Tolerance to some of the effects of barbiturates can be demonstrated, although the degree and rate of tolerance acquisition varies considerably with the dose, frequency of administration and the individual. The potential for tolerance is much lower with barbiturates than with the opiate narcotics, and appears to level off at a maximum of 1.0 - 2.5gm. per day. While this loss of drug sensitivity is quite general and applies to both sedative and mood effects, no tolerance appears to develop to the lethal toxicity level since chronic users are as susceptible to fatal over-doses as are initiates. In other words, the safety margin decreases with increased tolerance. Several mechanisms operate in producing tolerance.
Barbiturates stimulate the body's production of the metabolic enzymes which inactivate the drug.
Also, some insensitivity to the depressant effects appears which might reflect a general neurological adaptation. Certain learning processes are also probably involved in changing the character of the response upon repeated administrations. Most aspects of tolerance disappear after a few weeks of abstinence from the drug. Although barbiturates were not recognized as 'addictive' drugs for decades after their general medical acceptance and usage, in chronic users, physical dependence may develop along with tolerance. The abstinence syndrome following withdrawal of the drug in chronic heavy users may begin with a reduction in intoxication and an apparent improvement in condition.