SULPHATE IN CLINICAL MEDICINE: A SURVEY OF THE … · Limited as "Benzedrine" Tablets....
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BENZEDRINE SULPHATE IN CLINICAL MEDICINE: A SURVEY OF THE LITERATURE By W. R. BETT, M.R.C.S, L.R.C.P., F.C.S., F.S.S. "Some are born great, some achieve greatness, and some have greatness thrust upon them." History There is an element of historical curiosity in the reflection that benzedrine, which was born and baptised in America and which is so typically American in its psychology, was the academic brain child of two British scientists. As long ago as I9IO Barger and Dale' included this substance in their now classic study on the relationship between chemical structure and sympathomimetric action of amines. Chemically related to, and pharmacologically comparable with, adrenaline and ephedrine, ben- zedrine sulphate is systematically known as ,B-aminopropylbenzene, dl-c-methylphenethyla- mine or phenyl-l-amino-2-propane. Its formula is C6H5. CH2. CH (NH2). CH3. H H H C-C- CH <H H OH HNH It was first synthetised in I927 by G. A. Alles2 of Los Angeles, while searching for a substitute for ephedrine, which would be more economical and easier to prepare, "Benzedrine"* (Reg. U.S. Pat. Off.) is the trade name of Smith, Kline and French Laboratories of Philadelphia, for this chemi- cal compound which was given the nonproprietary name "Amphetamine" by the Council on Pharmacy and Chemistry of the American Medical Associa- tion. This name has since been adopted in Great Britain by the British Pharmacopoeia. It may be doubted whether, with the possible exception of the sulphonamides, penicillin, and streptomycin, any therapeutic agent of modern scientific medicine has aroused such vivid interest in professional circles and in the lay press as benzedrine. sulphate. A veritable deluge of litera- ture has been let loose concerning its uses and abuses, its virtues, vices, and potentialities. In the salad days of- its therapeutic career, benzedrine not so much achieved, as had thrust upon it, an immense Press publicity, even notoriety: the "Con- fidence Drug"-"Pep Pills"-"Reach for a Pill * Benzedrine carbonate was introduced into medicine in 1932 as a nasal vaso-constrictor (Benzedrine Inhaler). Amphetamine sulphate is issued in the U.S.A. by Smith, Kline and French Laboratories as "Benzedrine Sulfate' Tablets" and in a liquid dosage form as "Benzedrine Sulfate Elixir"; and in Great Britain by Menley & James Limited as "Benzedrine" Tablets. instead of a Cocktail." The wave of sensationalism engulfed apprehensive students, tired cify mag- nates, housewives bored with the monotony of their unexciting lives. The wave of sensationalism spread, engulfing psychologists and philosophers, who were intrigued by the vast possibilities of a drug which promised to open up unexplored fields in the study of consciousness. With the passage of the years and the ripening of experience benzedrine 'sulphate has found a rationally established place in clinical medicine as a drug with divers and valuable indications, if employed intelligently and with mild scepticism. For many of the published reports have been so striking as to encourage indiscriminate use without proper trial in controlled conditions. Since January I, I939, benzedrine has been obtainable only on the prescription of a registered medical practitioner or the signing of the Poisons Register.3 Mode of Action At a discussion on Modes of Drug Action held by the Faraday Society in I9434 interesting sug- gestions were advanced to explain the mechanism of action of benzedrine, especially on metabolic processes in the central nervous system. The presence of amines such as tyramine produces a marked diminution in the respiration of brain cortex examined in vitro. The addition of ben- zedrine neutralises this inhibition. The fall in brain respiration in the presence of tyramine is not due, wholly to the amine itself, but to a product of oxidation of the amine, the corresponding aldehyde. Benzedrine owes its stimulating action in brain respiration in the presence of inhibiting amines to its ability to compete reversibly with amines for the amine oxidase of brain, thereby reducing the rate of formation of the inhibitory aldehyde. It is either very feebly or not at all attacked by amine oxidase, for which it never- theless possesses a high affinity. The effects of benzedrine in vitro, in partially neutralising the inhibition of glucose oxidation by brain due to the presence of tyramine and other amines, take place at concentrations not considerably higher than those having pharmacological actions in vivo. Competition between benzedrine and other amines for amine oxidase occurring according to the laws of mass action, it follows that the influence of benzedrine may be exerted in the body at much by copyright. on August 28, 2019 by guest. Protected http://pmj.bmj.com/ Postgrad Med J: first published as 10.1136/pgmj.22.250.205 on 1 August 1946. Downloaded from
Transcript of SULPHATE IN CLINICAL MEDICINE: A SURVEY OF THE … · Limited as "Benzedrine" Tablets....
BENZEDRINE SULPHATE IN CLINICAL MEDICINE:A SURVEY OF THE LITERATUREBy W. R. BETT, M.R.C.S, L.R.C.P., F.C.S., F.S.S.
"Some are born great, some achieve greatness, and some have greatness thrust upon them."
HistoryThere is an element of historical curiosity in the
reflection that benzedrine, which was born andbaptised in America and which is so typicallyAmerican in its psychology, was the academic brainchild of two British scientists. As long ago asI9IO Barger and Dale' included this substance intheir now classic study on the relationship betweenchemical structure and sympathomimetric actionof amines.
Chemically related to, and pharmacologicallycomparable with, adrenaline and ephedrine, ben-zedrine sulphate is systematically known as,B-aminopropylbenzene, dl-c-methylphenethyla-mine or phenyl-l-amino-2-propane. Its formulais C6H5. CH2. CH (NH2). CH3.
H H HC-C- CH
<H HOH HNH
It was first synthetised in I927 by G. A. Alles2of Los Angeles, while searching for a substitutefor ephedrine, which would be more economicaland easier to prepare, "Benzedrine"* (Reg. U.S.Pat. Off.) is the trade name of Smith, Kline andFrench Laboratories of Philadelphia, for this chemi-cal compound which was given the nonproprietaryname "Amphetamine" by the Council on Pharmacyand Chemistry of the American Medical Associa-tion. This name has since been adopted in GreatBritain by the British Pharmacopoeia.
It may be doubted whether, with the possibleexception of the sulphonamides, penicillin, andstreptomycin, any therapeutic agent of modernscientific medicine has aroused such vivid interestin professional circles and in the lay press asbenzedrine. sulphate. A veritable deluge of litera-ture has been let loose concerning its uses andabuses, its virtues, vices, and potentialities. Inthe salad days of- its therapeutic career, benzedrinenot so much achieved, as had thrust upon it, animmense Press publicity, even notoriety: the "Con-fidence Drug"-"Pep Pills"-"Reach for a Pill
* Benzedrine carbonate was introduced into medicinein 1932 as a nasal vaso-constrictor (Benzedrine Inhaler).Amphetamine sulphate is issued in the U.S.A. by Smith,Kline and French Laboratories as "Benzedrine Sulfate'Tablets" and in a liquid dosage form as "BenzedrineSulfate Elixir"; and in Great Britain by Menley & JamesLimited as "Benzedrine" Tablets.
instead of a Cocktail." The wave of sensationalismengulfed apprehensive students, tired cify mag-nates, housewives bored with the monotony oftheir unexciting lives. The wave of sensationalismspread, engulfing psychologists and philosophers,who were intrigued by the vast possibilities of adrug which promised to open up unexplored fieldsin the study of consciousness.With the passage of the years and the ripening
of experience benzedrine 'sulphate has found arationally established place in clinical medicine asa drug with divers and valuable indications, ifemployed intelligently and with mild scepticism.For many of the published reports have been sostriking as to encourage indiscriminate use withoutproper trial in controlled conditions.
Since January I, I939, benzedrine has beenobtainable only on the prescription of a registeredmedical practitioner or the signing of the PoisonsRegister.3
Mode of ActionAt a discussion on Modes of Drug Action held
by the Faraday Society in I9434 interesting sug-gestions were advanced to explain the mechanismof action of benzedrine, especially on metabolicprocesses in the central nervous system. Thepresence of amines such as tyramine produces amarked diminution in the respiration of braincortex examined in vitro. The addition of ben-zedrine neutralises this inhibition. The fall inbrain respiration in the presence of tyramine isnot due, wholly to the amine itself, but to a productof oxidation of the amine, the correspondingaldehyde. Benzedrine owes its stimulating actionin brain respiration in the presence of inhibitingamines to its ability to compete reversibly withamines for the amine oxidase of brain, therebyreducing the rate of formation of the inhibitoryaldehyde. It is either very feebly or not at allattacked by amine oxidase, for which it never-theless possesses a high affinity. The effects ofbenzedrine in vitro, in partially neutralising theinhibition of glucose oxidation by brain due to thepresence of tyramine and other amines, take placeat concentrations not considerably higher thanthose having pharmacological actions in vivo.Competition between benzedrine and other aminesfor amine oxidase occurring according to the lawsof mass action, it follows that the influence ofbenzedrine may be exerted in the body at much
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lower concentrations than have been utilised inexperiments in vitro. It is suggested that theaction of benzedrine in vivo is linked with itsability to compete with amines which produce toxicsubstances by oxidation. The lower the concentra-tion of such amines, the lower the quantities of ben-zedrine needed to compete successfully with them.The length of action of benzedrine is approxi-
mately eight hours. People of pyknic build appearto tolerate it better than the asthenic. The formerreact to anxiety with a more parasympathetic typeof response, e.g; sensations of a dropping stomach,sweating, slower action of the heart, while the latterrespond more sympathetically, with palpitationsand tremors. Depending on the predominance ofone or other type of response, the effect of ben-zedrine will be mainly beneficial or mainly un-pleasant. In order to get the best out of the drug,the individual reaction should be observed, andthe beneficial effect may still be utilised, if itsunpleasant autonomic action is neutralised by someother drug such as a barbiturate.5
Physiological ActionsI. Body TemperatureDoses of 20 mg. or more of benzedrine sulphate
may cause a slight rise in body temperature lastingseveral hours.6' 7
2. Pulse RateThe effect of benzedrine on pulse rate is variable.
After IO to 20 mg. an increase of 9 beats a minutefor several hours has been observed.8
3. Blood PressureIn oral doses of less than 20 mg. benzedrine sul-
phate has little. effect on blood pressure.9. 10Twenty mg. by mouth has generally been consideredthe minimal pressor dose, the effect usually begin-ning within 15 to 30 minutes after administrationand reaching its peak within I to 3 hours. Returnto the original level occurs within 5 to 8 hours.On subcutaneous or intramuscular injection thepressor effect is more marked, more rapid, andmore evanescent,11' 12 When the drug is adminis-tered over long periods, tolerance to the pressoreffect is frequently developed.
4. RespirationIn man, benzedrine sulphate in therapeutic doses
has little or no effect on respiration, with possiblya slight tendency to decrease in rate and compen-satory increase in volume.13
5. Blood PictureParticularly after large doses of benzedrine, the
blood count is often greatly increased, apparently
due to mobilisation of blood cells from thesplanchnic area,11 the white blood count beingmore affected than the red. When the drug isadministered over prolonged periods, no demon-strable change results.146. Blood Chemistry
Benzedrine induces little change either in theblood sugar (with, perhaps, a tendency towardincrease9) or in non-protein nitrogen.15 * The acid-base balance of the blood is not appreciablychanged by I0 to 20 mg. under normal or anoxicconditions.'67. Gallbladder
Benzedrine retards the evacuation of the gall-bladder if a fatty meal is given two hours after itsadministration.178. Electrocardiogram
In therapeutic doses benzedrine causes no sig-nificant changes in the electrocardiogram.18
ExcretionThe excretion of benzedrine in the urine begins
within three hours after oral administration of 20or 30 mg. About 30 per cent of the base iseliminated during the first 24 hours, 40 per centover a period of 48 hours.19
Clinical Usesi. NarcolepsyFrom the historical point of view it is interesting
to recall that the first clinical report on the use ofbenzedrine sulphate was in the treatment ofnarcolepsy (Prinzmetal and Bloomberg, I935).20Though this strange disorder first attracted
attention in i88o, it remained little understooduntil World War I, when the problem of the sen-tinel asleep on duty focused practical interest onthe question of pathological somnolence. Beforethe advent of benzedrine ephedrine had been thefavourite treatment, accompanied by moderatesuccess. In I935 Prinzmetal and Bloomberg20revolutionised its therapy by introducing ben-zedrine in doses of I0 mg. once daily to 40 mg.three times daily, which they described as threetimes more effective than ephedrine in completelypreventing attacks of sleep and in giving practicallycomplete relief from cataplexy. They noted theabsence of side-effects such as stimulation of theperipheral sympathetic system, the low toxicity,and the prolonged action. In some of their cases ben-zedrine completely relieved symptoms which hadfailed to respond to enormous doses of ephedrine.To Ulrich2l two years later oral medication with
benzedrine sulphate appeared to be the only satis-
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factory method of treatment. No deleteriouseffects were observed in his cases, and there wasno evidence of habit formations Obesity is afrequent accompaniment of narcolepsy, and it isinteresting to note that some of his patients lostweight while takipg benzedrine.Lehrman and Weiss22 employed benzedrine suc-
cessfully in treating narcolepsy and cataplexy ina paranoid schizophrenic.To-day there is general consensus of opinion that
for narcolepsy benzedrine is specific and diagnostic.Anything from 20 to 6o mg. daily may be requiredto abolish the attacks of somnolence, but therequisite dosage, once attained, can be continuedfor years without increase.23Although the relief obtained with benzedrine is
on the whole symptomatic rather than curative,Gorrell24 was able at times to withdraw the drugentirely in mild cases, when new habits of sleepwere formed.
According to Modlin,25 "the use of benzedrinemarkedly helps the majority of patients and turnsthem from social and occupational misfits intouseful adjusted citizens. The stimulating effectsof this drug on the drowsy cerebral cortex areremarkable and completely alter the life of manynarcoleptics."One of the possible contraindications to the use
of benzedrine in narcolepsy was reported by Youngand Scoville26 who administered the drug in twocases complicated by anxiety neurosis, in whichit contributed to the precipitation of an activetemporary psychosis.
2. EpilepsyAnticonvulsant drugs such as phenobarbitone,
which constitute the most useful form of treatmentin epilepsy, may in susceptible persons give rise tounpleasant and incapacitating side-reactions suchas dullness, irritability, and ataxia. These are attimes so exaggerated as to necessitate withdrawalof the drug. There is general agreement in theliterature that benzedrine sulphate, taken bymouth, is a valuable adjunct to phenobarbitonetherapy, neutralising its sedative, without spoilingits anticonvulsant, effect.15, 27, 28, 29, 30 The ad-ministration of benzedrine permits phenobarbitoneto be continued in doses large enough effectivelyto control the epileptic fits, even though the amountgiven of the sedative drug would, by itself, producetoxic results.Cohen and Myerson15 spoke of benzedrine being
specific in the abolition of ataxia and drowsinesswhich complicated a course of phenobarbitonemedication in fifteen patients. In many casesbenzedrine can be omitted after a few weeks, whilein others it appears to be required permanently.There is a good deal of controversy whether the
drug affects the number and severity of the epilepticseizures. Benzedrine has been successfully usedin the management of petit mal in children,30 andimpulsiveness and violence in epileptoid childrenwith abnormal encephalograms are reported toyield to the drug in doses of 20 mg. daily3l. On theanalogy of its value in narcolepsy benzedrine mightwell be very useful in the so-called inhibitoryepilepsy (Feiling).323. Post-Encephalitic ParkinsonismWhile benzedrine sulphate does not benefit
the psychotic manifestations of post-encephaliticParkinsonism (Reznikoff),33 a number of authori-tative reports in the literature agree that suchsymptomatic features of the pathological conditionas general malaise, drowsiness, lethargy, anddepression yield to the drug in doses of io mg.morning and midday (Solomon et al.,34 Critchley35).Benzedrine is described as being particularly effec-tive when used in combination with scopolamineor stramonium.34 The drug appears to have aspecific action in abolishing or reducing the numberand severity of oculogyric crises, which occur in3 to 20 per cent of the cases. In Solomon, Mitchell,and Prinzmetal's 34 28 cases these crises ceased tobe troublesome in 93 per cent. Out of Weiner's3624 patients I9 showed definite decrease in thefrequency and severity of oculogyric crises, mus-cular rigidity, dysphagia, lethargy, narcolepsy, anddepression under treatment with a combinationof benzedrine and stramonium. Hoffman37 ob-tained 50 per cent relief in I7 patients exhibitingoculogyric crises with benzedrine in daily doses ofI0 to 30 mg. administered together with a drugof the belladonna group. Solomon and Prinz-metal's38 findings are interesting and significant:of i8 patients treated with from 5 to 6o mg. ben-zedrine a day i8 showed increased energy, I7disappearance of drowsiness, I4 decrease in muscu-lar rigidity, 13 increase in strength, and 5 decreasein tremor. Kamosh and Zucker:39 recommend amorning dose of i grain of benzedrine in additionto hyoscine or stramonium to produce increasedanimation and diminution of fatigue. WhileSolomon, Mitchell, and Prinzmetal34 found ben-zedrine ineffective in the arteriosclerotic groupof patients, according to Davidoff, Reifenstein,and Chambers 40 this drug constitutes the besttreatment for Parkinsonism, including arterio-sclerotic cases.4. Fatigue and Depression
It is in the treatment of depressive states,especially the milder types with retardation ofphysical and mental processes and absence ofanxiety or excitement, bringing in their train suchsymptoms as apathy, lassitude, difficulty in con-centration, indecision, irritability, pessimism,
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anorexia, constipation, vague abdominal discom-fort, and paraesthesiae, that benzedrine has builtup for itself a reputation unique in therapeutics.A large number of clinical observations both fromgeneral practitioners and from specialists testifyto its immediate and often dramatic value inbreaking the stranglehold of the depression, res-toring "energy feeling," and renewing optimism,self-assurance, increased initiative, appetite forwork, and zest for living. Among the conditionsbenefited by the drug are the mental sequelae ofinfluenza and other acute infectious diseases;depression incidental to dysmenorrhaea and themenopause; depression following child-birth; andthe persistent characteristic depression of old agewith its self-absorption, withdrawal from socialcontacts and former interests, and loss of enjoy-ment of the minor pleasures of life. All thesedepressive states are potentially dangerous, inter-fering as they do with sleep, appetite, and thenormal activities of life, and because of theirserious consequences in the shape of alcoholicoverindulgence and contemplated suicide. Wilburand his colleagues4' report favourable and in somecases spectacular results in 25 out of 32 patientswith the typical complaints of fatigue, lack ofenergy, and lassitude. Using benzedrine in dosesof 2-5 mg. on arising (repeated, if necessary, atI0.30 a.m. and I.30 p.m.) in 50 cases of milddepression not accompanied by agitation, Rudolf42found that those patients were most benefited whowere depressed in the morning, but brightened uplater in the day. The value of the drug in tran-sitory depressive states of the reactive type inwhich there is difficulty in meeting a situation isstressed by Eggleston and Weiss.43 The usefulnessof benzedrine in chronic exhaustion was effectivelyproved in 32 cases by Wilbur and his colleagues44,one or two doses leading to immediate improve-ment. In some instances the results are describedas spectacular: complete disappearance of exhaus-tion, marked exhilaration, and increased capacityfor physical and mental effort.
Benzedrine is of greater value in the acute toxicor infectious states of depression than in functionalstates and psychoneuroses or in the prolongedorganic conditions. It appears to be more usefulin those organic states where no psychosis is demon-strable and where deterioration or personalitychanges are minimal and non-progressive. In thepsychoses it is of value in cases of recent onset dueto intoxication, particularly alcoholic. Benefit inthe post-infectious and post-traumatic psychosesmay be marked. Paranoid conditions of whateverorigin are not infrequently aggravated by the drug(Davidoff and Reifenstein).45,46 The fact that theadministration of benzedrine often produceseuphoria, decrease in negativism, and increase in
accessibility, thus facilitating the management ofa case, has been emphasised by several clinicians.Guttmann's47 remark, "It is a relief to hear sucha patient say he feels better, instead of hearinghis usual daily complaints," vividly sums up thepresent significance of benzedrirte in the therapyof manic-depressive insanity. Woolley48 is con-vinced that benzedrine, properly administered instates of extreme depression and retardation, mayon occasion determine the difference betweenprolonged serious illness and fairly prompt recovery.That there is a sound basis for using benzedrine
in emergencies to tide people over periods of tem-porary, though acute strain, since it relieves tired-ness due to lack of sleep, postpones the necessityfor rest, and delays the onset of irritability,inattention, and fatigue, is brought out in thefollowing quotations:
"There are social and personal circumstanceswhere to fall asleep or to suffer with ternporaryfatigue would be disastrous in a somewhat imper-fect world. Under these exceptional circumstances5 to I0 mg. does no harm and meets a tryingsituation better than any other chemical of thepresent-day pharmacopoeia" (Myerson).49
"Often the physician is called upon to make animportant decision, perhaps a life-saving one, whenhe is sleepy, tired and emotionally fatigued. Poorresults in obstetric and surgical cases may be tracedto this factor of mental fatigue; a diagnosticpossibility is overlooked, and operation is post-poned until morning or a procedure is carried outdue to insistence of relatives. The doctor who iscalled to attend a seriously ill patient, performan operation or deliver a baby, should take a I0 mg.tablet of benzedrine as soon as he is notified.Within an hour he will be alert, his mind wideawake and his mental and physical skill will benormal. He need have no fear of addiction"(Gorrell).24 The drug thus possesses vast possi-bilities in nightwork, since it keeps people awakewhen there are long periods of inactivity, enablingthem to concentrate on their jobs and helping toclarify the brain.50 Though benzedrine does notactually diminish fatigue, merely stimulatingpsychomotor activity (Thornton et al.),51 its sub-jective effect on fatigue is very real. It is nota substitute for sleep and rest, but only postponestheir necessity during exceptional periods of physi-cal and mental stress and strain.The normal dosage of benzedrine advocated for
the depressive states is 5 to 20 mg. daily, adminis-tered in one or two doses before lunch. As a ruleit is not necessary to give more than I0 mg. at asingle dose. If there is no response to 20 mg., anincrease in dosage is generally accepted to proveineffective. Johnson52 recommends an initial doseof 7 5 mg. after breakfast and 5 mg. after lunch.
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This is increased by 2 * 5 mg. until the optimal levelis reached.
5. SchizophreniaOpinions on the value of benzedrine in schizo-
phrenia are divided. That it can be a dangerousdrug in this condition is agreed on by a numberof clinicians. Sargant and Slater,53 for example,issue the warning that, though on occasion it willrelieve the hebetude and inertia of the schizo-phrenic, it may do this only to precipitate an un-expected outburst of excitement or to provide theinitiative to carry out a murderous attack inspiredby the patient's delirium. Davidoff and Reifen-stein,54 on the other hand, report improvement in40 per cent of 57 cases, treated with benzedrinesulphate alone, either orally or intravenously, orwith benzedrine sulphate intravenously in com-bination with sodium amytal by mouth. Thefollowing dosage is recommended: on the first dayIO mg. benzedrine sulphate intravenously, followednext day by o i to o 2 gm. sodium amytal orally,repeated every hour until narcosis is obtained; onthe third day 30 mg. benzedrine intravenously, fortwo or three weeks. Orally IO to 30 mg. benzedrinemay be given from ten days to three months. Thedrug appears to be most effective 'in the treatmentof incipient dementia praecox of the catatonic type,and by the intravenous route. It is described asbeing of value in differentiating between schizo-phrenic and alcoholic psychoses, and also in ren-dering the schizophrenic patient more accessibleto investigation and to psychotherapy. InSereiskii's5r exPerience some effect is shown duringthe first few days, followed either by return to theoriginal state or by deterioration. Seven of 2Icatatonic schizophrenics treated by Woolley48 withbenzedrine by mouth in doses of from IO to 6o mg.in aqueous solution (i mg. per c.c.) either recoveredor improved during therapy. Psychotherapeuticaccess became possible through the improvedmental state. Twenty-one of 44 schizophrenicswere unaffected by the drug, and ii were madedecidedly worse. Among the more unfavourableresponses noted was the precipitation of panics intense or agitated, depressed or catatonic individuals.In one patient administration of benzedrine pre-cipitated a serious impulsive attempt at suicide.
6. AlcoholismThere is general agreement in the literature that
benzedrine is a most useful drug in the variousstages of alcoholism. The acute alcoholic cycleMiller56 was able successfully to interrupt withio mg. benzedrine orally after breakfast and afterlunch in 49 cases out of 56, the average durationof alcoholism being I6 years. Physical and mental"hangover effects" were markedly reduced. Soon
after treatment an impressive improvement wasnoted in awareness, sensory perception, and activitydrive. Mood and rapport were improved, patientsdemonstrating greater co-operation, increasedaccessibility, and decreased negativism. Basingtheir observations on a series of over ioo cases,compared with a comparable series of control cases,Reifenstein and Davidoff57 found that in the acutealcoholic psychoses the length of time necessaryfor recovery was considerably diminished by theemployment of benzedrine, frequently by half, andthe number of recoveries was slightly increased.In the protracted alcoholic psychoses tendingtowards deterioration the results were of very littlesignificance, except in the Korsakov group, where asmaller number of cases required commitment aftertreatment with the drug. While benzedrine wasuniformly effective in the acute phases of alcoholicintoxication, in the treatment of chronic alcoholicaddiction it proved uniformly unsatisfactory,exceptthat the depression associated with the latterresponded to the drug during an institutionalregime. The authors point out that in alcoholicstates complicating mental illnesses benzedrinemay be of value in differentiating depressive statesdue to alcohol alone, which are rapidly relievedby the drug, from states of alcoholic depressionsuperimposed on and masking depression of psycho-genic origin, which do not respond as readily.
In chronic alcoholism Bloomberg58 suggests thatthe employment of benzedrine introduces a sufficientinterval of sobriety for psychotherapeutic methodsto be instituted. Treating 2I ambulatory casesof chronic alcoholism (these were not asked to avoidparties) with io mg. on rising and again at noon,he found that 8 had completely abstained fromalcohol since beginning treatment, periods of treat-ment lasting up to I3 months. Only four aredescribed as total failures, though even in threeof these there were short periods of abstinence.If a patient had to fulfil an evening engagement,where drinks were likely to be consumed, an extraIO mg. benzedrine was given late in the afternoon.Of 55 cases of chronic alcoholism treated byBloomberg59 with benzedrine for periods varyingfrom a few weeks to 31 years about 25 per centhave remained totally abstinent and between 8oand 85 per cent have undergone significant modi-fication of th,eir drinking habits. By relieving thechronic "hangover" and depression of the chronicalcoholic during the period of withdrawal benze-drine is a useful adjuvant to any form of therapy.The patient is made to feel that something concreteis being done for him. According to the sameauthor60 benzedrine also successfully smoothes out"mood swings" and gives the patient a "lift" onhis bad days. "In benzedrine sulphate," writesMiller,61 "the medical profession is offered a new
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and relatively safe remedy with which to combathabitual alcoholism." Berwald and Williams62describe benzedrine sulphate in doses of IO mg. bymouth as the drug par excellence for the headachedue to overindulgence in alcohol. Rinkel andMyerson63 in a series of pharmacological studiesin experimental alcoholism found that benzedrinelowers the blood concentration of alcohol, probablyby inhibiting absorption from the alimentary tractand by delaying the emptying time of the stomach.Quantitatively it was more effective than paredrine,adrenalin chloride, and atropine sulphate.7. Barbiturate Intoxication and NarcosisMyerson and Loman64 suggest the utilization
of benzedrine sulphate by intravenous drip (50 mg.at 1 per cent concentration over a period of I to 2hours) in the treatment of barbiturate intoxication.Davidoff and Reifenstein45 successfully employedbenzedrine in combating coma and withdrawalsymptoms in barbiturate poisoning, but warnedthat in cases where respiratory paralysis threatenedthe toxic effect of the two drugs might be syner-gistic. Reifenstein and Davidoff65 used intravenousinjections of IO to 40 mg. of benzedrine to ter-minate amytal (isoAmylethylbarbituric acid) nar-cosis.
8. Avertin7AnaesthesiaMichelsen and Verlot66 overcame narcosis and
the depressor effects of avertin anaesthesia byinjecting 20 mg. of benzedrine sulphate. Boyd,67administering io mg. dissolved in I c.c. distilledwater intravenously to I2 children after avertinanaesthesia, obtained as the only immediate effecta return of the superficial reflexes. There wasdefinite reduction in the duration of the post-operative sleep as compared with control cases.The majority of the patients vomited profuselyafter benzedrine.
9. Morphine AddictionDuckworth68 found the administration of ben-
zedrine "an invaluable aid in combating thatphysical and mental inertia which is a commonfactor in all cases of drug addiction when recover-ing." In his patient, a man of 45 who had beentaking io gr. of morphine by injection daily forfour years, a fortnight after complete withdrawalof morphine, benzedrine was given in doses of5 mg. twice daily, on rising and at noon. This wasdiscontinued after two months. There was noinclination for the patient to fall on alcohol asa stimulant. "The quick return to physical well-being and mental alertness was most marked."Davidoff and Reifenstein,45 46 while regardingbenzedrine as a valuable aid in treating morphinepsychoses and withdrawal symptoms, issue thewarning that this therapy, in some patients at least,
might only lead to the substitution of one habitfor another. By means of benzedrine in I0 mg.doses Guyot69 was able to counteract the nausea,vomiting, constipation, fall of blood pressure,ventricular tachycardia, and hebetude producedby morphine in the treatment of coronary occlusion.io. Codeine Addiction
Sereiskii55 reports the case of a physician. whohad taken large quantities of codeine for manyyears and who, during the last few weeks of treat-ment, was completely satisfied with only I0 mg.of benzedrine a day.ii. Caffeine Mania
Sereiskii55 obtained successful results with ben-zedrine in two cases of caffeine-mania.I2. Nicotinism
Benzedrine in doses of io mg. after breakfastand lunch has been described as being of consider-able value in combating habitual smoking (Miller).70It is relatively safe; its therapeutic effect is sufficientto guarantee complete or partial abstinence inalmost every case; and, by creating a mild stateof euphoria, it eliminates the much feared with-drawal signs. Miller7l points out that benzedrinein doses of I0 mg. or more may produce drynessof the mouth and throat, thus increasing the desireto smoke. This can be overcome by reducing thedosage of benzedrine to 5 mg. after breakfast andlunch or by chewing candy or gum to help increasesalivation. A i or i grain tablet of luminal occa-sionally helps over initial periods of restlessness.Sereiskii55 agrees that -I0 mg. of benzedrine twicedaily may cause dryness of the mouth and throat,accompanied by increased urge to smoke, and thatthe reduction of the dosage to 5 mg. twice a dayeliminates this disadvantage.I3. Disseminated Sclerosis
Small doses of benzedrine enabled Lehoczky72to control spasmodic laughter and weeping in thisdisease. Brickner and Simons73 obtained betterresults in some disturbances of gait with this drugthan with ergotamine.I4. Myasthenia Gravis
In the hands of Thorner and Yaskin74 benzedrine(30 mg.) proved a useful adjuvant to prostigmin(five to seven I5 mg. tablets daily) in three of fivecases with myasthenia gravis, restricting the for-mer to the early part of the day and then switchingto the latter. Viets and Schwab,75 while obtaininggood results with benzedrine in four of five casesof myasthenia gravis, preferred ephedrine as asynergist.I5. MyotoniaThe response in patients with the atrophic form
of myotonia to 5 to 20 mg. of benzedrine a day
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Augzust, I946 BENZEDRINE SULPHATE 211in two or four doses is sometimes encouraging.76Guttmann and Stokes77 noted a favourable responsein mood and activity to the drug in a case ofThomsen's disease, but the ergograph showed earlieronset of fatigue and loss of the "practice effect."i6. Electric Convulsion Therapy
Bailey,78 utilising benzedrine sulphate, a knowncortical stimulant, in an attempt to lower theelectrical convulsion threshold in the therapy ofmental disorders, found this drug to be effectivein oral doses of I0 mg. given one hour before theelectrical treatment, so that smaller strengths ofelectricity could be used. As regards its mode ofaction, it is likely that it exerts this effect centrallyrather than by any accompanying peripheralchanges, such as the heightened blood pressure.In two cases there was some post-convulsion excite-ment. This was never very great and may nothave been due to the drug, since such excitementhas been observed after convulsions in cases wherethe drug has not been employed. No other un-desirable effects were noticed. Even in a patientwith a blood pressure of 2I0/I20 no harm appearedto result with the doses given.I7. Head InjuriesAccording to Coburn79 "one must do what one
can for the patient who remains just below aconscious level and who is on the verge of somepulmonary complication. It seems justifiable tostimulate such a patient strongly with benzedrinein the hope of rousing him sufficiently to preventa fatal pulmonary lesion."i8. Infantile Cerebral Palsy
Benzedrine in the hands of Nichols and Warson80affordedsymptomatic relief inthe treatment of infan-tile cerebral palsy, but tended to increase irritability.I9. Problem Children and Enuresis
In hyperactive, distractive children gratifyingresults have been reported with doses of I0 to20 mg. benzedrine, smaller doses being ineffectual.Attention span is increased, and noisy childrenbecome more subdued (Bradley).81 Sargant andSlater82 attribute to benzedrine a specific effectin relieving recurrent bouts of aggressiveness anddestructiveness. Paradoxically, in spite of thestimulant action of the drug, the noisy childbecomes more subdued. It is well recognised thatnocturual incontinence occurs only during sleep,enuretic children usually being deep sleepers. Itis not an uncommon experience for a child to beguided to the bathroom and back to bed withouthis awakening. Many clinicians agree that in thesleepy, slow child benzedrine may be a usefulsystematic stimulant (Braithwaite,83 Stockwell andSmith).84 Molitch and Poliakoff85 reported thatin 8 of 22 chronic bedwetters relief was obtained
psychotherapeutically with a placebo. Of the I4boys who failed to respond to placebos I2 (86 percent) were entirely relieved when given increasingdoses of benzedrine, up to 25 mg. daily. It isinteresting to note that all 22 reverted to theirformer habits within 2 weeks after withdrawal ofboth placebo and benzedrine. When enuresis hasbeen controlled, the dosage of benzedrine may bedecreased, and the drug gradually withdrawn ora placebo substituted. Other observers88 havepointed out that benzedrine controls incontinenceduring waking hours, suggesting that the drug actsalso on the bladder musculature.20. Migraine
Several clinicians have found benzedrine useful.in cases of migraine characterised by initial fatigueor dizziness (Nathanson).87 In Gottlieb's88 seriesof 22 patients 8 (36 per cent) had their paroxysmsof migraine aborted when the drug was givenduring the prodromal period. Three patients havingfrequent and severe attacks became symptom-freewhen this was taken daily and in divided dosesat varying intervals up to every four hours.Benzedrine may be used as a substitute forergotamine tartrate when this is either ineffectiveor productive of severe toxic symptoms.2I. Urticaria
In the experience of Roberts89 benzedrine sul-phate has proved of value in children with urticaria,fluids and laxatives being properly employed at thesame time. "The variable individual factors andthe potential toxicity of the drug make the esti-mation of dosage difficult."22. MjniAre's Syndrome
Prinzmetal and Alles,90 using dextro-, racemic,and laevo-benzedrine sulphates in two cases ofMeniere's syndrome, report improvement not asso-ciated with a rise of blood pressure. The corticalstimulating action of these compounds was foundhelpful also in relieving dizziness not due to obviousorganic disease in several patients, the majorityof whom had hypotension.23. Sea SicknessThe treatment of this condition has always been
notoriously uncertain, chiefly because differentcases present different symptom-complexes, somea predominant vagotonia, others a predominantsympathicotonia. The majority appear to beamphotonic, combining both elements. Since ben-zedrine stimulates both the central and the sym-pathetic nervous systems, the possibilities of itsvalue in sea-sickness have been investigated bya number of clinicians. Hill (1936), I" of theR.M.S. Aquitania, inclined to the view that sea-sickness in men is usually vagotonic, and in womenand children sympathicotonic, the latter being
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212 POST-GRADUATE MEDICAL JOURNAL August, 1946characterised by restlessness, broken sleep, andthe occurrence of nausea before, vomiting, theformer by vomiting unaccompanied by nausea,apathy, drowsiness, headache, and vertigo. Hill(1937)92 administered benzedrine in doses of io to20 mg. to 82 women and i8 men suffering withsea-sickness. His results were classified as satis-factory (39), doubtful (40), and failures (29)' Dis-cussing the last group, the author suggests thatin the amphotonic type of case benzedrine by itself,even in the presence of definite signs of vagotonia,may swing the balance towards sympathicotonia,so that the drug should be administered in com-bination with other remedies, such as belladonnaor bromides and chloral hydrate. In some caseswith extreme vagotonia the dosage may not havebeen large enough. The drug is described by Hillas an exception to the general rule that a rapidresult is apt to be of short duration. Keevil93found benzedrine in doses of I0 to 20 mg. beforebreakfast, and repeated at noon, effective'in theprophylaxis and treatment of sea sickness.Ekerfors,94 'of the Swedish American Line, statesthat the effects of the drug are noted within halfan hour, continued as a rule for 4 to 5 hours andsometimes longer. His II6 cases were divided intothree groups according to the chief symptomspresented: vomiting; vertigo in the upright posi-tion and vomiting; and 'vertigo in the uprightposition only. Of the 28 passengers in the firstgroup 2o responded favourably, and 8 were dis-tinctly or indefinitely improved. Of the 67 casesin the second group 6i were completely relievedof their symptoms, while the vasomotor instabilityof the remaining 6 was greatly diminished. Of the2I cases in the last group recovery was completein 20. Albrecht,95 in a therapeutic evaluation ofbenzedrine in the treatment of sea-sickness in I00cases, writes that, given in proper dosage (I5 to30 mg. daily) and under supervision of a doctor,it is a safe drug for the prophylaxis of this con-dition. Its use permits the patient to be up andabout and to eat his usual food. He cites casesof stewards who during rough weather habituallybecame sick at the sight and smell of food andwhom benzedrine enabled to perform their dutieswithout further nausea or vomiting; also of firemenand oilers who, with benzedrine, were no longermade ill by the motion of the ship and the -smellof the oil. Blackham,96 supporting the conclusionsarrived at by Hill and Keevil, adds that benzedrineis contraindicated in excitable persons or in thosesuffering from insomnia, hyperpiesia, heart trouble,or gastric and intestinal atony. A combinationof benzedrine with hyoscine was found by Hill andGuest97 to protect 72 per cent of British and Indiantroops liable to sea-sickness in an assault craftunder tropical conditions.
24. Persistent HiccupAt one time the hope was held out that benze-
drine in doses of I0 mg., repeated, if necessary,for three doses, was able to relieve, temporarilyat least this distressing complication, most oftenseen after upper abdominal operations, and liablein an ill patient to lead to a dangerous state ofextreme exhaustion. Shaine98 obtained good re-sults with its use in three cases, cessation ofhiccupping in a post-operative refractory casebeing described as spectacular. The initial doseadministered was 20 mg., the drug being re-peated twice the same day in doses of I0 mg.This prompt effect was attributed to its specificaction of relaxing smooth muscle. According toHamilton Bailey,99 however, "in true persistenthiccup specific drugs are quite useless. One andall are entirely empirical."
25. DysmenorrhoeaPrimary, essential, or functional dysmenorrhoea
has always been the despair of the general prac-titioner and the gynaecologist, the formidable num-ber of antispasmodic and sedative drugs andendocrine preparations used in its relief bearingeloquent testimony to its difficulty of treatment.Some 40 to 6o per cent of women are said to sufferfrom dysmenorrhoea, many of these leading activebusiness, industrial, and social lives, so that thequestion of treatment assumes economic impor-tance. Several interesting clinical reports areavailable which suggest that benzedrine is usefulin functional dysmenorrhoea in which othermeasures have failed. In Taylor'sl'0 34 patients40 per cent were completely and 40 per centmoderately relieved, not only of physical pain, butalso of fatigue and depression, by 5 to 20 mg. daily.Benzedrine is described as a valuable drug welladapted to ambulatory patients. The usefulnessof the drug in mild cases of dysmenorrhoea isattributed by Larkin'0l chiefly to the stimulationthat it gives to the tired or worried patient andto the change of mood that is so characteristic.In severe dysmenorrhoea he found it of very littlevalue. In his group of I34 student nurses withmild or moderate dysmenorrhoea 89 (66 * 4 per cent)were definitely improved on small doses, whereasof 25 moderately severe or severe cases improve-ment occurred only in four. Hundley's'02 figures-are sufficiently striking to be quoted in full.Treating i86 attacks of essential dysmenorrhoeaoccurring in 9I working girls, he obtained goodresults (complete relief by initial dose of io mg.)in II4 (6i per cent), fair results (required a furtherI0 mg. 4 hours later) in 27 (I5 per cent), and poorresults (medication seemed ineffective) in 45 (24 percent). Brown108 agrees that severe menstrualcramps are not relieved by benzedrine. In his
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August, 1946 BENZEDRINE SULPHATE 213
recently published textbook Janney'04 recommendsbenzedrine sulphate as the most satisfactory of theantispasmodic drugs which he has used in thesymptomatic treatment of primary dysmenorrhoea.In his experience I0 mg. administered at the onsetof pain and repeated in an hour's time, if necessary,relieves uterine cramps and, in addition, improvesthe patient's mental outlook. With this dosage(10 to 20 mg.) side-reactions are seldom encoun-tered. Nevertheless, the patient should be warnedthat wakefulness may occur if the drug is takenafter noon. Overdosage may occasionally be fol-lowed by nervousness or "jitteriness," which isharmless and passes off in a few hours withouttreatment. Several gynaecologists recommendthat, before beginning treatment, it is advisableto administet a test dose of 2*5 to 5 mg. on one ortwo days during the intermenstrual period, in orderto determine whether the patient is hypersensitiveto benzedrine and, therefore unsuited to the treat-ment. Satisfactory results are reported with adose of I0 mg. given at the onset of the pain andrepeated, if necessary, four hours later. In ner-vous patients it may be preferable to give I0 mg.on the morning of the two preceding days and onthe morning of the first day of the period. Thedose can then be repeated, if required, the treat-ment lasting three or four days.A new combination of benzedrine sulphate with
acetylsalicylic acid and acetophenetidin, knownas Edrisal, has recently been introduced by Smith,Kline and French Laboratories of Philadelphia.This preparation was used in the treatment of some200 cases of dysmenorrhoea by Hindes,'05 whoreported that a single dose of two tablets providedcomplete relief of pain in 6i - 5 per cent and partialrelief in 34*6 per cent. More than 96 per centwere thus benefited. A total of 88.4 per centexperienced a sense of well-being, mental depres-sion being relieved in every case. Loss of timefrom work was reduced 72 5 per cent. No un-favourable reactions to this medication were noted.26. Ureteral Colic
Carroll°06 recommended a combination of benze-drine and atropine in ureteral colic to promoterelaxation of the spasmodic ureter, while in thehands of Loman, Greenberg, and Myerson'07 :thedrug proved useful in renal visualisation, in ureteral'spasm, due to calculus or other causes, and for thepathologically contracted bladder.27. Obesity
Obesity is to-day recognised as a physiologicalcondition which frequently becomes pathologicaland thus constitutes a real danger, actual orpotential, to the health of the individual. It maybe associated with diabetes mellitus, hypertension,cardiac failure, chronic arterial degeneration,
coronary sclerosis and occlusion, hernia, andcholelithiasis. It lowers resistance to respiratoryinfections, shortens life expectancy, and greatlyincreases surgical risk. Since many grossly over-weight patients lack the necessary self-disciplinefor strict adherence to diet, medication may haveto be resorted to in their case.
Obesity is often due to a defect in the moodwhich upsets the appetite-regulating mechanism,when increased eating, not representing true hun-ger, takes pJace in order to compensate for thedisturJed mood. The commonest cause of thisdisturbance in the appetite is the anhedonia asso-ciated with psychoneurosis. Lesses and Myerson'98have demonstrated the value of benzedrine in obeseneurotic persons. Since this drug has a directeffect in depressing the appetite and in increasingphysical activity, it is useful in any type of obesity.Forty obese patients were treated for periods of3 to 9 months with an initial dose (graduallyincreasing) of 7-5 mg. on rising, 5 mg. at noon,and 2-5 at 5 p.m. There were no toxic signs orsymptoms. Cotton109 recommends 5 mg. on rising,5 mg. at ii a.m., and 5 at 4 p.m. This is continueduntil there is an absence of weight reduction fora period of two weeks. The daily dose even inmost resistant cases was not allowed to exceed30 mg. Treatment was continued in a few indi-viduals as long as i8 mbnths without any untowardeffects. Cotton suggests that the drug should onlybe used as a temporary expedient to facilitate theformation of restricted eating habits for a periodvarying from two weeks to six months.
In Chrisman and Maury's110 series of 27 obesepatients, who had proved refractory to weightreduction, there were only two failures with treat-ment by benzedrine in the absence of dietaryrestrictions. The average weight loss was twopounds per week. The majority of cases reporteddecreased appetite, increased energy, and improve-ment of mood.A large number of clinical reports testify to the
value of benzedrine in the treatment of obesitydue to overeating in children and adults. Ersnerll-describes it as the drug of choice. Albrecht112found that nearly all his 300 patients, treated withfrom IO to 30 mg. of benzedrine daily in divideddoses, lost the desire to eat between meals and,after withdrawal of the drug, could be put on aspecial diet. No case of habituation occurred inhis series. Rosenthal and Solomon'13 in a con-trolled study of 22 obese patients found benzedrinemore effective in inducing weight reductions thanthyroid extract. According to them nothingdefinite can be stated as to the mechanism of itsaction, but in addition to its effect on activity,mood, and appetite, they suggest that it may actas a diuretic, preventing the retention of excess
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214 POST-GRADUATE MEDICAL JOURNAL August, I946of water in the tissues. Studying the effect andmechanism of weight reduction with benzedrinein obese children, Kunstadter and Necheles"14 con-clude that the psychic effects and the depressionof gastric hunger mobility can explain the resultsin treatment. They also found that under theinfluence of the drug children are more disciplinedand follow their diet with greater ease.
According to the Journal of the American MedicalAssociation in its section Queries and Minor Notes(I943),115 stressing the fact that benzedrine shouldonly be used under careful supervision of a physi-cian, the depression of the appetite would seemto be the chief action of the drug in the treatment ofobesity, since the effect on the basal metabolic rateis neither constant nor significant. The loss ofappetite, the increased activity, and the restless-ness of the patient are sufficient to account for theweight loss which follows its continuous use. Whena patient loses his appetite, he is more likely tofollow diet.On a statistical basis about half the persons with
narcolepsy become obese, but only about one-tenthbecomes as much as ioo per cent overweight.Cutting,"16 reporting on 2I cases of narcolepsy,believes that abnormalities of hypothalamic func-tion may at times be responsible for unnecessaryfood intake.The value of benzedrine Aulphate as an adjunct'
to diet and other measures in the treatment ofobesity may thus be summarised: it decreasesappetite and helps the patient to follow a diet,possibly also by producing a sense of well-being.Increasing activity, it promotes proper balancebetween energy output and caloric intake. Iteducates the patient to new eating habits, so thatweight loss is maintained after stopping the drug.It has no appreciable effect on basal metabolic rate.More recently d-amphetamine-a dextrorotary
optically active isomer of racemic amphetamine(benzedrine)-has been introduced in the treatmentof obesity with good results. Of i62 persons treatedfor obesity by Hawirko and Sprague"17 I4 receivedbenzedrine sulphate 5 mg. at 8 a.m. and at IO a.m.In order to overcome excitability and insomnia of6 patients d-amphetamine was substituted. Forthe subsequent patients d-amphetamine was pre-scribed in doses of 2-5 mg. one hour before eachmeal. This depressed the appetite sufficiently toenable the. patient to follow the diet regimen and atthe same time eliminated the discouragement andirritability incidental to rigid adherence to prolongedlow calorie diet. When in spite of strict dietingweight remained stationary, the dose of the drugwas increased to 5 mg. before the biggest meal andfinally to 5 mg. before each meal, making a maxi-mum daily dose of I5 mg. Duration of treatmentvaried from 2 to I2 months. Of the I62 patients
treated unfortunately only 72 persevered with theirtreatment for more than two months. Theamountof weight lost varied in proportion to the numberof pounds the patient was overweight, the averagebeing .5 pounds per month. Six failures wereobserved, which reduced less than 20 per cent ofthe number of pounds overweight. Salyrgan is con-sideredavaluable adjunct inthetreatment ofobesity,especially when there is great water retention.28. The Irritable Colon
According to Ingelfinger,118 in constitutionallyworried or depressed individuals benzedrine sul-phate, which is also a mild antispasmodic, canbe advantageously combined with belladonna ortrasentin. The following doses are recommended:trasentin 75 mg. t.i.d., benzedrine sulphate 5 mg.b.i.d. morning and noon.29. X-Ray Visualisation
Several radiologists (Ritvo"9) have found ben-zedrine useful for relaxing or abolishing spasm inthe gastro-intestinal musculature, thus facilitating,for example, the X-ray visualisation of structuralabnormalities of the duodenum. Myerson andRitvo'20 administered the drug in doses of 30 mg.for this purpose. It was pointed out, however,by Smith and Chamberlin12' that this techniquemight produce churning in the small intestine.30. Irradiation Sickness
Jenkinson and Brown'22 report favourable resultsobtained in 69 patients with benzedrine in thetreatment of "the feeling of sickness with acutegeneral symptoms" which sometimes follows theapplication of massive doses of X-rays.3I. "Restless Legs"
Ekbom123 quotes the case of a hospital nurse whofor I0 years complained of periodic crawling sen-sations in her legs and thighs, induced by fatigue,but not by emotion (asthenia crurum paraesthetica).At one time she used benzedrine (dose not stated),which she found highly effective, but she did notdare continue with the drug as she began to sufferfrom palpitation.32. Carotid Sinus Syndrome
Benzedrine sulphate in doses of I0 to 50 mg.daily is described as the most effective drug forcontrolling'the circulatory types of this syndrome,characterised by sudden loss of consciousness and,postural control (Solomon and Yakovlev).124Robinson,'25' 126 was able to prevent syncope dueto a hyperactive carotid sinus reflex by adminis-tering benzedrine in doses of 20 to 40 mg., repeatedso as to bring the daily total to 6o to i6o mg. Theduration of inhibition extended over 3 to 6 hours.Induced seizures were sometimes prevented by thedrug, and spontaneous seizures were controlled orreduced in number.
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August, I946 BENZEDRINE SULPHATE 215
33. HypotensionA number of cases have been reported in the
literature of postural hypotension which have suc-cessfully yielded to the administration of benzedrinesulphate, usually in combination with paredrine,paredrinol, or ephedrine, in 5 to I50 mg. dosesa day.'27' 128, 129
34. Heart BlockPoole and Wilkinson"30 obtained reversion to
normal sinus rhythm in a case of complete heartblock by giving 2 * 5 mg. of benzedrine on alternatedays.35. Analgesia
According to Buscaino and Pero,'3' 20 mg. dosesof benzedrine by mouth or by injection help torelieve pain for I to I2 hours in cases of sciatica,arthritis, and cancer.36. MalingeringThe following quotation from H. C. Solomon
and P. I. Yakovlev's Manual of Military Neuro-psychiatry, Saunders, I944 (page I93) is of interest:"I believe that the use of such drugs as a com-bination of benzedrine sulfate and sodium amytalwould break down the reticence of the malingerer,although I have little personal experience to backup this statement."37. OphthalmologicalGiven by mouth, benzedrine sulphate has little
action on the eye. Instillation of a o025 per centsolution causes definite mydriasis within a fewminutes attaining its maximum in under one hour,and disappearing in about 8 hours.132 The drughas been used in combination with atropine toproduce cycloplegia.'32"33 Intraocular tension isnot significantly increased.13438. Night Blindness
Benzedrine has been claimed to produce tem-porary improvement in night blindness due tovitamin A deficiency (Yudkin).13539. Libido
Stimulation of libido, probably due to elevationof mood, has been reported by some clinicians.136' 137
BENZEDRINE IN WORLD WAR IIThat benzedrine played a vitally important part
in World War II is evidenced by the fact that underthe name "Energy Tablets" more than 72 millionbenzedrine tablets were supplied in Great Britainalone to the Admiralty, Ministry of War Trans-port, War Office, and R.A.F. via the Ministry ofSupply (approximately the same quantity wassupplied to the U.S. Armed Forces), as spectacular,yet safe, emergency measures, and also by nume-rous tributes in the literature. As the drug raisesthe level of physical performance in the course of
prolonged effort by lessening the appreciation offatigue'. it was considered wiser, when the emer-gency was acute, to resort to the use of a drugwhich makes men temporarily immune to fatiguethan to abandon the exhausted (Fetterman).188On many a dangerous mission benzedrine helpedtired men to win the battle against sleep, whenthey could not be replaced by rested reserves."As the result of extensive laboratory and fieldinvestigation of the value and limitations of ben-zedrine, it has been determined officially that thisdrug is the most satisfactory of any available intemporarily postponing sleep when the desire forsleep endangers the security of a mission," writesMajor-General David N. W. Grant.139 "The res-ponsibility for the tactical use of benzedrine restswith the commanding officer, who must decidewhen the situation demands it. Distribution andadministration, however, is the responsibility ofthe medical officer. When it should be used, howmuch is needed, and what the effects will be arematters of interest to every member of a tacticalorganisation.... The effect of benzedrine upona person ready to fall asleep is to restore his alert-ness and produce a sense of well-being and con-fidence without impairment , of judgment.Since benzedrine does not provide rest, but merelyconceals the need of it, sleep following a 'ben-zedrine alert' preferably should be of such durationthat the accumulated fatigue is completely re-lieved. . . . Properly employed, benzedrine willgive an army a few extra man-hours of fightingat the time they are most needed." Benzedrine"stimulates dynamic energy, postponing the desirefor sleep, and enables continuation of performancebeyond the point at which physical fatigue wouldbe overwhelming."140 The value of benzedrine infighting fatigue and heightening combat efficiencyduring prolonged battle was confirmed, in theSpanish Civil War by the psychiatrist EmilioMiro.14"The following quotations from "A Guide to the
Preservation of Life at Sea after Shipwreck,"M.R.C. War Memorandum No. 8, i943, pay tributeto thevalue of benzedrine for shipwreckedpersonnel:
"Energy tablets (i) lessen feelings of fatigue andexhaustion, promote alertness, raise the spirits,and prolong the will to 'hang on' and live; (2) pre-vent sleep. These effects take about an hour tocome on, and they last for several hours, butrepeated administration cannot prolong the effectsfor more than a few days." 'The warning is issuedthat the tablets should not be given to woundedmen, to excitable or hysterical men, nor to thosewhose minds are wandering.
Test DoseSince there is a wide variation in individual
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216 POST-GRADUATE MEDICAL JOURNAL August, I946
response to benzedrine, there is concensus of opinionin the literature on the advisability of beginningtreatment with a test dose not exceeding 2i to5 mg., and, if no ill effect is apparent on carefilsupervision during the test period, of increasingthis dosage cautiously and progressively. The firstfew doses will usually be sufficient to determine.whether or not a patient is susceptible to the drugand the correct dosage for his or her requirements.For X-ray visualisation a test dose of 5 mg. isrecommended. Overdosage may be controlled bymild sedatives such as the barbiturates. In casesshowing any tendency toward insomnia benzedrineshould not be given in the later afternoon or even-ing. Occasionally patients with depressive statesafter prolonged administration of the drug appearto become insensitive to its beneficial effects. Thiscan be quickly remedied by withdrawing the drugand resuming it after a certain length of time.
Contra-IndicationsThe following major contra-indications are men-
tioned in the literature to the use of benzedrine:severe hypertension, coronary artery disease (orother serious heart disease), and manic excitement.The drug should be-administered with caution inthe severer forms of vasomotor instability, in widedaily variations in blood pressure or pulse rate, ininsomnia and anorexia, in homicidal or suicidalpatients, in agitated depressive states, and in casesof proven idiosyncrasy.
Safety and the Question of AddictionThe great preponderance of competent clinical
opinion favours the, view that the incidence ofundesirable reactions complicating benzedrinetherapy in normal dosage range is negligible andthat the few cases reported in the literature areusually traceable to indiscriminate or unsuperviseduse. "Occasional reactions may occur," writesPelner,142 "including headache, restlessness, in-somnia, irritability, palpitation, and a disturbanceof bowel habit. However, it is necessary to statethat these reactions are exceedingly rare, and aremerely mentioned to call attention to theirTrarity.""When used in the proper manner, benzedrine hasno apparent permanent deleterious action. Allill effects noted thus far have been largely of minorcharacter and only temporary," writes Ulrich'43on'the strength of his experience in treating patientswith maintenance doses of the drug for two years.Rosenberg,144 giving benzedrine in daily dosesof I5 to 25 mg. for periods varying from I to 9months, found unpleasant reactions to be rare andtransitory, controllable by sedatives and othermeasures. Norman and Shea,145 quoting the caseof an alcoholic aged 49, who was admitted to
hospital with acute somatic, visual, and auditoryhallucinations of 4 months' duration and whohad been taking benzedrine in steadily increasingdoses-daily maximum 250 mg.-for 5 years,believe that psychoneurotic patients and alcoholicsare prone to become addicted to the use of ben-zedrine. Dermatitis (pruritic lichenified) as acomplication is mentioned by Kauvar and hiscolleagues.'46 Davies'47 reports the occurrence ina student of acute aplastic anaemia following,though not necessarily attributable to, self-administration of I90 mg. in I9 days. Severecardiovascular collapse occurred after the last dose.The patient recovered and was restored to normalhealth. In a case recorded by Smith'48 of astudent 'who dies suddenly after taking only 3Q mg.of benzedrine, there is considerable doubt as to therole which the drug played in the causation ofdeath. Autopsy failed to reveal any abnormalities.Apfelberg's149 patient became comatose for 36 hoursafter taking I40 mg., but made an uneventfulrecovery. A large number of convincing clinicalreports confirm the fact that benzedrine may besafely administered over prolonged periods of time.According to Myerson49 "long-continued use of thedrug in considerable dosage (30 to 50 mg. daily),does not seem to produce ill effects. . . Thereare no injuries to personality or intelligence, suchas take place with the narcotic drugs."
Administering benzedrine in daily doses of atleast 70 mg. to three narcoleptics for 20 to 32months, Bloomberg150 in exhaustive tests encoun-tered no significant abnormality.", The tempera-ture, pulse, and respiratory rates were normalthroughout. There was no increase in basal meta-bolic rate and no rise in blood pressure. Therewas no evidence of damage to kidneys or liver.General physical and neurological examinationswere entirely negative in all cases. No cutaneousmanifestation or gastro-intestinal upset occurred."In one of Bakst's15' patients, who had been taking I5to 30 mg. of benzedrine daily for approximately 9years, "no remarkable effects of the long-continuedusage of the drug could be demonstrated, nor wereany perceptible changes noted when the drug wasdiscontinued." Gorrell'52 reports the case of anarcoleptic who for a period of two years took8o to I00 mg.' of the drug daily without any illeffects. Solomon, Mitchell, and Prinzmetal34 recordthe remarkable story of a patient with Parkinson'sdisease, who took as much as i6o mg. a day for3 weeks without apparent harmful effect. A manic-depressive patient, who had taken the astonishinglylarge quantity of 350 mg. in a single dose, recoveredafter admission to hospital and the administrationof barbiturates (Ehrich et al.).153 An interestingcase is reported by Shorvon154 of a psychopathaged 35, who had consumed from twenty-five to
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August, I946 BENZEDRINE SULPHATE 217
thirty 5 mg. benzedrine tablets daily for manymonths periodically over 4 years. The onlyapparent withdrawal symptoms were increasedrestlessness and insomnia, well compensated bybarbitone. There were no apparent physicalchanges. It is emphasised that, although thepatient was abruptly deprived of the drug whenentering hospital, he did not miss it at all. Thewarning note sounded in an editorial in the Journalof the American Medical Association (I938)1'5that the use of benzedrine over long periods is"certainly not without danger, particularly to thecirculatory system," prompted this comment fromLesses and Myerson:156 "As to addiction, the drugsto which human beings become addicted are thenarcotics. There is no evidence in the entireliterature of medicine that stimulants become habit-forming." In his clinical experience with ben-zedrine for more than two yeairs in a very largenumber of cases Myerson had not seen "a singlecase of addiction. in the sense that a person, other-wise well, now feels it necessary to take the drughabitually and in ascending doses to produce thedesired effect." Guttmann and Sargantl57 havefound no case of addiction to benzedrine, the onlyqueries being a few instances in patients withabnormal tolerance. "The fact that patients clingto a drug from which they derive physiologicalbenefit cannot be regarded as liability to addiction.The same could be said of insulin or cough mix-tures." Just as most diabetics are efficient withand inefficient without insulin, so are some indi-viduals efficient with and inefficient without ben-zedrine (Shorvon).154 That benzedrine is not ahabit-forming drug and possesses unusually widemargins of safety is confirmed by Sargant andSlater:',8 "Despite popular fears, addiction is veryrare and only occurs in the severe psychopath whowould have probably become addicted to somedrug or other anyway. There are no withdrawalsymptoms. Some constitutionally lethargic peopledemand it, and, if they are benefited by it, maybe allowed to remain on it permanently; it isprobable that in such persons it has a real partto play in remedying a constitutional inadequacyof the autonomic system or of bodily metabolism."
ADDENDUMIn an interesting study on the effects of amphetamine
upon the performance and symptoms of anoxaemic airmen,R. C. Browne, (Brit. med. J. June 8, I946, I, 870) foundthat I5 mg. amphetamine produced a consistently smaii,but technically insignificant, improvement in performance,reducing the incidence of sleepiness by nearly three times,but having no beneficial effect upon the other symptomsof anoxaemia. "There is, however, an element of 'whatis gained on the swings is lost on the roundabouts', in thatamphetamine may increase visual symptoms, headache,and euphoria."
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COMMON CASES SEEN IN THE V.D. DEPARTMENTBy EVELYN GOURLAY, M.D. *
About 8o per cent of the cases attending ourV.D. Department this last year have been finallydiagnosed as non-venereal, and only the remaining20 per cent were actually infected with Syphilis,Gonorrhoea or soft sore.
This large percentage of non-venereal cases, whichI think is usually much the same in the return ofmost women's V.D. clinics, seems to surprise manypeople, and they may ask why so much publicmoney should be expended on treating such alarge number of uninfected cases.
I thought it might be of interest to talk of the* Based on a lecture given at the South London Hospital
for Women on May ii, 1946.
problems presented by these non-venereal caseswhich often give us much more trouble in treat-ment than the straightforward case of Syphilis orGonorrhoea. To begin with, when the patientscome up often it is by no means certain whetherthey are or are not infected until tests have beenrepeated several times. During the war years wehave had a great number of Services contacts wherethe husband or contact has written to say that heis infected and to ask the' wife or friend to beexamined. Some are obviously infected or showpositive pathological resullts at once. Some appearto be quite free from infection when first seen, andlater develop positive signs while being observed.
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