Cross-tolerance

Physiological tolerance to similar drugs

Cross tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. Cross tolerance has been observed with pharmaceutical drugs such as anti anxiety agents and illicit substances, and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function. This phenomenon allows one to become tolerant to a drug that they have never used before.

Excitation of the GABA receptor produces an influx of negatively charged chloride ions, which hyperpolarizes the neuron and makes it less likely to give rise to an action potential. In addition to gamma Aminobutyric acid (GABA) itself, the GABAA receptor can also bind barbiturates and benzodiazepines. Benzodiazepine binding increases the binding of GABA and barbiturates maximize the time the pore is open. Both of these mechanisms allow for influx of chloride ions. When these drugs are taken together, especially with ethanol (drinking alcohol), there is a disproportionate increase in toxicity because the effects of both occur simultaneously and add up since they act on the same receptor at different sites. Convergence upon the GABAA receptor is why tolerance for one drug in the group will most likely cause cross tolerance for the other drugs in the group.

Cocaine, amphetamines, methylphenidate and ephedrine block the reuptake of dopamine and norepinephrine. With increasing doses, amphetamines also cause the direct release of these neurotransmitters.

Serotonergic psychedelics act through modulation of serotonin receptors. Most of these drugs share a high affinity for the 5 HT2A receptor subtype, known to result in their common perceptual and psychological effects.

Sometimes cross tolerance occurs between two drugs that do not share mechanisms of action or classification. For example, in rats some amphetamine like stimulants have been shown to exhibit cross tolerance with caffeine, though this effect was not observed with amphetamine itself. It is likely that this mechanism of cross tolerance involves the dopamine receptor D1. Amphetamines also have cross tolerance with pseudoephedrine, as pseudoephedrine can block dopamine uptake in the same manner that amphetamines do, but less potently. Alcohol is another substance that often cross tolerates with other drugs. Findings of cross tolerance with nicotine in animal models suggest that it is also possible in humans, and may explain why the two drugs are often used together. Numerous studies have also suggested the possibility of cross tolerance between alcohol and cannabis. Cigarette smoking produces increased metabolic tolerance to caffeine due to upregulation of the CYP1A enzyme family (see aryl hydrocarbon receptor).