discovered.

The effects of methadone on the heroin addict have been described diagrammatically by Dr. Vincent Dole."'

Fig. 1. Diagrammatic summary of the functional state of a typical "mainline" heroin user. Arrow shows the repetitive injection of heroin in uncertain dose, usually 10 to 30 mg but sometimes much more. Note that the addict is hardly ever in a state of normal function ("straight").

Fig. 2. Stabilization of the patient in a state of normal function by blockade treatment. A single, daily, oral dose of methadone prevents him from feeling symptoms of abstinence ("sick") or euphoria ("high"), even if he takes a shot of heroin. Dotted line indicates the course if methadone is omitted.

Fig. 3. The induction of narcotic tolerance by the gradual increase of methadone dosage. Two typical patients are shown: one starting with tolerance (from previous use of heroin) and the other with little or no tolerance (e.g., recently in hospital or jail). The right-hand ordinate shows the total daily dose of methadone (given in divided portions during the first months); the left-hand ordinate indicates the degree of narcotic blockade on an arbitrary scale (O to ****).

Some important questions about the nature of methadone treatment remain unanswered. Because methadone and heroin can be substituted for each other in so many ways, it would seem logical that their effects would be cumulative, and that the addict on methadone would be able to achieve the euphoric state with a smaller dose of heroin than he normally used. Certainly, other drugs, such as alcohol and the barbiturates, have cumulative effects. Yet, many of the discussions about methadone treatment evidently assume, with actually saying so, that their effects are not cumulative.

The explanation may lie in the pharmacological principle that the body's response to many drugs is logarithmic, not linear. That is, as the dosage is increased, steadily larger incremental doses are required to produce a constant increment of response. Heroin and methadone may be cumulative in their effects, but the administration of methadone elevates the recipient to a point on the dose-response curve where only very large additional amounts of heroin have discernible impact."

In this context, it is important to remember the suggestion made earlier that there may be a limit of 120-150 mg. per day of heroin (the equivalent of 400-500 mg. of morphine) above which additional amounts of the drug have no euphoric effect. If this limit is roughly true, even with substantial individual variations, then many methadone programs may simply boost the addict to the point where he cannot attain euphoria. Either he reaches this limit, which would be true at about 180 mg. per day of methadone, or he reaches a dosage that leaves too small a margin between his tolerance level and this limit for a euphoric dose. Lower doses (e.g., 50 mg.) would not approach the euphoric limit, but they might shift an addict to a point on the doseresponse curve where the heroin dose he is used to taking would not have any euphoric effect.

Physiological Factors Underlying Addiction. It is commonly assumed that the causes of addiction are psychological, and that there is no inherent physical predisposition to addiction. There is, however, no experimental evidence that would rule out the possibility that drug addiction, or at least vulnerability to drug addiction, has a physiological basis. As Goldstein says:

Certainly socioenvironmental reasons can be found, ex post facto, to explain each case of addiction to heroin, the barbiturates, or alcohol, or of habituation to lysergic acid diethylamide [LSD], marijuana, nicotine, or amphetamine. But most people afflicted by the same adverse environmental circumstances do not seek escape through drug abuse. Despite the present paucity of evidence, therefore, the possibility should be entertained that the characteristic effects of psychotropic drugs upon mood, which underlie the development of drug abuse, may be at least in part genetically determined.

Investigation in this field has not yet transcended the difficulties of designing experiments free of self-selection or other kinds of bias, and of working out methods suitable for quantitation of subjective responses. It has been found, for example, that housewives who drink large amounts of coffee responded entirely differently to a test dose of caffeine in a placebo-controlled experiment than did housewives who never drink coffee. The coffee drinkers felt more alert and had a sense of well-being after caffeine, as compared with placebo. The non-drinkers obtained significantly fewer effects of this kind; on the other hand, caffeine made them feel nervous and "jittery." But it is not known if the group habituated to coffee would have reacted in the same way at an earlier age, before their first exposure to caffeine. Large individual differences are observed in the sensitivity of people to the sleep-disturbing actions of caffeine, but again it is not clear whether or not these are innate differences, independent of any prior exposure to caffeine. One investigation on the coffee drinking and smoking habits of monozygotic and dizygotic twins suggests that these two kinds of drug-seeking behavior are subject to genetic influences.411

Dole has suggested that an addict may have an underlying neurological vulnerability to addiction that is triggered by opiate use." More recently, he has indicated that opiate use may induce a metabolic change that will cause the body to crave opiates thereafter." But he is not optimistic about the potential of research on the question, given the present lack of testable hypotheses that might explain it."

Another theory concerning physiological propensity to addiction is more complex. Martin has suggested that an addict has a particular physiological vulnerability to stress either before he takes his first narcotic drug or after he starts taking it. In Martin's view, this vulnerability is not lost after withdrawal from the drug, and stress situations will trigger a physiological reaction that results in a craving for the drug. Martin believes that there is some experimental evidence for this view and is more optimistic than Dole about possible research."

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THE HALLUCINOGENS

The Drugs."

LSD (lysergic acid diethylamide) is a synthetic drug discovered in 1938. It is closely related to the ergot family, and ergotamine tartate, used in treatment of migraine headaches, can be used as raw material in the manufacture of LSD.

Mescaline, an alkaloid of the peyote cactus, was isolated in 1896. It is about .025 per cent as potent as LSD in producing an altered state of consciousness. But it is probably just as powerful.

Psilocybin and psilocin are the active alkaloids of the Mexican magic mushroom and are about 1 per cent as potent as LSD.

DOM (also called STP) and MDA are other hallucinogens chemically related to both mescaline and amphetamine.

DMT (dimethyl tryptamine) is a short-acting hallucinogen.

Medical Uses." Although there are no recognized medical uses for the hallucinogens at present, some of them have been, and are being, used experimentally for a variety of research and therapeutic purposes. LSD and mescaline, for instance, have been used for research on mental illness and in psychotherapy. Since certain effects of these drugs mimic the symptoms of schizophrenia in some ways, it has long been thought that study of these effects will yield insights into the nature and causes of psychotic states. A few experiments have been conducted in which terminal-cancer patients are given LSD in order to make the "waiting for death" period more meaningful. Through the LSD experience, the patient learns to live in the "here and now," taking each day as it comes rather than dwelling on his past. Alcoholics and drug addicts have also been given LSD as part of more comprehensive courses of treatment.

Physical Eflects and Toxicity. LSD is effective when taken orally, which is the usual method of administration. Some users claim to have taken it nasally or by injection and state that injected LSD produces a powerful rush. It produces some somatic effects that are sympathomimetic, such as pupillary dilation, increased blood pressure, tremor, nausea, muscular weakness, and increased body temperature, but these effects are usually minor. The major effects are almost entirely on the CNS."

The effective dosage is quite small. Perceptual changes, the most dramatic result, can be produced by as little as 251 mcg. (micrograms). (I gram = 1,000 milligrams = 1,000,000 micrograms.)" The standard dose taken by LSD users is probably around 200 mcg., although the variability of street drugs makes it difficult to be accurate.

Although no human deaths as a result of the pharmacological action of LSD have been reported, animal deaths due to respiratory failure have occurred in response to massive doses. At present, it is not clear whether there is a fatal dose for humans, but it is clear that the ratio of the lethal dose (if there is one) to the therapeutic dose is very high. It is difficult to determine the significance of animal experiments for humans, because different species have markedly different reactions. Some animals, for example, have been found to be resistant to LSD; mice, in particular, detoxify the drug quickly, and the half-life (the period within which half the drug is metabolized) in a mouse is only seven minutes. In a human, the half-life is approximately three to three-and-a-half hours; the total duration of action of the drug is about twelve hours .57

Despite claims to the contrary, there is no reliable evidence that LSD causes birth defects. The early studies on this have been discredited, and no definitive work has been done since." One exhaustive study concluded that pure LSD, in moderate doses, "does not produce chromosome damage detectable by available methods."" This problem is difficult to study, because that part of the population that uses LSD heavily is also likely to be malnourished, careless about hygiene and prenatal care, and prone to a variety of physical problems. Since LSD seems to be a relatively specific drug, in that it acts primarily on the CNS and has few peripheral effects, it is not particularly logical to expect that it will produce birth defects. It would be more sensible to study the large number of legal drugs that have massive effects on various body systems, because they would be more likely to affect the reproductive system as well. The stress on birth defects as a possible result of LSD appears to be motivated more by the desire to prevent its use than by the desire to prevent birth defects.

Psychoactive Eflects." The hallucinogens do not produce hallucinations in the classic sense-it is rare for a user to see things that are not there. Rather, perception is altered: Afterimages are prolonged and overlap with present perceptions; objects seem to move in a wavelike fashion or melt; and sensory impressions become overwhelming. Synesthesia-a state where colors are "heard" and sound is "seen"-is common.

Perhaps more important to the user than these perceptual effects are the subjective effects. Time may seem to pass very slowly; self-boundaries appear to disintegrate; and the user soon comes to feel a sense of oneness with the universe. There may also be a sense of unusual clarity, and one's thoughts may begin to assume extraordinary importance. Moods may change radically, from gaiety to depression, from elation to fear, or vice versa.

Many users attach great meaning to their experiences. Some regard the use of LSD as a form of psychotherapy, since they believe it increases one's self-knowledge and self-awareness, largely through the recall of old and hitherto buried memories. Others may go further and emphasize the mystical and religious aspects of their drug-induced feelings.

Some of the possible, long-term psychological reactions were examined in an experiment in which LSD was administered to previously naive subjects. The subjects were given a number of psychological tests-before taking LSD, immediately after the experience, and six months later." All changes were quite small; the main findings indicated a negative correlation between the use of LSD, on the one hand, and aggression, competition, and preference for structure and conformity, on the other. Rather, a positive correlation with an increase in aesthetic appreciation was found. One result of the experiment was proved particularly illuminating: Fifty-nine per cent of the subjects who had been given 200 mg. of LSD thought that the drug had had lasting effects on their personality, even though the tests "provided only minimal supportive evidence."" In the control groups, none of those given 25 mg. of LSD, and 13 per cent of those given 20 mg. of amphetamine, had similar feelings about the experience. While other researchers have found a negative correlation between chronic LSD use and aggression and competition," there is a self selected quality to the voluntary chronic user that did not exist in the above experiment.

The major short-term risk of taking LSD is the "bad trip," a term used to describe several different types of adverse experiences. A mild adverse reaction can mean only that the images and feelings during the experience were unpleasant. At the other extreme, a serious panic reaction, accompanied by immense anxiety and fear, may occur. Bad trips are probably common, but most of them do not reach the severe level.

Under clinical conditions, serious adverse reactions appear to be rare. In one study, for instance, it was found that 25,000 administrations of LSD to 5,000 people in clinical settings had resulted in only 0.08 per cent serious reactions in experimental subjects and 0.34 per cent in subjects undergoing therapy. "Serious" was defined as causing either suicide or a suicide attempt or a psychotic break lasting more than forty-eight hours. 14

Of course, most LSD use does not take place under clinical conditions; some observers believe that such use may therefore result in higher percentages of adverse effects, for several reasons. To begin with, putative LSD may be heavily adulterated with substances ranging from strychnine to methamphetamine. Also, use of LSD has been an illegal and deviant activity; this may make users anxious and more susceptible to bad reactions. It is also possible that a higher proportion of street users have psychological factors impelling them toward deviant behavior than would be true of an experimental population. Age differences may also be an important factor in adverse reactions (a theory in the field is that young users are more likely to lack the experience and identity that enable a more mature person to handle the powerful impact of the drug) .

One could, of course, argue the precise opposite on almost every point made in the last paragraph. For example, street users may seek out warm and supportive settings that reduce the incidence of bad reactions as compared with the clinical setting. LSD use may be deviant in the context of the larger culture but not in the subculture within which most users live. Older people, generally more rigid in their attitudes, may resist the drug effect and panic, while younger people, being more flexible, may accept -the drug experience more easily. Contact with a subculture in which LSD is common may reduce fear of the drug, regardless of age, more than will clinical reassurances.

At present, there is no rational way to choose between these arguments. It should be emphasized that reports of large numbers of serious adverse reactions among street users have not been documented. What evidence there is consists mostly of anecdotes.

Chlorpromazine, a powerful tranquilizer used in the treatment of psychiatric illness, will counter the physical effects of LSDalmost immediately. If, however, the LSD user is having a panic reaction, it may continue in spite of the chlorpromazine. Physicians familiar with this phenomenon believe that chemotherapy may prolong panic because of the anxiety its administration arouses in the patient. "Talking the patient down" in a calm manner is the preferred treatment .115

There are some long-term risks associated with LSD use. In some individuals, prolonged negative effects are associated with use of hallucinogens; cases of serious depression, paranoid behavior, and prolonged psychotic episodes have been documented. Whether the hallucinogens cause these effects is not clear. LSD may serve only to precipitate them in someone who is about to have such a problem anyway. The frequency of such effects is not known.

Another possible long-term effect of the hallucinogens is the flashbacks recurrence of some aspect of the drug experience vhen the subject is nor under the influence of the drug. The flash)ack encompasses a wide range of possible LSD-like perceptual or subjective effects of varying degrees of severity and duration, lasting from a few minutes to several hours and occurring with indeterminate frequency. The user is not affected between experiences. Causation has not been definitely proved, however, and it could be that a controlled experiment would find similar experiences in a non-LSD-using populations"

The most common type of flashback recorded is the recurrence of perceptual distortion; the rarest is the recurrence of altered physical sensation; and the most dangerous is the recurrence of disturbing emotion and panic. (This may be hard to distinguish from the depressive reaction or schizophrenic episodes discussed above.) The last two types of flashbacks are more likely to occur after a bad trip than after a good one.

Assuming that flashbacks are caused by LSD, the mechanism responsible is a mystery. The theory that LSD persists in the nervous system is not compatible with its known short life, and the theory of a persistent, undiscovered metabolite is incompatible with the wide variations in onset and duration. Nevertheless, there is no lack of other theories, ranging from semipermanent changes in the optic pathways, to learned responses to stress, to dissociative reactions. Generally, it is probably psychological rather than chemical, but, given the lack of knowledge about the relationship between psychological and chemical events, this conclusion does not tell very much."

There is no information on the incidence of flashbacks, the extent to which they occur after only one LSD experience, or the relative frequency of the different types.

The effects of the other hallucinogens are similar to those of LSD. Mescaline, which lasts as long and has about the same effects, although it is less potent, seems to be the usergs drug of choice. It is unclear whether this preference is due to the publicity regarding possible birth defects caused by LSD or to some subtle difference in effect. It may just as well be due to the belief of many users that natural substances are superior to synthetics, a factor that may also account for the preference for the mushroom hallucinogens. This question has not been studied clinically, and it is difficult to know the effects of natural hallucinogens, since they are rarely available. Most street mescaline is either LSD or LSD plus speed or some other adulterant.

DOM (STP), MDA, and some other drugs are a cross between hallucinogens and amphetamines. The duration of action of DOM is sixteen to twenty-four hours, and rough observations indicate that the incidence of panic reactions and flashbacks has been higher than that associated with LSD. The physiological effects (rapid heart rate, dry mouth, dilated pupils) are also more pronounced. It is possible that, when the drug first appeared, users were more prone to panic, because they were not prepared for the long duration and greater physical reaction." Jaffe states that low doses of DOM give some of the subjective effects of LSD without the perceptual or hallucinogenic effects, although the drug has typical psychedelic action at higher doses."

According to some sources, MDA causes an LSD-type reaction for the first six to eight hours, but it also has amphetaminelike effects that persist for a longer time. Other reports are that MDA is sui generis, with LSD-like subjective feelings but without the perceptual distortion of LSD or depersonalization."

DMT is a hallucinogen whose effects last only forty-five minutes to an hour. It is sometimes called "the businessman's lunch."

Tolerance. Tolerance to the hallucinogens develops rapidly. If taken daily for three or four days, LSD will cease to have any substantial effect." The tolerance does not appear to be so closely tied to the dosage as in the case with other drugs to which tolerance develops-that is, it seems that one cannot achieve the desired effect simply by increasing the dose. The sources, however, are ambivalent on this. Sensitivity returns after a few days of abstinence.

There is cross-tolerance among LSD, mescaline, and psilocybin but not between any of these and the amphetamines." There is no information on DOM, MDA, or DMT on this point.

Physical Dependence and Withdrawal. Hallucinogens such as LSD and mescaline do not produce physical dependence, and there are no withdrawal symptoms after discontinuation." Again, there appears to be little information on DOM, MDA, or DMT; at least, there are no reports of dependence or withdrawal. They are likely to be about the same as LSD.

Mechanisms of Action. A number of CNS effects of LSD are known; the manner in which LSD causes these effects, however, is still not known. LSD and the other hallucinogens interfere with the production and action of serotonin (also called 5-HT or 5-hydroxytryptamine) in the brain. This is an important body substance with significant effects on many organ systems. But, since the functions of serotonin in the CNS are not known, this does not represent substantial progress in understanding LSD."

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CANNABIS"

The Drugs. Cannabis sativa, the hemp plant, grows almost everywhere in the world. It flourishes in hot, dry climates, and it is generally believed that plants produced in such regions have the most pronounced psychoactive effects. Marijuanaconsists of the chopped leaves and stems of the cannabis plant. It is usually smoked, but it can be taken orally. Hashishis formed of resin scraped from the flowering top of the cannabis plant. It, too, can be smoked or eaten, and it is thought to be about five to eight times as potent as marijuana. Some experts believe there are qualitative differences in effect as well as simple differences in potency. Kil, bhang, and gania are other preparations of cannabis used in various parts of the world. Their potency lies between that of marijuana and that of hashish.

The most important psychoactive ingredient of cannabis is known to be delta-9-tetrahydrocannabinol (THC), but the possibility of additional ingredients exercising some effect has not been precluded.

Cannabis is a difficult drug to classify. Although it is often referred to as a mild hallucinogen, it does not have many of the effects associated with hallucinogens, and probably has a different mechanism of action altogether. It also has some sedative effects but lacks many of the other characteristics of the sedative hypnotics. With good reason, therefore, it is usually classified as unique."

Medical Uses. There is no accepted medical use for cannabisin the United States. In the past, especially during the late nineteenth century, it was quite popular among European and American doctors, who prescribed it for a variety of ailments ranging from menstrual cramps to migraine headaches. It was thus used generally as a mild anodyne (pain killer) or tranquilizer-but it may have more specific effects as well."

By the early twentieth century, the use of cannabis for medical purposes had declined, largely because of inconsistency in the potency of the drug. Since cannabis was cultivated in many places with wide variations in climatic and soil conditions, no physician could be sure of potency of any given batch. This made it difficult to predict results. It also inhibited research, since nonreplication of scientific findings might invariably have been due to differences in the drugs used.

Another problem was that there was no satisfactory way to administer the drug for medical purposes. Smoking is not a medically acceptable method, because the doctor cannot know how much of the drug is being inhaled and absorbed. Oral administration is possible, but effects are delayed. Moreover, since neither the plant material nor the resin is soluble in water, injection is difficult. Thus, as other drugs became available-particularly the barbiturate sedative hypnotics, which began appearing on the market in 1903-cannabis was replaced.

Almost no research has been done on the drug since the late nineteenth century, and government policies made such research impossible from 1937 to about 1968. Whether cannabis has unique medical uses or is in some ways superior to common tranquilizers now in use is therefore an open question. A revival of interest is now taking place, however, in the medical community. For example, several doctors are using cannabis to treat migraine headaches, and some research is being done into its effectiveness as a treatment for epilepsy. Certain variants of THC may lower the blood pressure of hypertensive people."

The isolation and synthesis of THC-achieved in the early 1960's-has promoted such research by making consistency in dosage conceivable for the first time. In addition, NIMH has a project under way to cultivate cannabis in Mississippi, with the objective of providing drugs of constant quality to researchers. But there are still problems: For example, there is some evidence that THC is subject to oxidation, and that the potency of cannabismay therefore change over a period of time that varies with storage methods. Also, THC is expensive to synthesize and remains in short supply. Recent work has developed at least one water soluble derivative of THC with a pharmacological profile similar to that of the original drugs. This should aid research further.

Physical Effects and Toxicity. The immediate physical effects of cannabis on man are mild. Heart rate is increased moderately. There is a dilation of the conjunctival blood vessels (i.e., a reddening of the eyes) and sometimes an increase in heart rate. There appear to be no changes in respiratory rate, pupil size, or blood-sugar level. After a single inhaled dose, measurable physical effects reach a maximum within half an hour and diminish three to five hours later." When cannabis is eaten, the effects are delayed for several hours, and symptoms may persist for up to twenty-four hours.

As discussed in the next section, subjective effects of high doses of the cannabinols may be similar to those of LSD. This has led some to classify them as mild hallucinogens. Physical effects are not the same, however, because cannabis does not have the stimulating effects of LSD and has sedative properties that LSD lacks. There is no cross-tolerance between the cannabinols and the hallucinogens."

At present, there is no reliable evidence of organic damage, and the most that can be said against cannabis is that the effects of long-term or heavy use have not been ascertained. To be sure, heavy, long-term smokers of cannabis develop bronchial disorders, but these seem no different from the difficulties experienced by heavy smokers of tobacco. Reports of long-term brain damage are suspect, at best. For one thing, they derive from studies of cannabis users in underdeveloped countries, such as India and Morocco. These studies, furthermore, are skewed by the fact that they used inmates of mental institutions as subjects and assumed a causative relation if they found that the inmates had been users of cannabis. Scientific protective devices, such as control groups and blind studies, were lacking. The recent crash program of federal research has not filled this gap, and many experts do not expect that it will do so. In this view, gross organic damage would have been found before now, and long term subtle damage is difficult to study retrospectively.

The lethal dose of THC for humans has not been determined, but it is known that the cannabinols are not very toxic: There has yet to be a report of a human death due to an overdose of THC. Animal experiments have found that the 16thal dose for rats is between 800 and 1,400 milligrams of drug per kilogram of body weight for oral administration. Extrapolating from studies in mice, the ratio of the lethal dose to the effective dose for humans would be about 40,000 to 1. (The effective dose is that amount necessary to produce clinically desired effects. For THC in humans, it is about 50 micrograms per kilogram.) By way of comparison, the ratio for barbiturates is about 10 to 1"

Recent research has found that injected THC has a half-life in the body of fifty-six hours, and that traces can be found in the urine for up to eight days. There is also a possibility that it may accumulate in lung or fat tissue." The clinical implications of these facts, however, are not known.

Psychoactive Effects. The general effect of cannabisis "a subtle mood change not easily perceived by the novice."" The most common mood encouraged by the drug is a sense of increased well-being, but this is heavily dependent on the setting and expectations of the user. The nervousness that may accompany first use, for example, can negate any reaction to the drug. Set and setting help to produce a wide range of reactions and may be more crucial determinants of the effects of cannabisuse than those of most other drugs." The effects described below are those observed in clinical trials and obtained from interviews with users.

One important effect is the enhancement of the senses. Sensitivity to colors, sounds, patterns, textures, and taste is greatly increased. Perception of space and time is distorted in ways that can be either pleasing or disconcerting. In particular, time passes very slowly. Inhibitions may be relaxed in a manner reminiscent of the effects of low doses of alcohol. The subject may develop a sense of being in a fantasy or dreamlike state (an effect achieved also by sedatives and anesthetics).

In clinical experiments, large doses of THC have produced LSD-type experiences, but this requires quantities of THC far in excess of the concentrations found in organic cannabis. Real hallucinations do not occur.

The dose-response curve of THC has not yet been established; nor have systematic comparisons of THC and LSD been made.

Significant adverse reactions to cannabis are rare, but they do occur. They are more common when strong forms, such as hashish, are used. There are four types that may result:

(1) simple depression, (2) a panic state, (3) toxic psychosis, and (4) psychotic break.

Of the four, the simple depression reaction is the mildest and most common. Its genesis is not known. People may be responding idiosyncratically to pharmacological effects of the drug; or the cannabis may intensify pre-existing but suppressed psychological states or traits. It is likely, also, that the different explanations might each account for some of the depressions seen. In any event, the reaction ends spontaneously.

The panic reaction occurs when a user interprets the use or effects of cannabis as a threat to life or sanity. It is most likely to occur in subjects with no prior drug experience who are ambivalent toward drug use and possibly fearful of police arrest. Verbal and personal support by peers is the most effective therapy; hospitalization and the use of tranquilizers are usually contraindicated unless the person is highly agitated."

Many panic reactions have been misdiagnosed as examples of toxic psychosis-a condition in which the presence of toxins in the body causes organic malfunction in the cerebral cortex and a resultant psychotic state. This reaction is even rarer than the panic reaction and ends when the toxins are flushed from the system. A user is vulnerable to such a reaction when consuming cannabisin concentrated forms, especially if the drug is mixed with food and drink. The effects are delayed while the drug is being absorbed, and the user cannot use the effects of the drug as a measure of when he has had enough. In the view of some experts, smoking cannabis allows the user to regulate consumption in reaction to the immediate effects of the drug's passing into the blood stream via the lungs.

The view that differences in reaction to the two methods of administration are due to control of dosage can be questioned, however. Dr. Andrew Weil states:

This theory of autotitration sounds nice, but I do not see it happen much. Most marijuana smokers I know smoke as much as they are handed. What is interesting is that one reaches some sort of ceiling in smoking: beyond a certain point, one does not get any higher, only more sedated. With oral ingestion, on the other hand, one can
easily get into the toxic range. These observations suggest pharmacological differences between the two routes of administration.86

The use of cannabis may also trigger a psychotic break in individuals who have normal psychological histories. Although evidence is scarce, the degree of risk is probably very small. A recent study reviewed twelve cases of cannabis-related psychotic breaks arising over a ten-month period among soldiers stationed in Vietnam. Only two of the twelve had "significant psychiatric histories and diagnosis of personality disorder." In all cases, the reaction occurred after the first use of cannabis and was self limiting, in that the condition cleared spontaneously." Since about 30 per cent of the 500,000 American soldiers in Vietnam at the time had probably consumed cannabis at least once, often in potent form, the incidence seems low.

Other data support this conclusion. During a fifteen-month period, approximately 30,000 persons were treated at the Haight Ashbury Clinic for a variety of medical and psychiatric problems. An estimated 95 per cent had used cannabis. No case of a psychotic break was recorded."

The risk of a psychotic break may be higher for users who have a history of mental disorder. There is some evidence to support this, but there are no statistical data on the degree to which such population is at greater risk than "normals."

Tolerance. Cannabis appears to have the unusual property of "reverse tolerance," in that regular users are more sensitive to the drug than novices. This characteristic has been conventional wisdom within the drug culture for some time; it is supported by a recent scientific study that used radioactive isotope tagging to detect THC in body tissues several days after the drug had been injected. The conclusion was that THC may accumulate in the body, so that a regular user may already have a "basic dose" and require only a small, additional amount to obtain a psychoactive effect."

It is not known whether pharmacological tolerance to cannabisdevelops. Because of the "reverse tolerance" effect, experts have assumed that there was no such tolerance; but, if the effects are cumulative, then "reverse tolerance" in users could be accompanied by pharmacological tolerance. For example, when synhexyl, a potent synthetic cannabisderivative, is administered, tolerance develops in four to six days."

Physical Dependence. There is little evidence that physical dependence develops with the consumption of cannabis,and no significant withdrawal symptoms accompany cessation of use. If dependence of any kind develops, it is probably psychological, but even this appears to be minimal."

Mechanisms of Action. The way in which cannabis causes CNS effects is not known.

Additional Sources. A number of comprehensive reviews of marijuana have recently been published, taking up many of the above issues in greater depth. Some of these are

U.S. Government, Secretary of Department of Health, Education and Welfare, Marihuana and Health: A Report to Congress, January 31, 1971 (GPO, 1971)

Federation of American Societies for Experimental Biology, A Review of the Biomedical Effects of Marijuana on Men in the Military Environment (Bethesda, Maryland, December, 1970)

Lester Grinspoon, Marihuana Reconsidered (Harvard University Press, 1971)

Leo E. Hollister, "Marihuana in Man: Three Years Later," Science, CLXXII, No. 21 (April, 1971)

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THE MAJOR STIMULANTS

The Drugs." This category of drugs includes those that have the effect of stimulating physical and mental activity and of providing a feeling of such stimulation to the user:

Amphetamines are synthetic drugs that are part of the general category of sympathomirnetic agents-a group of drugs whose effects resemble the response to stimulation of certain nerves of the sympathetic nerve system (hence "sympathomimetic"). They are CNS stimulants.

Methamphetamine is a close relative of the amphetamines. The major distinction is that it has a different ratio between central effects and peripheral actions than do the basic amphetamines. Small doses of methamphetamine produce prominent central stimulant reactions without significant peripheral effects.

Cocaine is an alkaloid of the coca plant. In general effects, it is quite similar to the amphetamines.

Methylphenidate (Ritalin) is a mild CNS stimulant, between caffeine and the amphetamines in its effects.

Phenmetrazine (Preludin) is also a sympathomimetic agent. Its effects are almost indistinguishable from those of amphetamines.

This section discusses amphetamines primarily, as the prototype. Significant differences are noted as relevant.

Medical Uses." The amphetamines are used to treat a rare condition called narcolepsy-the inability to stay awake. They are also used in the treatment of obesity because of their characteristic of depressing the appetite centers, but the results in this area are unimpressive. Amphetamines are useful in the treatment of children with hyperkinesis. This condition, which is also called minimal brain dysfunction, is one in which a child shows an inability to concentrate, a deficiency in motor skills, a low frustration level, and often an abnormal EEG pattern.

Quasimedical uses are very common. Amphetamines increase short-term physical and mental performance and are widely used by people who desire this effect, such as students and athletes. They are also used by people who have become dependent on or habituated to them to maintain their normal level of functioning.

Cocaine is not used medically for any of the above purposes, but it is used as a local anesthetic.

Ritalin is effective in treating hyperkinesis and, because it is milder than the amphetamines, may be the drug of choice."

Physical Effects and Toxicity. In different relative degrees, sympathomimetic agents have the following major actions:"

A peripheral excitatory action on such smooth muscles as those in blood vessels supplying the skin and on salivary and some sweat glands;

A peripheral inhibitory effect on other types of smooth muscles, such as those in the wall of the gut, on the bronchial tree, and on the blood vessels supplying the skeletal muscle; A cardiac excitatory action that increases heart rate and force of contraction;

Certain metabolic actions;

CNS excitatory actions, such as respiratory stimulation and others.

Amphetamines follow this scheme. Blood pressure is increased, and the smooth muscle responses, while somewhat unpredictable, are as indicated. The amphetamines are more potent in their CNS effects than other drugs in the group, and it is through the effects on the CNS that they stimulate respiration, depress the appetite, and reverse fatigue. The results of an oral dose of 10 to 30 mg. of amphetamine (the standard therapeutic dose is 10 mg.) are wakefulness, alertness, decreased sense of fatigue, elevation of mood with increased initiative, confidence, and ability to concentrate, elation and euphoria, and an increase in motor and speech activity. Prolonged use or heavy dosage is followed by mental depression and fatigue.

Cocaine has the same effects as the amphetamines. The major difference is that the effects of the amphetamines last several hours, while those of cocaine seem to last only minutes." Ritalin has less motor effect on motor and mental activities than do the amphetamines. Some CNS effect is produced by doses that have little effect on respiration and blood pressure."

The amphetamines can be quite toxic. Severe reactions have occurred with only 30 mg., and death has resulted from 120 mg. of injected amphetamine. The range is wide, however, and doses of 400 to 500 mg. have been survived by nontolerant individuals. Death from overdose is quite rare, possibly because the ratio of lethal to effective psychoactive dose is high for a tolerant user."

Cocaine is toxic because the central stimulation that is the immediate effect of the drug is followed by depression of the higher nervous centers. Death from respiratory depression occurs when the vital medullary centers are sufficiently depressed. The fatal dose of cocaine has been estimated to be about 1.2 grams taken at one time, but severe toxic effects have been reported on doses as low as 20 mg."

The basic symptoms of amphetamine poisoning are extensions of its normal therapeutic effects on the CNS, the cardiovascular system, and the gastrointestinal system. A fatal dose ends in convulsions and coma. Cerebral hemorrhage is a common autopsy finding, but it is rarely massive. "Pathological findings in both man and animals are generally nonspecific and show pulmonary congestion and often congestion of other organs including the brain.""'

Amphetamines are usually taken orally, but they can be injected. Cocaine is not effective when taken orally, but it can be snorted and absorbed through the mucous membrane or taken intravenously. Medically, cocaine is only applied to body surfaces as a local anesthetic; it is not injected or used internally.

The major, long-term toxic effect of amphetamine use is a paranoid psychosis that is often indistinguishable from a schizophrenic reaction. This can occur after continued use or even after an extremely heavy single dose. It usually disappears within a week if the individual stops using the drug. Cocaine can cause the same condition even more rapidly.

Whether these drugs cause long-term organic damage to the body is at present unknown. Some experts who have worked with amphetamine users believe that there is a long-term deterioration that is explicable only in terms of organic damage. At present, however, this has not been definitely established. In animal experiments, death often results from continued administration of methampbetamine, but the reason appears to be that the animal's disinterest in food, combined with its hyperactivity, results in a malnourished conditi6n that leaves it vulnerable to infection. There have been some preliminary reports attributing arterial disease to methamphetarnine use, but these have not yet been substantiated and should not be accepted until further evidence develops.

Hepatitis is very common among amphetamine users. This is to be expected when hypodermic needles are used without proper sterilization, but its incidence goes even beyond the level logically attributable to this cause alone. Some consideration is now being given to the possibility that amphetamine is itself directly toxic to the liver. No clinical evidence on this possibility has been developed, however, and it remains only a possibility."'

Psychoactive Effects. When taken orally, amphetamines produce an elevation of mood and feeling of power and intensity that many persons find quite pleasurable. The drugs increase concentration and physical and mental performance and reduce fatigue. Some users claim that orgasms are delayed and made more intense when they occur, but no objective experiments have been done.

The drugs produce the same effect even when taken intravenously. In addition, the user obtains a "rush" that is reputed to be different from, although related to, the effect obtained from opiate injection. Again, sexual analogies are often made by users. It is difficult to know whether the rush is a product of the drug itself or of the process of intravenous injection. Some users actually prefer impure methamphetamine because of the belief that the impurities cause a faster, more intense rush."'

As the dosage increases, the experience seems to become more fragmented. Increased ability to concentrate turns either into a compulsion to do repetitive tasks over and over or into a total focusing of attention on some object or toy. Heavy users have a compulsion to take mechanical objects apart and a similar compulsion to try (unsuccessfully) to put them together again. Such repetitive behavior occurs in animals as well as in humans."'

Eventually-and fairly predictably-heavy amphetamine use during a limited period of time will result in paranoid ideation and the toxic psychosis discussed above. To some extent, users are aware of this aspect of amphetamine use and can make allowances for it during the experience. They will not act on moderate ideas of persecution or visual illusions. If the run continues long enough, this control will be lost.

Some heavy users may become chronically psychotic, in that they exhibit psychotic symptoms even when not taking the drug. The California experience is that normal functioning returns over a period of six to twelve months, although the user himself may feel some residual disablement .104

Cocaine has roughly the same effects as amphetamines in terms of creating feelings of well-being, euphoria, and power. According to the accounts of users, these feelings are even stronger with cocaine than with the amphetamines, but reliable evidence is unobtainable.

Tolerance." Tolerance to most effects of the amphetamines develops rapidly, and very high dosage levels can be reached. A speed user on a run may inject as much as a gram of the drug every two or three hours around the clock for several days. Whether this is drug disposition or cellular tolerance is not known. The development of tolerance is not uniform, however, and the ability to withstand what would otherwise be a fatal dose does not confer tolerance to the toxic psychosis.

It is not certain that tolerance to cocaine develops. There are reports of very large doses-such as 10 grams per day-but individuals seem able to tolerate the same doses after a period of abstinence as before. it is known that the liver is extremely effective at detoxifying cocaine and can process a lethal dose every hour.

There are no reports of cross-tolerance between cocaine and the amphetamines, but cross-tolerance between amphetamine and the other stimulants has been reported clinically.

Physical Dependence. For a long time, it was believed that there were no withdrawal symptoms from amphetamines and therefore no physical dependence. At present, it is thought that the prolonged sleep, lassitude, and depression that follow discontinuation of the drug are greater than would be attributable to the preceding loss of sleep and weight. These may be withdrawal symptoms. In addition, the percentage of REM sleep increases after discontinuance of amphetamine, returns to normal when amphetamine is given, and rises again when amphetamine is withheld. This meets the criteria for a withdrawal symptom."' The sources are silent, however, on the extent to which these symptoms are dose-related.

Some experts in the field believe that amphetamines are far more dangerous than the opiates. This is related not only to the typicality of the euphoric effect but also to the problems of tolerance and stabilization. Dr. Weil elaborates:

In fact, amphetamine dependence is more serious than narcotic dependence because it is inherently less stable. When a person begins using a tolerance-producing drug, he must soon face the problem of trying to stabilize his use in order to keep his life from being disrupted. More than any other class of drugs, the amphetamines foil the user's attempt to reach equilibrium with his habit because they produce such powerful and unrelenting tolerance. Consequently, users develop erratic patterns of use such as "spree shooting," alternation with barbiturates and, eventually, with heroin. The high correlation of amphetamine use with impulsive and violent behavior is consistent with this pharmacological instability.107

Because intensive use of amphetamines is a relatively recent phenomenon, there is little information on such problems as readdiction vulnerability, physiological bases of abuse, or comparative success of different methods of treatment. There is no treatment comparable to methadone, but neither is there any particular evidence that such treatment is needed. The pattern of heavy amphetamine use is probably too hard to sustain for an extended period of time anyway, and there is increasing indication that heavy amphetamine users eventually turn to "down" drugs, such as heroin or barbiturates."'

Mechanisms of Action. There are several theories about the mechanisms of the CNS effects of the amphetamines, most based on analogies to their peripheral effects, but none is definitive."' While the effects of all the drugs are similar, the mechanisms may be different; for example, there are probably significant differences between the amphetamines and cocaine."'

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BARBITURATES AND TRANQUILIZERS

The Drugs."' Barbiturates and tranquilizers are sedatives (calming agents), hypnotics (sleep-inducing agents), and depressants. The category encompasses a wide range of drugs of different families. For example, over 2,500 barbiturates have been synthesized, and at least twelve are in common clinical use. In the area of nonbarbiturate hypnotics, Sharpless lists twenty-three commonly used drugs belonging to ten different families. In addition to these two groups, there are a number of major tranquilizers that are used in the treatment of psychiatric disorders.

More is known about these drugs than about those discussed in previous sections. This is in part because they have been in wide use for a long time, and in part because most of them have more general effects than do other drugs of abuse. Drugs of this category act on a number of bodily systems besides the CNS, and these other systems are more easily studied. This section discusses the effects of the drugs only insofar as these are relevant to their abuse potential.

The major drugs involved are as follows:

Barbiturates are derivatives of barbituric acid; they were first used medically in 1903. The major abused drugs in the series are secobarbital and pentobarbital.

Meprobamate (Equinil, Miltown), glutethimide (Doriden), chlordiazepoxide (Librium), and diazepam (Valium) are CNS depressants belonging to several different families. Medically, they are regarded as anti-anxiety agents-not hypnotics-and they and similar drugs are called the minor tranquilizers.

One group of powerful tranquilizers, the phenothiazines (Chlorpromazine), are not covered. While they are in common use, especially for the treatment of serious mental illness, this class of drugs does not appear to be abused."' There is no satisfactory explanation of why they are not attractive to drug abusers. Obviously, their psychoactive effects must differ significantly from those of barbiturates or the minor tranquilizers, but the nature of these differences is unexplored.

The discussion here centers on barbiturates-the most powerful and often abused drugs-and brings in others as relevant.

Medical Uses."' The barbiturates are used as calming agents and as sleeping pills. Some of them are also used as anticonvulsants in the treatment of certain types of poisoning or epilepsy. The tranquilizers are used in any situation where the patient will benefit from an anti-anxiety drug. They are not sleep-inducing, except insofar as insomnia may be caused by anxiety. Both are widely used in the practice of medicine.

Physical Effects and Toxicity."' The barbiturates are general depressants of a wide range of cellular functions in many organ systems. They are not general anesthetics or analgesics, however, and will not prevent or relieve pain. (Some of the ultra-shortacting barbiturates are anesthetics when injected, but this is a minor exception.) They are respiratory depressants, and in high concentrations they have direct effects on the cardiovascular system. Most of the peripheral effects-the effects directly on the organs themselves-occur only at concentrations of the drug that exceed those necessary to affect the CNS and are thus relatively rare. "The CNS is exquisitely sensitive to the barbiturates, so that, when the drugs are given in sedative or hypnotic doses, direct actions on peripheral structures are absent or negligible.""' The effect on the CNS can range from coma to mild sedation, depending on the particular drug, the method of administration, and the dose. In some individuals, and in some circumstances, low doses will act as a stimulant rather than a sedative. It is not clear whether this depends on the mental set of the user or on the pharmacological phenomenon that the first effect of a drug is sometimes on brain centers that regulate and inhibit excitatory bodily functions.

For short- and intermediate-acting barbiturates, the hypnotic dose is 100-200 mg., which will give six or seven hours of sleep in the proper environment. The sleep is like physiological sleep, except that the proportion of REM phase is reduced. (The amphetamines also reduce REM.) The usual sedative dose is 30-50 mg., given two or three times daily.

The duration of action varies with the particular barbiturate. Some will last only ten or fifteen minutes, some for more than a day. Performance degradation, however, may last longer than overt effects. A 200-mg. dose of secobarbital (which is known as intermediate in its duration) may cause decreased performance ten to twenty-two hours later. The aftereffect of the drug may be hyperexcitability, even though functioning is, in fact, still impaired.

Taken in large quantities, barbiturates can cause death. The lethal dose varies, but it can generally be assumed that anything over ten times the normal hypnotic dose administered at one time will cause severe poisoning. Moderate poisoning is strikingly similar to alcoholic intoxication, with slurred speech, poor reflexes, and the rest of the well-known syndrome. Severe poisoning is characterized by a deep coma, with respiratory depression, falling blood pressure, shock syndrome, kidney failure, and other complications.

The long-term effects of barbiturate use seem to be in some doubt. The pharmacology books mention only the results of severe intoxication, not the effects of chronic use. At the same time, it is known that alcohol and the barbiturates have many characteristics in common and are to some extent substitutes for each other. Barbiturates will suppress the withdrawal symptoms of alcohol and vice versa; the intoxications are similar, and so are the withdrawal symptoms. In the formal literature, abuse of the two kinds of drugs is linked as "drug dependence of the barbiturate-alcohol type.""' The destructive effects of long-term heavy alcohol use are familiar, and some authorities believe that barbiturates may have very similar effects on the cells of the liver and brain. Presumably, our knowledge of the toxicity resulting from long-term but moderate use of barbiturates is in the same limbo as our knowledge of comparable use of alcohol.

Psychoactive Effects. The literature contains numerous descriptions of the effects of barbiturates on outward behavior. Intoxication may cause sluggishness, slowness of speech and comprehension, bad judgment, exaggeration of basic personality traits, moroseness, or irritability."'

The sources do not contain a description of the subjective effects, however, and the nature of the "high" involved in heavy use is less discussed than is the case for any of the other drugs of abuse. The general effect seems to be one of tranquility and peace. How this compares with an opiate high is not clear.

At doses only slightly in excess of the therapeutic dose, the effect may be one of excitation and mood elevation rather than of tranquilization.

A combination of barbiturates and amphetamines produces more elevation of mood than either taken separately. The reason for this is not known. Nor is it known whether this is the reason for the common drug abusers' practice of taking the two in combination.

The other depressants in this category are abusable and have much the same effects and symptoms as abused barbiturates. Abuse in the sense of self-administration does not seem to be terribly common, however; some of them, such as Librium, have rather minimal euphoriant effects. In general, from the standpoint of the abuser, barbiturates-particularly short-acting ones-are a superior good, with others acceptable as substitutes only if barbiturates are unavailable.

Tolerance. Both drug disposition and pharmacodynamic tolerance to the barbiturates develop with repeated administration. The first is caused by the activation of drug-metabolizing enzymes in the liver and consequent increase in the speed of detoxation of the drug. A higher dose is then required to maintain a given tissue concentration. The second involves the adaptation of nervous tissue to the presence of the drug. Tolerance develops quickly, and the CNS probably becomes resistant to the effects of the drug during the action of a single administration."'

The tolerance, however, is largely limited to the sedative and intoxicating effects of the drug. The lethal dose is not much greater for addicts than for nonaddicts. In addition, the range of tolerance is narrow. An individual tolerant to 1.2 grams of a particular drug may show acute intoxication if the dose is raised as little as 0.1 gram per day.

The other drugs of this class develop tolerance in the same way and with the same limitations as do the barbiturates.

Physical Dependence and Withdrawal. Severe physical dependence on the barbiturates develops, but, unlike the situation for the opiates, the dosages required for this effect are higher than the therapeutic dose. With pentobarbital, for example, 200 mg. per day can be taken for months without producing withdrawal, and 400 mg. per day for three months will produce EEG changes in only 30 per cent of the cases. The other 70 per cent apparently show no effects. After 600 mg. per day for one to two months, half the subjects will have minor withdrawal symptoms, and 10 per cent may have a seizure. After continuous, intoxication with doses of 900 mg. to 2.2 grams, 75 per cent of the subjects may have seizures, and 60 per cent delirium; all experience lesser symptoms."'

Defining "major" withdrawal symptoms as seizures or psychoses, the time and dosage necessary to produce severe physical dependence for different sedative hypnotics have been calculated as follows: ...

TABLE 1-1

ADDICTING DOSES OF COMMON SEDATIVE-HYPNOTICS*

Drug	Dependence- producing dosage (mg. daily)	Time necessary to produce dependence (days)	Drug dosage equivalent to 30 mg. of phenobarbital (mg.)
Secobarbital Pentobarbital	800-2,200	35-37	100
Diazepam (Valium)	80-120	42	10
Chlordiazepoxide hydrochloride (Librium)	300-600	60-180	25
Meprobamate (Equanil)	2,400	270	400

* Dosages sufficient to produce "major" withdrawal signs in humans.

As Table 1-1 indicates, the other sedative hypnotics are thought to produce dependence similar to that caused by barbiturates. They have not been as carefully studied.

We have found no study that divides opiate withdrawal into major" and "minor" symptoms. Thus, it is not possible to compare the development of barbiturate dependence with that of opiate dependence.

Once physical dependence develops, withdrawal from barbiturates is severe, and-unlike opiate withdrawal-may be life threatening. For one of the short-acting drugs, for the first twelve hours or so the patient seems to improve as the intoxication clears. He then becomes restless, anxious, tremulous, and weak, and sometimes has nausea or cramps. Within twenty-four hours, he may be too weak to get out of bed, experience severe tremors in the hands, and have hyperactive deep reflexes. The peak is reached on the second or third day, and convulsions may occur. Half the patients who have convulsive seizures go on to delirium, which occurs between the fourth and seventh days. This consists of high anxiety, hallucinations, and disorientation. Once delirium occurs, it may not be suppressed even by large doses of barbiturates. This is contrary to the normal course of withdrawal symptoms, which are quickly suppressed by the drug of addiction. The reason for this anomaly is not known. During the delirium, exhaustion and cardiovascular collapse may occur. The withdrawal syndrome usually clears by about the eighth day, if untreated. For longer-acting drugs, seizures may not occur until the seventh or eighth day, and the general course is slowed down accordingly."'

Hallucinations sometimes persist for months, but "this is felt by most investigators to be a manifestation of an underlying psychosis.""' The sources do not discuss whether barbiturates, like the opiates, have early and protracted abstinence syndromes.

Meprobomate (Equanil, Miltown) follows the short-acting course. Libriurn follows that of the long-acting barbiturates.

Mechanisms of Action. More is known about the fate of barbiturates in the body than is known about the other drugs of abuse. It is known, for example, that they are transformed by the liver into a number of inactive metabolites that are in turn excreted. This lessens the concentration of the drug and causes the withdrawal from its site of action in the CNS. The general state of knowledge concerning metabolism, physical redistribution, and excretion is discussed in the sources, as are the general theories of sites of action in the CNS. These are too technical to discuss here. The mechanisms by which barbiturates operate to cause CNS effects are not well understood."'

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A WORD ON ALCOHOL

Problems of alcohol and alcoholism were not within the mandate of the Drug Abuse Survey Project, and they have not been included in the report or in any of the supporting papers. In the context of this chapter, however, one comment should be made: Alcohol is a drug and could easily be analyzed in the same terms as the drugs that are covered. It has a potent psychoactive effect and is, like most of the drugs with which we are concerned, highly specific to the CNS. Both tolerance and physical dependence develop, and withdrawal can be a very serious clinical condition. The drug causes organic damage. The interplay of physiological factors and psychological factors involves as many uncertainties for alcohol as for the opiates.

In short, the common distinction between alcohol and "drugs of abuse" is based on the fact that alcohol is known and accepted in the culture, not on any pharmacological considerations. It is entirely possible that alcohol is inherently more dangerous than most of the other drugs discussed.

In his listing of the hazards of different drugs, Dr. Samuel Irwin makes the following rankings, starting with the most dangerous: ...

1. Glue sniffing

2. Methamphetamine

3. Alcohol

4. Cigarettes

5. Barbiturates and hypnotics

6. Heroin and related narcotics

7. LSD and other hallucinogens

8. Marijuana

---

NOTES

Because the same authors are cited continually in this staff paper, footnotes give only the author, date of publication when necessary, and page number. The complete references are as follows:

Baden, M. Interview by Project Staff.

Ball, I., and 1. Urbaitis. "Absence of Major Medical Complications Among Chronic Opiate Addicts," in 1. Ball and C. Chambers (eds.), The Epidemiology of Opiate Addiction in the United States (Springfield,

Ill.: Charles C. Thomas, 1970), p. 301.

Blacker, K. "Aggression and the Chronic Use of LSD,"journal of Psychedelic

Drugs, 111, No. I (September, 1970), 32.

Brazeau, P. "Oxytocics," in L. Goodman and A. Gilman, The Pharmacological Basis of Therapeutics (4th ed.; New York: Macmillan, 1970), p. 893. (This book is hereafter referred to as Goodman and Gilman.) Brotman, R., and A. Friedman. "Perspectives on Marijuana Research"

(Center for Studies in Substance Use; mimeograph, undated).

Chopra, C. "Man and Marijuana," The International journal of the Addictions, IV, No. 2 (June, 1969), 219-33,

Cohen, S. "Lysergic Acid DiethyIamide: Side Effects and Complications," journal of Nervous and Mental Disease CXXX (1969), 30. Cooper, J., F. Bloom, and R. Roth. The Biochemical Basis of Neuropharmacology (Oxford: Oxford University Press, 1970).

Dishotsky, N., W. Loughman, R. Mogar, and W. Lipscomb. "LSD and

Genetic Damage," Science, CLXXII (April 30, 1971), 431.

Dole, V. "Narcotic Blockade," Archives of Internal Medicine, CXVIII

(October, 1966), 304, 305.

... "Research on Methadone Maintenance Treatment," The International journal of the Addictions, V, No. 3 (September, 1970), 359.

Dole, V., and M. Nyswander. "Methadone Maintenance and Its Implications for Theories of Narcotic Addiction," in A. Wikler (ed.), The Addictive States (Baltimore, Md.: Williams and Wilkins, Inc., 1968), p. 359. Douglas, W. "Histamine and Antihistamines: 5-Hydroxytryptamine and Antagonists," in Goodman and Gilman, p. 620.

Eddy, N. Interview by Project Staff.

Eddy, N., et al. "Drug Dependence: Its Significance and Characteristics,"

Bulletin of the World Health Organization, XXXII (1965), 721.

Egozcue, J., and S. Irwin. "LSD-25 Effects on Chromosomes: A Review,"

journal of Psychedelic Drugs, 111, No. 1 (September, 1970), 10.

Esplin, D., and B. Zablocka-Esplin. "Central Nervous System Stimulants,"

in Goodman and Gilman, p. 348.

Fingl, E., and D. Woodbury. "General Principles," in Goodman and Gilman, P. 1.

Goldstein, A. Interview by Project Staff.

Goldstein, A., L. Aronow, and S. Kalman. Principles of Drug Action (New

York: Harper & Row, 1968).

Grinspoon, L. Marihuana Reconsidered (Cambridge, Mass.: Harvard University Press, 1971).

Health, Education and Welfare, Secretary of, Marihuana and Health: A Report to Congress, January 31, 1971 (GPO, March, 1971). Innes, 1. R., and M. Nickerson. "Drugs Acting on Postganglionic Adrenic Nerve Endings and Structures Innervated by Them (Sympathomimetic Drugs)," in Goodman and Gilman, p. 478.

Irwin, S. Drugs of Abuse: An Introduction to Their Actions and Potential Hazards (Student Association for the Study of the Hallucinogens, 1970).

Jaffe, J. "Narcotic Analgesics" and "Drug Addiction and Drug Abuse," in

Goodman and Gilman, pp. 237 and 276.

Jarvik, M. "Drugs Used in the Treatment of Psychiatric Disorders," in

Goodman and Gilman, p. 15 1.

Koelle, G. "Neurohumoral Transmission and the Autonomic Nervous System," in Goodman and Gilman, p. 402.

Kramer, J. "An Introduction to Amphetamine Abuse," journal of Psychedelic

Drugs, 11, No. 2 (1969), 1.

Lemberger, L., et al. "Marijuana: Studies on the Disposition and Metabolism

23. This estimate is based on interviews with several experts.

24. We found no studies on deaths by overdose.

25. Martin, 1970, p. 4.

26. Goldstein et al., p. 592.

27. Based primarily on Jaffe, pp. 239-60.

28. Martin, 1970, p. 4.

29. Jaffe, p. 240; Irwin, p. 5.

30. Goldstein et al., p. 474.

31. jaffe,p.279.

32. Ibid., pp. 279-80.

33. Ibid., p. 279; Goldstein et al., pp. 593-94.

34. Goldstein et al., pp. 597-99.

35. Eddy, 1965, p. 721.

36. Goldstein et al., pp. 600, 603.

37. jaffe,p.280.

38. Ibid., p. 288; Goldstein et al., pp. 602-3.

39. Martin, 1970, pp. 2-3.

40. Goldstein et al., p. 603; Jaffe, p. 281.

41. Goldstein et al., p. 605.

42. jaffe,p.283.

43. Goldstein, p. 605.

44. Jaffe, pp. 281-82.

45. Ibid., p. 282.

46. Dole, 1966, p. 305.

47. Goldstein, interview.

48. Goldstein et al., pp. 474-75.

49. Dole, 1968, p. 364.

50. Dole, 1970, p. 373.

51. Dole, interview.

52. Martin, 1970, pp. 8-9.

53. See Jaffe, pp. 296-97, and Brazeau, pp. 899-900.

54. This section is summarized from the Journal of Psychedelic Drug

September, 1970.

55. Jarvik, p. 196.

56. Ibid., p. 197.

57. Ibid.; laff e, p. 296; Shiek and Smith, p. 16.

58. Egozcue and Irwin, pp. 1 0-1 1.

59. Dishotsky et al., p. 439.

60. See Irwin, p. 8; Jaff e, p. 296.

61. McGlothlin et al., pp. 20-31.

62. Ibid., pp. 30-31.

63. Blacker, pp. 32-37.

64. Cohen, p.30.

65. Irwin, p. 9.

66. Shick and Smith, pp. 13-19.

67. Ibid.

68. D. Smith, 1969, p. 75.

69. jaffe,p.297.

70. D. Smith, 1969, p. 82; STASH, 1970.

71. Irwin, p. 8; Jaffe, pp. 297-98.

72. jarvik, p. 197.

73. Irwin, p. 9; Jaffe, p. 298.

74. Jarvik, p. 196; Cooper et al., pp. 157-59; Douglas, p. 656.

75. This section was written with the assistance of Peter Wilson.

76. Jaffe, p. 300; Meyers, p. 32.

77. Snyder, pp. 121-25.

78. Ibid.

79. Irwin, p. 7; Weil et al., p. 1242.

80. jaffe,p.300.

81. HEW, p. 68; Grinspoon, pp. 227-28.

82. Lemberger et al., p. 1322.

83. jaffe,p.299.

84. Tart, pp. 701-4.

85. Weil, p. 999.

86. Weil, letter.

87. Talbot and Teague.

88. D. Smith, 1968, p. 41.

89. Lemberger et al., p. 1322.

90. jaffe,p.300.

91. Brotman and Friedman, p. 20; Jaffe, p. 300; Irwin, p. 7.

92. See Innes and Nickerson, Jaffe, and Ritchie et al.

93. Innes and Nickerson, except as otherwise noted.

94. Esplin and Zablocka-Esplin, pp. 354-55.

95. Innes and Nickerson, p. 478.

96. Ritchie et al., pp. 379-82; Jaffe, p. 293.

97. Esplin anl Zablocka-Esplin, p. 354.

98. Kramer, p. 10; Jaffe, p. 295.

99. Ritchie et al., p. 381.

100. Kramer, p. 1 1.

101. Ibid., p. 12.

102. Jaffe, pp. 293-94; R. Smith, p. 35.

103. Jaffe, p. 294; Kramer, p. 9.

104. Kramer, p. 7.

105. Jaffe, pp. 294-95; Ritchie et al., p. 381.

106. jaffe,p.295.

107. Weil, Staff Paper 6.

108. R. Smith, p. 184.

109. Innes and Nickerson, pp. 503-4.

110. Jaffe,p.293.

111. Sharpless, pp. 98-134.

112. Irwin, p. 9; Weil, interview.

113. Sharpless, pp. 98-120.

114. Ibid.

115. Ibid., p. 100.

116. Eddy, p. 725.

117. Jaffe, pp. 289-90.

118. Sharpless, pp. 107-8.

119. laffe,p.290.

120. Ibid.

121. D. Smith and Wesson, pp. 294-95.

122. laffe,p.290.

123. Ibid.

124. Sharpless, pp. 101-2, 1 1 0-1 1.

125. Irwin, pp. 3-4.

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