Mechanisms of Drug Tolerance

New data emerging from the investigation of the death of Michael Jackson reveal that the iconic pop star was taking very high doses of sedative medications during the course of his career. At the time of his death, it was reported that he was taking at least ten tablets of the powerful sedative Xanax every night. Some report that this was an improvement over his previous ingestion of 30 to 40 tablets nightly.

To the uninitiated, doses that high would be lethal. To someone who had developed a tolerance to the medication, however, doses in that range may be necessary to achieve the desired effect. It seems to defy physiology that what would kill one individual would merely mellow out another, but therein lies the enigma of drug tolerance.

Certain medications, such as narcotic painkillers and sedatives such as Xanax, are known to create tolerance. In the case of opiate narcotics, this occurs at several levels within the body. Chronic use of opiate medications causes partial loss of function of its neural receptors’ ability to signal within brain cell. It also causes adjustment of the signaling systems within the cell, leading to alterations in its excitability. These changes, in turn, can indirectly affect the excitability of nerve cells throughout the body, further contributing to overall tolerance. Interestingly, the signaling systems involving cAMP also play a role in synaptic plasticity, leading to potential consequences of opiates on learning and memory. Combined, these changes lead to a blunting of the body’s response to a given dose of an opiate over time, and therefore an ever-escalating need for higher doses of opiates in order to achieve the same effect.

The development of tolerance to sedatives such as Xanax is less well understood, but may involve down-regulation of the benzodiazepine and GABA receptors within the brain. Reduction in the number of chloride channels within the cells and the resultant changes in the GABA receptors may also play a role. Chronic use may alter the gene regulation of the receptor itself. However tolerance to sedative medications occurs, it is known to occur swiftly, particularly with respect to their depressant effects.

While the amount of medications that Jackson was taking may seem shocking, it is a well-known consequence of chronic use of these medications. Unfortunately, while tolerance to the sedative effects of these medications may occur, tolerance to some of their other effects may not, frequently leading to illness, and in some cases, death.


Christie, M. (2008). Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction British Journal of Pharmacology, 154 (2), 384-396 DOI: 10.1038/bjp.2008.100

Bateson, A. (2002). Basic Pharmacologic Mechanisms Involved in Benzodiazepine Tolerance and Withdrawal Current Pharmaceutical Design, 8 (1), 5-21 DOI: 10.2174/1381612023396681

Miller LG. Chronic benzodiazepine administration: from the patient to the gene. J Clin Pharmacol. 1991 Jun;31(6):492-5.

Hutchinson, M. (1996). The behavioural and neuronal effects of the chronic administration of benzodiazepine anxiolytic and hypnotic drugs Progress in Neurobiology, 49 (1), 73-97 DOI: 10.1016/0301-0082(96)00011-1

T. A. McNamee, MD

T. A. McNamee, MD, is an associate professor and internal medicine residency program director at Sanford School of Medicine of the University of South Dakota.
See All Posts By The Author