that the so-called anorectic effect is the direct consequence of the central stimulant action common to all. From the accumulated experience, it seems unlikely that any minor structural change in this group which continues the same theme will separate the effect on appetite from the other effects of the central stimulant action that may be clinically undesirable. Yet it is precisely this which is inferred from many claims made for these drugs, namely, the recurrent claims for reduced incidence of insomnia, anxiety, and nervousness, with potent anorectic effect.

ever.

Although deaths have occurred from the amphetamine drugs, relatively few cases of acute poisoning and serious reactions have been reported as a result of their present large-scale and continued use. They are not innocuous, howSince they tend to induce insomnia, it is not surprising that the amphetamine drugs are of no value for the night-eating syndrome. They also may cause restlessness, excitement, depression, irritability, exhaustion, headache, dizziness, halitosis, dryness of mouth, burning in the throat, heartburn, nausea, vomiting, and diarrhea.

The typical sympathomimetic effects on the cardiovascular system, more developed in some members of this group than in others, provide a special area of potential danger. A rise in blood pressure, increase in cardiac work and heart rate, or the development of cardiac arrhythmias may be a serious matter for some patients who must lose weight.

Some tolerance may also develop, such useful actions as these drugs may have are relatively short-lived unless dosage is increased. Habituation has been reported after the continued use of some members of this group. The others may not have been in actual use for a sufficient period of time to have had this possibility fairly explored. On the basis of experience with the wellestablish members as well as one relatively new one and because the indica

tions are that the fundamental action is the same, this may well be a potential hazard for all these agents. The drugs, therefore, are not desirable for prolonged therapy.

The amphetamines present special problems in the evaluation of their effectiveness. Patients often promptly recognize the drug by one or another of the central stimulant effects (usually the "lift"). Thus, they can distinguish between drug and placebo when these are used in what theoretically appears to be a well-designed clinical evaluation with a double blind control. In patients with emotional disturbances particularly, who include most compulsive overeaters, the ability to distinguish medication from placebo by any effect other than the one under examination (in this case weight loss) makes it exceedingly difficult to prevent bias and psychological factors from shaping the apparent effects of the drug. This tends to reduce the sensitivity of methods of clinical evaluation of these drugs as well as to make it especially difficult to design a study in which these factors do not bias results. In other studies in which doses are so small as not to induce recognizable "lift," the doses are likely also to be too small to influence overeating by pharmacological action and hence either indicate a negative result for what might otherwise be an effectvie drug or produce effects due entirely to placebo action.

This raises the question of the validity of reports in which drugs of this series are said to have induced weight loss in a series of patients without causing any disturbing psychic effects. For example, there is no pharmacological basis for the implication that levo-amphetamine alginate can induce the effects of amphetamine on appetite without the usual undesirable central effects of the common salts of levo-amphetamine. The probable basis for a difference between them is that the alginate is relatively heavy compared to the sulfate and phosphate radicals, so that 5 mg. of levo-amphetamine alginate contains only about one-third as much levo-amphetamine as the commoner and less costly levo-amphetamine sulfate or phosphate. The early reports on levo-amphetamine alginate, therefore, most probably describe a placebo action in a study in which adequate dosage was not given. This is supported by other investigations which reveal that in order to reproduce the weight-losing effects of amphetamine sulfate three or four times as much levo-amphetamine alginate has to be used.

The racemic and levo forms of amphetamine are apt to cause palpitations because their cardiovascular action is relatively well developed, a fact which limits their usefulness in hyperphagia. Used in equiactive dosage, the alginate of levo-amphetamine is likely to reproduce all the cardiac effects of any other salt of levo-amphetamine.

Amphetamine resin complex is an exchange resin which releases racemic amphetamine slowly in the intestinal tract, thereby perhaps providing the amphetamine a little differently than usual; nevertheless, it is still amphetamine. Provided the resin is given in adequate dosage, there is no evidence that the exchange process in the intestine makes the amphetamine either more effective or less likely to induce undesirable central stimulant or cardiovascular actions. Indeed, failure to evoke the latter suggests inadequate dosage or such slow release as to be without any effect in the face of relatively rapid excretion. In exchange resins, since the rate of exchange in the intestinal tract is dependent on the nature of the intestinal contents, the release of amphetamine is likely to vary greatly in rate from time to time and from patient to patient. Its effects, therefore, are likely to be quite variable, if not undependable.

The dextro form of amphetamine differs pharmacologically from the levo form, in that the cephalotropic actions are intensified but the cardiovascular actions are feebler. The relative segregation of effects makes feasible doses which utilize the central actions sought in the treatment of patients who overeat, without inducing appreciable cardiovascular disturbance. It is a natural consequence, therefore, that dextro-amphetamine should also have a relatively greater tendency than does levo-amphetamine to cause anxiety, restlessness, insomnia, and other manifestations of its central stimulant action. This reemphasizes the close and inseparable correlation between potency of cephalotropism, usefulness in the treatment of overeating, and the incidence of undesirable central stimulation.

Methamphetamine, a simple analogue of amphetamine, seems to differ very little in pharmacological action from dextro amphetamine, although its effect on the cardiovascular system may be somewhat greater. Because it is not protected by a patent, it is cheaper.

Phenylpropanolamine has been suggested as an appetite depressant. Since it may be sold without prescription, it has found its way into remedies sold over the counter (e.g., Regimen tablets, Di-Dol, Rx 121) which are said to induce weight loss without dietary restriction. Although there is some evidence that if phenylpropanolamine is given in large enough dosage it will induce some anorexia, a recent study by Fazekas and others indicates that, in the usual doses found in these remedies (25 mg. or less), it is no more effective than a placebo. In any event, it is likely that, if doses were used which induced anorexia, difficulties would arise due to elevation of blood pressure.

Phenmetrazine has probably been better studied than any of the newer members of the group. Although it was originally claimed to be something different, the evidence is clear enough now that it is a typical amphetamine congener of about the same effectiveness as dextro-amphetamine, and, when given in dosage sufficient to suppress the appetite, it also promptly induces the undesirable cephalotropic actions typical of the amphetamine group in a large proportion of patients. In the doses ordinarily used, it has relatively little effect on the cardiovascular system. Habituation and psychotic reactions, indistinguishable from bromide hallucinosis, have been reported after its use. Phenyl-tert-butylamine resin, which is advertised as not being an amphetamine drug, is a carboxylic acid-type of exchange resin which contains substituted phenylbutylamine moieties that are released in the gastrointestinal tract. As shown in the formulas, the amine itself clearly belongs to the amphetamine series. Thus, although the statement that this product is not amphetamine is technically defensible, the biological fact is that the active agent is a close relative of amphetamine. This is released in the intestine by the resin, and any effect on appetite or elsewhere follows from the typical effects of an amphetamine-like drug. The intensity of central stimulant effects, characteristic of those induced by amphetamine, depends on the rate of the release of the amine in the exchange process. The same reservations about the regularity and reliability of the rate of release from an exchange resin in the intestine made for amphetamine resin complex hold for phenyl-tert-butylamine resin. There is little in the literature on which to base a substantial evaluation of the clinical effectiveness of this drug. Only a guess is possible, and a good guess is that the general picture of the treatment of overeating with amphetamine congeners will be unaltered by this agent.

At present, diethylpropion is the latest addition to the series. The drug is clearly one of the amphetamine series (see formulas), and, in view of the accumulated experience with these drugs, despite early statements in the limited literature on the drug, it seems likely that the actions and limitations will be the same for this as for the others in the group. It is stated in advertisements that "tolerance, habituation and addiction have not developed," but this is not necessarily a meaningful statement. It usually takes several years of general experience with drugs before such predilections are brought out, as was the case with amphetamine, for example. Since diethylpropion is a new drug, it may not have been in use for a sufficient period to have had all its limitations revealed and published. On the basis of previous experience with other members of the amphetamine series, the possibility of habituation also must be seriously considered.

In short, the field of the amphetamine-like compounds is likely to be enlarged still further. as each new drug adds nothing but a new name to the total problem of overeating. In any member of this series, there is no evidence that the characteristic central stimulant actions are so segregated that the drug retains its effects on overeating while it loses its tendency to cause restlessness, insomnia. and anxiety. As a matter of fact, it would be much more realistic to view these not as side-effects but as part of the outstanding pharmacological action of the drugs, with distraction of the abnormal appetite being a secondary effect. There is no evidence that any member of the series is distinguished by a decreased tendency to habituation and tolerance.

In a search for advantages, it seems obvious that some new pharmacological series should be investigated. Only a few reports have been noted at this time suggesting that distinctly different central stimulants (amine oxidase inhibitors and others so-called psychic energizers such as pipradrol [Meratran] and methylphenidate [Ritalin] might be useful in a similar way. They require further trial.

Metabolic Stimulants.-About 25 years ago, dinitrophenol was used briefly in the treatment of obesity. Dinitrophenol increases the basal metabolic rate, apparently with little stimulation of appetite and the sensation of warmth which limits the use of effecitve doses of thyroid hormone for the same purpose. Weight loss was achieved with use of the drug, but the development of cataracts and other toxic effects led to its early abandonment. No similar drug is currently in use.

Thyroid has been used on occasion over the years. If the patient's diet can be limited, despite the stimulation of his appetite by the hormone, use of thyroid results in weight loss. Since obese patients have difficulty in restraining their appetites under the best of circumstances, most patients fail to limit their intake sufficiently (with the added stimulus to their appetites provided by thyroid medication) to lose encouraging amounts of weight. This, together with discomfort due to palpitations, warmth, nervousness, insommia, and excessive perspiration, makes it uncommon for the treatment to be effective, to be continued long, or to be used in patients with heart disease. Reports of good results with sodium liothyronine (Cytomel) in obesity have recently appeared. Small doses which did not disturb metabolic function, cholesterol levels, blood pressure, and heart rate were used. Central stimulation as evidenced by nervousness or tremors was not noted. It should be pointed out, however, that the effect of liothyronine per se was not examined-rather its influence on a regimen, which also included amphetamine and amobarbital (Amytal), was examined. None of these results, therefore, applies to the liothyronine alone. Further examination is warranted.

Sedatives and Tranquilizers.-Since an emotional disturbance of some sort is the basis of overeating in many persons, sedation and tranquilization may possibly assist in depression of appetite. The effect of chlorpromazine (Thorazine) on overeating has been reported to be effective in some cases. Unfortunately, the study was poorly controlled, and the necessary confirmation has not been forthcoming. It is possible that this form of medicament will be effective for the night-eating syndrome-a situation in which the stimulant action of amphetamine is likely to make matters worse. Mixtures of an amphetamine material with a barbiturate or a tranquilizer, such as amobarbital, rauwolfia (Raudixin, Rauserpa, Rauval), or meprobamate (Equanil, Meprospan, Meprotabs, Miltown) to counteract the undesirable central stimulant effects of the amphetamine drugs, have been tried and reported to be both effective and useful. Better studies are necessary to confirm the usefulness of the combination.

Bulk Producers.-Bulk has long been suggested as a means of satiating the appetite of the obese. Unfortunately, cabbage, lettuce, and other articles of the typical grassy, high-bulk, low-calorie diet do not appeal to the average overeater, who perversely prefers to distend his stomach with undiluted fat, protein, and carbohydrate. Cellulose and similar materials have been suggested as a substitute for food but since this provides bulk for the intestine as well as for the stomach, in the amounts necessary to stay gastric activity, it could never be a satisfactory substitute for food. With these limitations in mind, it is no surprise that methylcellulose has been found neither to appeal to nor to stay the appetite of the average person who overeats. The physiological basis for this is very nicely explained in experiments by Miller.

Purgatives and Diuretics.-Many expensive obesity cures and regimens depend on an exhibition of weight loss to entice the patients into continuing treatments, especially in expensive salons. In order to induce gullible persons to a course of treatments, devices are used which provide spurious evidence of prompt effectiveness, without a difficult dietary regimen. Cathartics, diuretics, and salt restriction are often used in such schemes, for, through dehydration, they induce some weight loss very promptly. In contrast to the effect in the edematous patient, however, in the obese patient, weight loss by water excretion is both meaningless and senseless. Through the operation of the normal homeostatic mechanisms, the moment an opportunity arises to retain electrolyte and the water it binds through osmotic tension, the lost water is retained, and, with it, the lost weight is regained. In any event, it does not represent a loss of fat.

Miscellaneous Devices.-Although there is no reason to think that vitamins and minerals would have any merit, it is not at all surprising that they should be recommended for use in the treatment of obesity (since they have been tried for virtually everything else). What is strange, however, is that sweets (Ayds, R.D.X.), containing other nutritional elements in addition, should have been introduced and should have their enthusiastic supporters. Weight loss through the use of such unscientific preparations can only be excellent proof of the importance of the psychogenic elements involved and of the effectiveness of suggestive advertising.

SUMMARY

New and logical pharmacotherapy for persons who overeat will more likely come with understanding of the processes involved than through the current practice of developing more variations on old themes which have already been well exploited and have not satisfied the need. There is really nothing new on the scene. There are no "anorexiants" to fit specific disturbances in eating patterns, and there are no useful depressants of the appetite center, wherever it may be. Total therapy must consider the psychosocial aspects of eating patterns and the desire to lose weight, as well as the specific psychological or physiological disturbance which has brought on the hyperphagia. In virtually every instance, motivation for losing weight as well as the psychological reasons for overeating are important considerations in determining the therapeutic regimens which are likely to be effective and to lead to sustained benefits. Current pharmacotherapy for persons who overeat has limited use. Insofar as drugs are concerned, at the very best, their potential is secondary to the elimination of the cause of the hyperphagia. Drugs which give assistance along the lines now available provide short-lived symptomatic relief only. These seem to be useful only as adjuvants to a carefully controlled diet and, in many cases, some sort of psychotherapy.

NOTE. References for this article are available in reprints.

73753 0-61-pt. 2- -S