and other drugs
E. s S. Livingstone
Br. It. Addict., 11376, Vol. 71, pp. 321-326. Longman. Printed in Great Britain.
A Comparison of the Effects of Propranolol
and Diazepam in Alcoholics Carl Carlsson M.D. and Bengt-Goran Fasth Ph.D.Dept. II, Lillhagen Hospital, Gothenburg, Sweden
In a double-blind cross-over study, propranolol in a dosage of 120 mg daily vaas more effective than 30 mg a day of diaz.epam in relieving symptoms of tension and depression in chronic alcoholics. Speculations are made regarding the mechanism of action.
A number of studies showing the effect of propranolol on tension symptoms in neurosis have been reviewed by Gardos (1973).
In chronic alcoholics, as in anxiety neurosis, hyperkinetic circulation is a common finding and out of twenty alcoholics who had passed the abstinence phase, only four had a cardiac output within normal limits at rest (Carlsson, unpublished). During the abstinence phase everyone of eight alcoholics had raised cardiac output at rest and during exercise (Carlsson, 1969). Propranolol (Inderal R) was found to normalise the circulation in all cases and, unexpectedly, in five out of eight patients, symptoms of tension appeared to decrease after 40 mg propranolol.
In a later study propranolol was shown to have a significant effect on tension and depressive symptoms in the abstinence phase of alcoholism (Carlsson & Johansson 1971). This has been confirmed by Gallant et al. (1973).
There is conflicting evidence as to the effect of propranolol on psychiatric symptoms. In small doses it appears to have a sedative effect and in larger doses an antipsychotic effect (Atsmon et al., 1972). One of its active metabolites is 4-hydroxypropranolol which is formed in the liver (Fitzgerald, 1971) and this may be the cause of the different effects of propranolol when given by mouth and by injection.
In the treatment of alcoholics there is a gre at need for drugs which reduce tension and depression without the risk of habituation. Formerly we used diazepam. but alcoholics are much more likely to become habituated to such preparations than other people. It was difficult to find other suitable drugs, phenothiazine derivatives are liable to cause too many side-effects, but propranolol seemed to be the drug of choice in a number of cases. Thus we felt that there was a need for a double-blind comparison between propranolol and diazepam.
The material consisted of 52 males diagnosed Oll medical grounds as chronic alcoholics or as gamma-alcoholics according to the classification of Jellinek (1960). They could also be described as alcohol addicts. The mean age was 39 8 years (range 25-26) and most of them had at least a ten year history of alcohol abuse. They were treated voluntarily as inpatients in a mental hospital in an open ward used specifically for the treatment of alcoholics. All patients showed marked signs of tension and depression.
322 Carl Carlsson
A double-blind cross-over technique was used. Every patient was treated for 14 days with each drug in random order and the code was broken only after the study had been completed. The dose of diazepam was 30 mg a day and that of propranolol 120 mg a day. Both drugs were given in identical capsules in three daily doses. The trial started one to three weeks after admission. All other medicines were discontinued before the trial started and no disulfiram was given. In a few cases a shortacting hypnotic was given at night ( 1 tablet of Modirax R = 0 4 g hexapropymate) .
Table 1. Results of a double-blind, cross-over study propranolol-diazepam.
DIAZEPAM 30 mg/d-PROPRANOLOL 120 mg/d; DOUBLE-BLIND CROSS-OVER 14 + 14 days; P=propranolol; D =diazepam; n =40 chronic alcoholics
Results of the statistical analyses of treatment effects zeith the Chi-Square test.
Subscales: Period I Period 2
THE MIDDLESEX HOSPITAL QUESTIONNAIRE (MHQ)
P>D X2 =2=0.78
P>D X2=5.62 s.
P>D X2=7.03 s.
ZUNG SELF-RATING DEPRESSION SCALE
P<D X2=l 39
TAVISTOCK SELF-ASSESSMENT INVENTORY
P>D X2 =2 67
ADJECTIVE CHECK LIST
P>D X2=3.13 .
P>D X2=5.58 s.
P>D X2=11.12 s.
P>D X2= 5.71 s.
s.=Significant at 0 05 level (Critical value=3 84)
Loss Diazepam 8, propranolol 3, between diazepam and propranolol 1.
A Comparison of the Effects of Propranolol and Diazepam in Alcoholics 323
The patients were told that we wanted to investigate a new drug (Inderal R) which had not been used before in the treatment of alcoholics. Diazepam was not mentioned. The patients were asked not to take alcohol or any other drug and told that they could leave the trial if they wished. They were examined three times by the psychologist (B.G.F.): prior to the start of the study and after 14 and 28 days of treatment. The following psychological methods of assessment were used:
The Middlesex Hospital Questionnaire (Crown & Crisp, 1966).
The Zung Self Rating Scale (Zung, 1965) .
The Tavistock Self Assessment Inventory (Sandler et al. 1958) .
The Adjective Check List (Gough, 1960).
The results are given in Table 1. Whichever method of assessment is used, the significant differences of psychic symptoms in alcoholics are in favour of propranolol compared to diazepam. Tiredness appeared as a side effect in some patients taking diazepam and insomnia occurred in a few patients under propranolol treatment.
Twelve patients left the trial because of alcohol intoxication; of these, eight were lost during diazepam treatment and three while taking propranolol. One patient left after he had completed treatment with diazepam and was due to start treatment with propranolol.
All the significant differences in the trial results were in favour of propranolol and this was an unexpected and remarkable finding. Neither the staffnor we were able to guess which drug the patients had received. The patients were not asked about drug preference as they were not aware that two drugs were being used.
Figure 1 shows a very speculative and simplified scheme. There is a rewarding system in the brain, ascending from the brain stem to the lateral hypothalamus and through the middle forebrain bundle to the cerebral cortex. Several studies indicate that noradrenaline is a transmitter substance, at least to some extent, in this system (Arbuthnott et al., 1971) . If electrodes are placed in the lateral hypothalamus of the rat, self-stimulating behaviour can be elicited, sometimes even to the extent of killing the animal. This can be called a new kind of "addiction". There is reason to believe that d-amphetamine, for example, operates on this system. The learning theories of behaviour may have their biochemical basis in the rewarding centre, and even also in the punishment centre, where serotonin may be the transmitter. Like d-amphetamine alcohol has a central stimulating effect (Carlsson et al., 1973) and these effects of both d-amphetamine and alcohol can be blocked by alfa-methyl-ptyrosine which blocks the synthesis of catecholamines in the CNS (Ahlenius et al., 1973) .
There is a very interesting theory that, in schizophrenia, 6-hydroxydopamine is an abnormal metabolite which blocks the noradrenaline in the rewarding centre (Stein & Wise, 1971). In the peripheral nerve endings, at least, 6-hydroxydopamine is blocked by propranolol and the effect in the CNS may be similar (Atsmon et al., 1971).
324. Carl Carlsson
In vitro experiments in mouse brains show that tetrahydropapaveroline is formed from dopamine in the presence of alcohol. This gives rise to a hypothesis for the biological basis of alcoholism (Walsh & Davis, 1970). Tetrahydropapaveroline is an alkaloid found in opium and is the precursor of, for example morphine and papaverine. Pharmacologically, it acts as a beta receptor stimulant in the sympathetic nervous system, like amphetamine and noradrenaline. It is very interesting that the closely related substance apomorphine can prevent the craving for alcohol (Schlatter & Samarthji, 1972). Apomorphine has a suppressive effect on self-stimulation in rats
A Comparison of the Effects of Propranolol and Diazepam in Alcoholics 325
and this can be reversed by d-amphetamine (Stein & Wise, 1973). It is possible that all addictions have factors in common and that toxic psychosis could be explained from such theoretical speculations as are outlined in the figure. Of course, systems with, for instance, serotonin as the transmitter substance could be involved and the figure must be regarded as a "biochemical trans-section".
Propranolol has been found to be of value in the treatment of heroin and morphine addiction (Grosz, 1972) and the mode of action may resemble that of apomorphine which is also used successfully in sub-emetic doses in the treatment of various kinds of addiction (Feldman, 1952, Martensen-Larsen, 1973).
Apart from this controlled study, we have had a great deal of clinical experience in treating alcoholics as out-patients with propranolol. The only notable side-effects at a dosage of 12s160 mg a day have been bradycardia in a few cases and emesis. We have the impression that the greater the tension symptoms the better the effect of propranolol. The same clinical results are reported by (Drew et al., 1973). We have received reports from patients of decreased craving for alcohol, but these may be due to a placebo effect, as may be the reports of diminished euphoria during alcohol intoxication. In mice propranolol is an inhibitor of ethanol-induced narcosis (Smith et al., 1970). We also have the impression that 10 mg capsules of apomorphine are of value in the treatment of alcohol addiction.
In conclusion, there is reason to believe that there is a system of beta adrenergic receptors in the central nervous system. This system seems to be involved in both the satisfaction of drives (reward) and tension symptoms (the defence-alarm reaction). Propranolol has effects on the CNS which could explain its action in essential hypertension, formerly believed to be mainly peripheral. It is possible that propranolol could be of value in the treatment of various kinds of addiction, perhaps in each through an effect on a beta receptor mechanism in the central nervous system. Of course the effects on CNS by propranolol can be explained in other ways, i.e. propranolol is an inhibitor of aldehyde dehydrogenases (Duncan, 1973) and this may influence amine metabolism.
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ATSMON, A. et al. The short-term effects of adrenergic-blocking agents in a small group of psychotic patients. Psychiat. Neurol. Neurochir. 74, 251-258, 1971.
ATSMON, A. et al. Further studies with propranolol in psychotic patients. Psychopharmacol. (Berl.) 27, 249-254,1972
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DUNCAN, R. J. S. The inhibition of alcohol and aldehyde dehydrogenases by propranolol. Mol. Pharmacol. 9, 191-198, 1973.
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326 Carl Carlsson
GALLANT, D. M. A controlled evaluation of propranolol in chronic alcoholic patients presenting the symptomatology of anxiety and tension. i. Clin. Pharmacol. 13, 41-43, 1973.
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GROSZ, H. J. Narcotic withdrawal symptoms in heroin users treated with propranolol. Lancer, Sept. 16, ii, 564-566, 1972.
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SCHLATTER, E. K. E. and SAMARTHJI LAL, M B. Treatment of alcoholism with Dent s oral apomorphine method. Quart. 7. Stud. Alc. 33, 430-436, 1972.
SMITH, A. et al. Inhibition by propranolol of ethanol-induced narcosis. ,7. Pharm. Pharmac. 22, 644-645, 1970.
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Requests for reprints should be addressed to Carl Carlsson, Nordhemspolikliniken,
Fjarde Langgatan 7 A, 413 05 Gothenburg, Sweden.
by C. Carlsson, P. R. Johansson, B. Gullbergt Nordhemspolikliniken, Gothenburg, Sweden
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