2) Tetrahydroisoquinolines and tetrahydro-[J-carbolines and alcohol dependence.
3) Similarities between opiate alkaloid and alcohol dependence.
ALCOHOL: THE OLO RASCAL IN NEW CLOTHES 365
tendency has been confirmed in several studies. However pCPA also induces
aversion to saccharine fluid (Parker & Radow, 1976) and therefore it is not clear ifthe
drug itself may be more important than 5HT depletion in alcohol aversion. Liver
toxic levels ofacetaldehyde (Myers, 1978).
Injection of 5HT-lesioning compounds, such as 5,6-d ihydroxytryptamine and
5,7-dihydroxytryptamine, directly into the cerebral ventricles, enhances alcohol
drinking in rats (Ho, Tsai, Chen, Begleiter & Kissin, 1974). In other studies, depletion
of 5HT by 30% or even 69% did not alter the amount of alcohol drinking
The role of 5HT depletion, or 5HT metabolism, in alcoholism is not clear from
these experimental studies. Ahtee & Eriksson (1972) reported increased 5HT and
5HIAA contents in the brains of alcohol preferring rats and chronic use of alcohol
Isoquinoline alkaloids are widely distributed in nature. Some ofthese alkaloids are
known hallucinogens. During the last ten years , several studies have claimed that
catecholamine derived tetrahydroisoquinolines (TIQ) may be involved in the
In 1970 Davis & Wafsh reported tetrahydroisoquinoline formation, in biological
preparations, from acetaldehyde and ethanol in vitro. The compound formed,
salsolinol, has also been found in the brain of rats after ethanol administration.
Highly sensitive and specific assay methods are needed to detect TIQ compounds and
their metabolism in brain tissue . Recently Collins, Nijm, Borge, Teas & Goldfars
(1979) detected from five to six times higher concentrations of dopamine-related
tetrahydroisoquinolines (salsolinols) in the dail y urine sampies of alcoholics than in
the daily urinesampies ofnonalcoholic control subjects.
TIQ compounds, harman, or ß-carbolines can be formed in condensation
reactions of tryptamines with carbonyl compounds, that is, aldehydes. McIsaac
(1961) gave ethanol, 5HT and monoamine oxidase inhibitor (MAOI) to rats and
found a ß-carboline in the urine. p-carbolines are hallucinogenic compounds and
they also induce tremor (Ho , Fritchie, Idänpään-Heikkilä, Tansey & McIsaac, 1970).
They have been detected in brain tissue after treatment ofrats with acetaldehyde but
also in the untreated rat brain. Recently Airaksinen, Peura, Kari & Mikkonen (1980)
reported that a moderate alcohol intake (50-100 g in 4 h) induced detectable amounts
of a ß-carboline (tetrahydroharman) in the plasma and platelets of normal healthy
dependence. While ß -carbolines have now been shown to exist in the animal brain,
and to appear in human plasma and platelets, after alcohol intake, it would be
interesting to know if there are any dose response efTects in regard to the amount of
Both tetrahydroisoquinolines and p-carbolines seem to be important compounds
in trying to explore the biochemical mechanism of alcoholism and alcohol
dependence. The speculation that TIQ and /or ß-carbolines are involved in physical
dependence, requires a demonstration that they are formed in significant amounts to
cause the symptoms ofdependence.
Sinclair, Adkins & Walker (1973) found that morphine markedly decreased, in
rats, the daily intake 'of fluid containing alcohol. In hamsters, morphine, and
levorphanol to a lesser degree, reduced alcohol intake, whereas the narcotic
antagonist, naltrexone, had an opposite etTect. In rats, an injection of methadone or
levorphanol decreased voluntary alcohol inta ke. It seems that morphine exacerbates
the degree of physical dependence on alcohol in rats . A conflicting factor was the
fmding that in rats, wh ich prefer and drink solutions of morphine, alcohol does not
decrease the inta ke ofmorphine.
In general, narcotics see m to interact with ethanol in animals. There are also so me
clinical experiences as to the fact that many narcotic addicts use alcohol when heroin
or morphine are not available. In methadone maintenance programmes, addicts are
frequently also heavy users of alcohol. However, there is no evidence that similar
behavioural mechanisms are involved in alcohol and narcotic abuse. The evidence is
also very weak if one considers the neurochemical mechanisms of alcohol or opiate
intoxication and withdrawal symptoms. The controversies may in part be explained
by the fact that there is a lack of agreement concerning the methods for inducing
dependence and what are the withdrawal signs .
Although alcohol may have some beneficial etTects, its list of sins is long and
voluminous. Taken together, the medical, psychiatric and social cost of drinking and
alcoholism is a heavy economic burden in an increasingly large number of countries.
There is no reason to believe that alcohol could be used rationally as a preventive
agent, for example, against ischaemic heart disease.
However, it has been interesting to note that the recent studies have shown many
new aspects, which make us re-evaluate the old and well-known views about alcohol.
Ahtee, L. & Eriksson, K. (1972). 5-hydroxytryptamine and 5-hydroxyindolylacetic acid content
in brain ofrat strains selected for their alcohol intake. Physiol. Behav.. 8, 123-126.
Airaksinen, M. M., Peura, P., Kari, J. & Mikkonen, E. (1980). Tetrahydro- ß-carbolines in man
after alcohol drinking. Abstract in Annual Nordic Meeting on Biological Alcohol Research
British Medical Journal (1979). Alcohol heart muscle disease. Leading article, Brit. med. J.. 2,
Castelli, W. P., Douyle, J. T., Gordon, T., Harnes, C. G., Hjortland, M. c.,Hulley, S. B., Kagan,
A. & Zukel, W. J. (1977). Alcohol and blood lipids. Lancet, 1, 153-155.
Clarren, S. K. & Smith, D. W. (1978). The fetal alcohol syndrome. New Eng. 1. Med.. 298,
Collins, M. A., Nijm, W. P., Borge, G. F., Teas, G. & Goldfars, C. (1979). Dopamine-related
tetrahydroisoquinolines: Significant urinary excretion by alcoholics after alcohol
consumption. Science, 205, 1184-1185.
Davis, V. E. & Walsh, M. J. (1970). Alcohol, amines, alkaloids: A possible biochemical basis for
alcohol addiction. Science, 167, 1005-1007.
Hennekens, C. H., Rosner, B. & Cole, D. S. (1978). Daily alcohol consumption and fatal
coronary heart disease.Am. J. Epidem., 107,196-200.
Hennekens, C. H., Willett, W., Rosner, B., Cole, D. S. & Mayrent, S. H. (1979). EfTects ofbeer,
wine and liquor in coronary deaths. J. Am. med. Ass.. 242, 1973-1974.
Ho, A. K. S., Tsai, c.s., Chen, R. C. A., Begleiter, H. & Kissin, B. (1974). Experimental
studieson alcoholism. Psychopharmac.. 40, 101-107.
Ho, B. T., Fritchie, G. E., Idänpään-Heikkilä , J. E., Tansey, L. W. & Mclsaac, W. M. (1970).
(lH)-Harmal ine distribution in monkey brain, pharmacological and autoradiographie
study. Brain Res.. 22,397-400.
ALCOHOL: THE OLD RASCAL IN NEW CLOTHES 367
Idänpään-Heikkilä, J. E., Fritchie, G . E., Ho , B. T. & McIsaac, W. M. (1971). Placental transfer
of 14C-ethanol. Am. J. Obst. Gynec.,110,426-428.
Idänpään-Heikkilä, J. , Jouppila, P., Äkerblom, H. K., Isoaho, R., Kauppila, E. & Koivisto, M.
(1972). Elimination and metablie etTeets of ethanol in mother, fetus and newbom infant.
Am. J. Obst. Gynec.. 112, 387-393.
Johansson, B. G. & Medhus, A. (1974). Increase of plasma rr-lipoprotein in chronic a lco holics
after acute abuse. Acta med. Scand., 195,273-278.
Jones, K. L., Smith, D. W., Ulleiand, C. N. & Streissguth, A. P. (1973). Pattern ofmalformation
in otTspring ofchronic alcoholie mothers. Lancet, 1, 1267-1271.
Kaminski, M., Rumeau-Rouquette, C. & Schwartz, D. (1976). Consommation d'alcohol chez
les femmes enceintes et issue de la grossesse. Rev. Epidem. Sante Publ., 24,27-40.
Kiianrnaa, K. (1975). Evidenee for involvement of noradrenaline and against
5-hydroxytryptamine neurons in alcohol consumption by rats . Finn. Found. AlcoholStud.,
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infarction: result s from the Kaiser-Permanente epidemiologie study of myocardial
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La Porte, R., Kuller, L. & Cresanta, J. (1979). Geographie and secular relationship of alcohol
intake to ASHD death rate s. Abstract in Conference on cardiovascular epidemiology, New
Lemoine, P., Harousseau, H., Bortegru, J. P. & Menuet, J. C. (1967). Les enfants de parents
alcoholiques: Anomalies observees apropos de 127 cas. Arch. Fr. Pediat., 25,830-832.
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Myers, R. D. (1978). Psychopharmacology ofalcohol. Ann. Rev. Pharmac. Toxicol.. 18,125-44.
Myers, R. D. & Melehior, C. L. (1977). Alcohol drinking: Abnormal intake caused by
tetrahydropapaveroline in brain. Science. 196,554-556.
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Sinclair, J. D., Adkins, J. & Walker, S. (1973). Morphine-indueed suppression of voluntary
alcohol drinking in rats. Nature, 246,425-427.
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Porchester Road, Mapp erley, Nottingham NG3 6AA. England
Benzodiazepines are the mo st commonly prescribed drug s in the world. They are
etTective in reducing anxiety and promoting sleep , safe in overdosage and greatly
year (Skegg, Doll & Perry, 1977) and similar ftgures are found in most other countries
concern in many quarters (Lancet , 1973; Trethowan, 1975), although it mu st be
added that th is increase was accompanied by a fall in barbiturate pres criptions and
often represents substitution rather than new pre scribing . In recent years the increase
has been less dramatic, of the order of three to five per cent per year (Department of
Health & Social Security, 1972-1978) but the concern over benzodiazepine
dependence continues (Greenblatt & Shader, 1978; Cornmittee . on the Review of
Mcdicines, 1980). What is disturbing is that repeat pre script ion s make up such a large
proportion of total pre scribing and that in man y cases such prescriptions are
inappropriate (Tyrer , 1978). One of the possible reasons for repe at prescribing is
dependence, leading to pati ent s demanding more drug s even ifthey are not clinically
indicated. Thi s can either be because the drug induces pleasure or at least avoids
regular consumption of benzodiazepines leads to dependence is an important
question and has generated a great deal of debate. The results of animal and human
pharmacological studies hav e both been relevant in assessing the que stion, but for
reasons that will become clear later in this review a distinction is made between
dependence occurring in high (non-therapeutic) dosage , and the lower range of
There are good animal models of drug dependence (Kumar, 1974). Opiate and
barbiturate dependence has been amply demonstrated by drug-seeking behaviour in
dependent an ima ls, who regularly choose food or drink containing their drug.
CLINICAL PHARMACOLOGY OF BENZODIAZEPINE DEPENDENCE 369
Benzodiazepines have much less potential to induce dependence, significantly less so
than barbiturates (Findlay, Robinson & Peregrino, 1972) but physical withdrawal
symptoms can occur. The reasons for the pharmacological dependence are not yet
clear, The recent discovery ofbenzodiazepine receptors in the central nervous system
(Möhler & Okada, 1977) has been a powerful impetus, particularly as there is a close
relationship between the pharmacological potency of the benzodiazepines and their
affmity for the receptors. However, one possible explanation for dependence in high
dosage, an increase in the number of benzodiazepine receptors after long term
administration, has been disproved (Braestrup, Nielsen & Squires, 1979).
There are no animal studies suggesting that benzodiazepines at dosages equivalent to
those used in human therapy lead to pharmacological dependence.
It has been known for many years that prolonged, high dosage ofbenzodiazepines can
sometimes lead to pharmacological dependence, with the development of tolerance
and withdrawal symptoms when the drug is stopped abruptly. This was Irrst
described by Hollister, Motzenbecker & Oegan (1961) with chlordiazepoxide and has
been reported with other benzodiazepines since (Fruensgaard, 1976; Oysken & Chan,
1977; Preskorn & Oenner, 1977; Oe Bard, 1979). The dosage taken at the time of
withdrawal is usually five to ten times the normal therapeutic dose (for example,
chlordiazepoxide 300 mg daily; diazepam 100-150 mg daily) , and the withdrawal
symptoms include epileptic seizures, acute 'psychotic' reactions with agitation,
confusion, paranoid symptoms and perceptual distortion. Most of these symptoms
are re1ieved by retaking the drug, confirrning that they are part of a withdrawal
syndrome. Interpretation of these reactions is complicated by the frequency with
which other drugs, particularly alcohol, had been taken at the same time as the
benzodiazepines, and is common with individuals prone to drug abuse. Marks (1978)
has recentl y reviewed all the literature on benzodiazepine dependence and concludes
from a number of cases of dependence published (which are almost certainly an
underestimate of the true incidence) that only one case of dependence occurs in five
million patient months 'at risk' , and in comparison with dependence on other
psychotropic drugs this figure is very small.
Whilst the existence of true dependence on high dosage of benzodiazepines is
undisputed there are disagreements over the nature of the syndrome that often
follows withdrawal of benzodiazepines prescribed in therapeutic dosage. This
syndrome comprises anxiety, insomnia, dizziness, headache and perceptual
disturbance (Lancet, 1979). All these symptoms can be found with anxiety states
(Roth, Gurney, Garside & Kerr, 1972) and when they occur after benzodiazepine
withdrawal they may represent areturn ofpre-existing anxiety previously relieved by
the drug (Covi, Lipman, Pattison, Oerogatis & Uhlenluth, 1973; Rickels , Oowning &
that they are part of a withdrawal syndrome. The most convincing evidence of true
withdrawal symptoms has come from Kaies and his colleagues who have described
'rebound insornnia' following cessation of benzodiazepine hypnotic drugs (Kaies,
Scharf & Kaies, 1978; Scharf, Kaies & Soldatof, 1979), although several single case
reports are also difficult to interpret except by postulating a withdrawal syndrome
(Mendelson, 1978; Pevnick, Jasinski & Haertzen, 1978; Winokur, Rickels,
Greenblatt, Snyder & Schatz, 1980). There are also a few case reports of physical
withdrawal syrnptoms, including fits, after chronic benzodiazepine consumption in
low dosage (Rifkin, Quitkin & Klein, 1976; Einarson, 1980), supporting the case that
a true withdrawal syndrome can occur after therapeutic dosage. The presence of
dysphoric symptoms during the withdrawal phase, described by Lader (1980, in
preparation) as 'an amalgam of anxiety, depression, nausea, malaise and
depersonalisation' is also a little difficult to interpret as areturn of pre-existing
Pharmacokinetics ofbenzodiazepines in relation to withdrawal symptoms
One explanation of benzodiazepine withdrawal symptoms occurring after stopping
the drug is that it is a 'reverse placebo' effect. According to this argument the drug is
providing no real pharmacological benefit but when it is stopped the subject feels
worse because he lacks the placebo support ofthe tablet. 1fthis were so the apparent
withdrawal syndrome would show itselfimmediately after stopping the drug. In fact,
in almost all reported cases of withdrawal symptoms there has been aperiod of
between three and thirteen days (with a peak of frve days) before the withdrawal
reaction has become manifest, so the 'reverse placebo' argument loses much of its
chlordiazepoxide all have a common metabolite, desmethyldiazepam,
(nordiazepam) which has a half life of 50-120 h (Hillestad, Hansen & Melson,
1974). Desmethyldiazepam accumulates after chronic administration and takes
many days to be cleared from the body. In the one case where plasma levels were
recorded during the withdrawal syndrome the symptoms were temporally related to a
delayed fall in plasma desmethyldiazepam (Winokur et al., 1980). Benzodiazepines
with no active metabolites, or short acting ones, such as lorazeparn, oxazeparn,
triazolam, nitrazepam and flunitrazepam, might be expected to show withdrawal
symptoms earlier and this is supported to some extent by the work of Kaies and his
colleagues (Kaies et al., 1979).
It has been suggested that, like the barbiturates, benzodiazepines may induce their
own metabolism in chronic dosage (Kanto, Iisalo, Lehtinen & Salminen, 1974) but
this has not been confirmed (Rutherford, Okoko & Tyrer, 1978). Kaies et al. (1979)
after abrupt withdrawal of the exogenous drug; this could also explain other withdrawal symptoms.
Since 1976, a double-blind study of the ß-adrenoceptor blocking drug,
propranolol, and placebo in the treatment of bensodiazepine withdrawal symptoms,
in psychiatrie out-patients and general practice patients, has been in progress in
collaboration with colleagues at the Poisons Unit at Guy's Hospital. As propranolol
reduces the somatic aspects of anxiety (Tyrer & Lader, 1974), it was feit to have
potential in treating withdrawal symptoms, although it is only minimally effective in
treating the symptoms of opiate withdrawal (Hollister & Prusmack, 1974). All
patients taking diazepam or lorazepam only in regular dosage for at least four months
seen by the author in general practice and psychiatrie out-patient clinics have been
considered for the trial, if their drug therapy was considered to be no longer
appropriate. Most such patients were feit to be taking their drugs unnecessarily and
this is in keeping with the recent report ofthe Committee on the Review ofMedicines
CLINICAL PHARMACOLOGY OF BENZODIAZEPINE DEPENDENCE 371
who recommend that patients receiving benzodiazepines should be 'carefully selected
and monitored and prescribing limited to short term use', (Committee on the Review
Patients entering the tr ial , stop their lorazepam or diazepam and take between 60
and 120 mg of propranolol (or placebo) for two weeks, according to a flexible dose
regime. Drug levels of desmethyldiazepam and diazepam are taken before stopping
the benzodiazepines and seven and fourteen days after withdrawal. Patients record
their symptoms daily on selfrating scales during the fourteen days after withdrawal.
Unfortunately the study has taken longer than expected because over fifty per cent
of the patients have refused to consider stopping their benzodiazepines. This itself
suggests some degree of dependence. The study is planned to end when forty patients
have entered the trial, after which the code will be broken. To date thirty eight
patients have entered the study and the results should be available soon. It is hoped
that they will give a better idea of the incidence of withdrawal symptoms in
therapeutic dosage and also determine whether pharmacokinetic factors are
important in determining the onset ofwithdrawal symptoms.
It is weil established from animaI and human studies that regular high dosage of
Most benzodiazepines are taken in low dosage and there is growing evidence that a
proportion of patients may become dependent on these drugs after chronic therapy.
The dependence shows itselfprimarily by the onset ofa withdrawal syndrome several
days after stopping the drug and tolerance and habituation are rare. The incidence of
such withdrawal symptoms is at present unknown.
Pharmacokinetic factors and studies on benzodiazepine receptors have not as yet
explained the nature ofbenzodiazepine dependence.
Braestrup, c., Nielsen, M. & Squires, R. F. (1979). No changes in rat benzodiazepine receptors
after withdrawal from continuous treatment with lorazepam and diazepam. Life Sei., 24,
347-350. Committee on the Review ofMedicines (1980). Systematic reviewofthe benzodiazepines. Brit.
Covi, L., Lipman, R. S., Pattison, J. H., Derogatis, L. R. & Uhlenluth, E. H. (1973). Length of
treatment with anxiolytic sedatives and response to their sudden withdrawal. Acta
Oe Bard, M. L. (1979). Oiazepam withdrawal syndrome: a case with psychosis, seizure and
coma. Am. J. Psychiat.,136, 104-5.
Oepartment of Health and Social Security. Health and Personal Social Services Statistics for
England.1972-1978. London: H.M.S.O.
Oysken, M. W. & Chan, C. H. (1977). Oiazepam withdrawal psychosis; a case report. Am. J.
Einarson, T. R. (1980). Lorazepam withdrawal seizures. Lancet, 1, l51.
Findlay, J. 0 ., Robinson, W. W. & Peregrino, L. (1972). Addiction to secobarbital and
chlordiazepoxide in the Rhesus monkey by means of a self-infusion preference procedure.
Fruensgaard, K. (1976). Withdrawal psychosis: A study of30 consecutive cases. Acta psychiat.
Hillestad, L., Hansen, T. & Melson, H. (1974). Diazepam metabolism in normal man . ii. Serum
concentration and clinical effect after oral administration and accumulation. Clin.
Hollister, L. E., Motzenbecker, F. P. & Degan, R. O. (1961). Withdrawal reaction from
chlordiazepoxide ("Librium"). Psychopharmac., 2,63-8.
Hollister, L. E. & Prusmack, J. J. (1974). Propranalol in withdrawal from opiates. Arch. gen.
KaIes, A., Scharf, M. B. & KaIes, J. D. (1978). Rebound insomnia; a new c1inical syndrome.
Kaies, A., Scharf, M. B., KaIes, J. D. & Soldatof, C. R. (1979). Rebound insomnia. A potential
hazard following withdrawal ofcertain benzodiazepines. J. Am. med. Ass., 241, 1692-95.
Kanto, J., Iisalo, E., Lehtinen, V. & Salminen, J. (1974). The concentrations of diazepam and its
metabolites in the plasma after an acute and chronic administration. Psychopharmac., 36,
123-131. Kumar, R. (1974). Animal model forevaluating psychotropic drugs. Psychol. Med., 4, 353-9 .
Lancet (1973). Leading article - Benzodiazepines; use, over-use, misuse, abuse? Lancet, I, 1101.
Lancet (1979). Leading article - Benzodiazepine withdrawal. Lancet, I, 196.
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