An experimental study of tolerance among alcohol dependent individuals

An experimental study of tolerance among alcohol dependent individuals

Ballakoor, K

Background & objectives: Continued alcohol use leads to tolerance, however, some dependent individuals lose tolerance despite continued alcohol consumption. The exact mechanism for this is not known. This study evaluated tolerance in alcohol dependent patients in a treatment centre using multiple measures.

Methods : Male patients with alcohol dependence (DSM III R criteria) were chosen and detoxified in an inpatient setting. On day 14 of detoxification, each subject was given ethanol (0.75 g/kg body wt) mixed in an equal amount of placebo (cola) drink once and an equivalent amount of placebo (cola) during the other occasion in a single blind, randomised, cross over manner. Assessment of each subject was made using multiple measures (clinical, neuro-psychological tests, scales for subjective effect and blood alcohol levels), 30 min after intake of each drink.

Results : The subjects (n=26) did not vary under the two conditions (alcohol/placebo) as regards subjective effects, tests on logical memory and Bender Gestalt test (BGT). Cognitive screening scores though different under the two conditions, were within the normative range. Of these 26 subjects, 50 per cent showed clinical signs of intoxication after consumption of alcohol. These two groups (impaired vs unimpaired) were comparable on all base-line clinical parameters, assessment of euphoria and sedation, and various neuropsychological tests except BGT under the two conditions (placebo/alcohol). The non-tolerant (impaired) group scored significantly (P

Interpretation & conclusions: The study suggests that clinical tests were more sensitive in detecting intoxication. Further studies are needed to understand the mechanism of loss of tolerance.

Key words Alcohol dependence-assessment-reversal of tolerance-tolerance

Alcohol is the commonest substance of abuse the world-over. Acute ingestion of alcohol causes behavioural changes and manifests as intoxication. However, regular use leads to diminished responsiveness and many alcohol dependent individuals are tolerant to as much as 760-900 ml of distilled liquor1. Tolerance is one of the major factors responsible for excessive alcohol intake and is closely linked to development of dependence.

From a clinical perspective, behavioural tolerance is more important than metabolic tolerance. Besides the length of exposure, dosage of alcohol consumed and pattern of exposure, tolerance may be related to the tests used to assess tolerance. Different tests yield different results and thus more than one test should be used while studying,tolerance. Various tests used to measure tolerance include evaluation of the acute effects of alcohol consumption on mood, clinical signs of intoxication at different blood levels, performance on neuro-psychological tests and electro-physiological studies2.

It has also been observed that some alcohol dependent individuals, including some in our centre, tend to lose tolerance over time. Thus they experience intoxication at a dose which normally should not cause drunkenness in a dependent individual. The time course for the development of loss of tolerance may be after months and more often after a few years of consumption3. The exact mechanism of reversal of tolerance or acquisition of sensitivity following chronic exposure is not yet known. It has been postulated that chronic ethanol consumption leads to production of chemically induced brain lesions, which cause reversal of tolerance4. Alternatively, loss of tolerance may be related to ageing or liver damage. There is a paucity of literature about this pehnomenon. After the publications by Khanna and colleagues in 1982(4), there have been few publications in this area till the resurgence of interest in 1997.

In this study, we assessed behavioural tolerance through evaluation of clinical signs of intoxication, measurement of subjective effects and performance on neuro-psychological tests among alcohol dependent subjects following a single dose challenge with alcohol and placebo at different points oftime in an experimental situation. This study is the first of its kind in Indian subjects and it is possible that manifestation of tolerance may be different in Indian subjects, as ethnic differences in alcohol metabolism are well known5.

Material & Methods

Males who were alcohol dependent, aged between 16-45 yr with a minimum education of eight years of schooling (completed class 8) were taken up consecutively for the study with informed consent following their detoxification. As a result the subjects had been free of alcohol for 12-15 days and off psychotropic medication for at least 7 days. The study was carried out in the in-patient setting of our centre in 1996. The departmental committee on research cleared the study. Patients with illnesses where administration of alcohol was contraindicated viz., advanced liver damage, clinically diagnosed dementia, amnestic syndrome and psychiatric illness, were excluded.

Following their inclusion, the subjects were asked to drink alcohol 0.75 g/kg of body wt (90-120 ml of rum, alcohol content-40% v/v), diluted with an equal amount of cola drink on one occasion and an equal amount of placebo (cola drink, 180-240ml) on the other occasion, in a single blind, randomised, cross over manner. Blood alcohol levels of 80-100 mg/dl are expected following consumption of this amount of alcohol6 and should cause intoxication in non-tolerant subjects. The subjects were blind to the nature of beverage consumed. There was a minimum period of 48 h between the two ingestions. The addition of two drops of vanilla essence in the glasses masked the flavour of both the beverages. Following an overnight fast, the subjects sipped the beverage over 20 min, 2 h after a non-fatty breakfast.

Information on demographic variables, history of alcohol use, self-report of tolerance (capacity to hold) in the last month was collected; height and body weight were also recorded. The subjects were informed that they would receive either alcohol or a non-alcoholic drink on two different occasions and they were to report the subjective effects as accurately as possible and carry out the psychological tests. They were asked to identify the beverage consumed and were assessed on the following parameters 30 min after the end of consumption of the drink (placebo/alcohol).

Intoxication: This was assessed clinically by the presence of impairment on at least one of the following tests: finger nose test, tandem walking, Romberg’s test and nystagmus7.

Subjective effects: (i) Euphoria and sedation were assessed using short forms (Hindi version) of the morphine benzedrine group (MBG) and pentobarbital chlorpromazine alcohol group (PCAG)- scales of the Addiction Research Centre Inventory (ARCI)8. MBG has 16 questions (maximum score 16), PCAG has 15 questions (maximum score 15) and measure drug induced euphoria and sedation respectively; and (ii) euphoria was also assessed with the help of the visual analog scale (VAS)9, score 0-100, where ‘0’ represents no effect and ‘100’ maximum pleasure.

Neuro-psychological assessment.- Hindi version of the following instruments was used. Two forms (A&B) were used to obviate the process of learning. Form A was used after the subject consumed alcohol, and Form B after the consumption of placebo.

(i) Cognitive impairment was assessed by Form A: Jacob’s cognitive capacity screening10 and Form B: Mini mental status examination (MMSE)11. Out of a possible score of 30, a score of 25 or less in MMSE, and in cognitive screening, a score of 20 or less suggests brain damage. These have been standardised in our department12.

(ii) Short-term logical memory was measured by Forms A and B, which are adapted sub scales of Weschler memory scale13. The maximum score is 23. This is a culture fair test and has been used extensively in the Indian setting (Dube S, personal communication).

(iii) Perceptual-motor functions and visual memory were measured by copying Bender Gestalt test (BGT) using Hains’ scoring and recall by Wepman’s method14. BGT is a culture fair test and a score of 9 or more suggest cognitive damage.

(iv) Motor speed, visuo-motor tracking and attention was assessed by Forms A and B of trail making15. These are also culture fair tests that have been used extensively in our department (Dube S, personal communication).

Laboratory tests: (i) Blood alcohol levels (BAL) were estimated 30 min after the end of alcohol consumption on Hewlett Packard 5890 Series II gas liquid chromatograph (HP, GLC, USA), equipped with glass Porapak Q column, FID detector and HP 3396 Series II integrator16 . A Savion(R) swab was used to clean the area before drawing a blood sample; (ii) complete haemogram was carried out at the time of inclusion; and (iii) liver function tests: Total protein, albumin, globulin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT) were carried out by using Hitachi-704 auto analyser (Japan).

Statistical analysis: The mean and SD scores of various tests were calculated. Paired ‘t’test was used to compare the mean scores of tests after alcohol and placebo intake. Student’s ‘t’ test (two tailed) was used to compare the two subgroups (tolerant and non-tolerant subjects) on various parameters.


Twenty nine consecutive patients met the inclusion criteria for the study, however, three patients refused to participate. Thus 26 subjects completed the study. No incentives for participation were given to these subjects and there was no subjective bias in their selection. Their mean age was 36.3 +/- 4.9 yr, 92.4 per cent were married and all were employed. Eighteen (69.3%) had studied up to class 12, the remaining had higher levels of education. The subjects had used alcohol for 12.8 +/- 6.9 yr with a mean duration of dependence for 4.8 +/- 4.2 yr (range 0.2 – 16 yr). In the previous month, the average consumption of alcohol per day was 325.8 +/- 197 g, and 78.5 +/- 64 g per drinking session. As per the individual’s self-report, in the last one month the amount of alcohol which could be consumed in a single drinking session without being intoxicated (capacity to hold) was 135.1 +/- 114.4g (range 19.2-48 g). In other words, the subjects claimed that they could drink between 60-1440 ml (mean 400m1) of distilled spirits without getting drunk.

The subjects were healthy and their mean height was 166.8 +/- 5.3 cm, mean weight was 55.6 +/- 8.9 kg and mean haemoglobin was 12.5 +/- 0.6 g/dl.

Twenty four subjects (92.4%) identified the alcoholic beverage correctly but six persons (23.1%) misidentified the placebo (cola beverage) as alcohol. After administration of alcohol, 13 subjects (50%) showed at least one clinical sign of intoxication while none was intoxicated following administration of placebo. Nystagmus was present in nine subjects (34.6%); Romberg’s sign in eight subjects (30.8%); impaired tandem walking in seven (26.9%) and two subjects (7.6%) showed incoordination on finger nose test. However, all the signs were not present in all of them. It can be interpreted that these 13 individuals had lost tolerance to the administered amount or alcohol (expected BAL-100 mg/dl) even though they were dependent users. No aversive effects like nausea, vomiting or flushing were reported.

The subjects in this study did not show higher euphoria (MBG & VAS scores) or sedation (PCAG scores) after consumption of alcohol. This would indicate presence of tolerance to these effects (Table I).

The scores on cognitive screening, logical memory and BGT were within the normal range, however, the subjects performed significantly (P

BAL achieved by GLC amongst these subjects was 78.7 +/- 24.6 mg/dl. Results of liver function tests showed impairment of AST – 58.1 +/- 41.3 (lab normal up to – 50 IU), ALT – 58.6 +/- 48 (lab normal up to 50 IU) and GGT – 85.8 +/- 70.9 (lab normal up to 40 U).

Data on the 13 subjects who showed signs of clinical intoxication (Gr.1- loss of tolerance/impaired) were compared with those of the other 13 subjects who showed no signs of clinical intoxication (Gr.2-tolerant/ unimpaired). The two groups did not differ significantly as regards age, duration of alcohol use and dependence, average amount of alcohol consumed per day and per drinking session in the previous one month. They also did not differ significantly on the amount of alcohol they could consume in a single session without being intoxicated in the previous month (Gr. 1- 125.5 +/- 113.9, Gr. 2- 144.7 +/- 118.6 g of ethanol). BAL achieved was comparable in the two groups (Gr. 1- 74.9 +/- 25.3, Gr.2– 82.9 +/- 24.8 mg/dl). Scores on euphoria (MBG & VAS), and sedation (PCAG) scales were also comparable (Table III).

The scores on the neuro-psychological tests were comparable in the two groups under two conditions except on BGT. Among the impaired subjects (Gr. 1) following consumption of alcohol, BGT scores were significantly higher than the tolerant group (Gr.2), and suggested cognitive damage (Table IV). Values of the liver function tests were comparable.


Studies measuring behavioural tolerance have used two approaches viz. (i) comparing intoxication among dependent and non-dependent subjects on equivalent doses of alcohol or (ii) comparing the performance of dependent subjects during sobriety and intoxication. This study assessed intoxication and tolerance in individuals who were alcohol dependent, using various measures, after administration of a single dose of alcohol and a single dose of placebo. There was an adequate washout period between the administration of these two drinks. Long-term cognitive changes can occur in as many as 75 per cent of alcoholics as measured by neuropsychological tests17 and the within group design of our study took care of this confounding variable as the subjects acted as their own controls.

The subjects were evaluated 12-15 days after their last alcohol intake, when their withdrawal symptoms had subsided, as these might have interfered with assessment of intoxication. The subjects had also been free of benzodiazepines and other psychoactive medication for an adequate period to ensure that these did not interfere with their test performance. Blinding was attempted by masking the odour of the beverage using an essence, however, this might have been inadequate. Most (92.4%) subjects identified alcohol although some (23. 1%) misidentified the placebo. This could be explained on the basis of the subjective effects of alcohol experienced by the subjects and the expectancy effect related to placebo. Blinding cannot be assessed based on recognition of the drink as the subjects were evaluated for recognition after consumption of the drink (subjective effects) and not based only on it’s sight or smell.

Blood alcohol level (BAL) was measured at 30 min, the expected time to reach peak blood alcohol levels after a standard ethanol dose18. The dose of alcohol administered in this study is expected to produce a peak BAL 80-100 mg/dI6, (actual value obtained – mean 78 mg/dl), which should not cause intoxication in dependent subjects. In fact, the National Council on Alcoholism, USA suggests that tolerance to alcohol dependent individuals is evident even at a BAL of 150 mg/dl1.

The assessment for intoxication was comprehensive and based on several tests most often used to assess tolerance to alcohol2,19. In this study, 50 per cent subjects displayed at least one clinical sign of intoxication indicating loss of tolerance. On various other tests, scores on euphoria and sedation did not show any alteration after alcohol intake (presence of tolerance) as against placebo and thus were less sensitive than clinical testing. Scores on Trail Making test were poor even after consumption of placebo, thus suggesting impaired perceptuo-motor function. Only cognitive screening scores were significantly lower after alcohol intake although they were still well within the normal range.

The subjects were classified as tolerant and nontolerant subgroups on the basis of clinical testing. These groups were comparable on demographic variables and clinical history of alcohol use. All test scores except BGT were comparable in the two groups wherein the scores were significantly higher in the non-tolerant (clinically impaired) group than the tolerant group after alcohol consumption, but were only slightly above the normal range, thus did not suggest brain damage leading to loss of tolerance. However, as stated earlier, the scores on Trail Making tests did suggest cognitive damage.

Loss of tolerance despite continued alcohol use has been attributed to several factors like advancing age, nutritional deficiency, or liver damage leading to reduced capacity of liver to metabolise alcohol, VSA.6,20. The subjects in this study were healthy and not old. The two groups were comparable on age and other background parameters, values of liver function tests and BAL were not higher among the impaired group. Thus these factors did not seem to play an important role. Since this study was conducted at least 12-15 days after stopping alcohol, it could be presumed that reversal of tolerance due to abstinence had not yet occurred. It would have taken months of an alcohol free status forsuch a phenomenon to happen3. The two sub-groups also did not differ on any base-line neuro-psychological impairment i.e. test scores under the two conditions, viz. consumption of placebo or alcohol. More sensitive tests to detect cognitive damage and neuro-imaging may be required to assess such individuals. Recent reports suggest the sensitisation (reverse tolerance) to alcohol may be due to exposure to various toxins and is under genetic control21,22. It has also been hypothesised that the above factors along with the serotonergic system may influence the maintenance/loss of tolerance to alcohol through the effects on endogenous vasopressin23.

To summarise, the findings of this study document that some alcohol dependent individuals may lose tolerance to alcohol. It also shows that physical signs of intoxication are more sensitive in detecting lack of tolerance than observation of mood and cognitive screening tests. The study did not find any factors that could be related to loss of tolerance e.g. demographic variables, drinking history or cognitive impairment. This may be because of the small sample size and low power of the study. More sophisticated studies are needed to explain this clinical observation. Patients who show clinical signs of loss of tolerance should be informed about it and educated about its implications.


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K. Ballakoor, R. Ray, S. Dube, R. Jain, M. Vaswani & A. Dhawan

Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India

Accepted December 4, 2000

Reprint requests: Dr R. Ray, Additional Professor, Drug Dependence Treatment Centre, All India Institute of Medical Sciences

Ansari Nagar, New Delhi 110029, India

Copyright Indian Council of Medical Research Jan 2001

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