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Cross-tolerance is a phenomenon that occurs when someone who is tolerant to the effects of a certain drug also develops a 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.[1] This phenomenon allows one to become tolerant to a drug that they have never even used before.[2]

Major Drug Classifications and Cross-Tolerance[edit]

Groups of Psychoactive drugs Drug examples
Antianxiety drugs and sedative hypnotics Benzodiazepines (valium, xanax, klonopin)

Barbiturates, alcohols Other anesthetics (GHB, Special K, PCP, angel dust)

Antipsychotics Phenothiazines: chlorpromazine (thorazine)

Butyrophenones: haloperidol (Haldol) Clozapine (Clozaril), Aripiprazole (abilify, aripiprex)

Antidepressants and mood stabilizers MAO inhibitors

tricyclic antidepressants: imipramine (Tofranil), SSRIs, fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil, Seroxat), Mood stabilizers (Lithium, sodium valproate, carbamazepine)

Opioid analgesics Morphine, codeine, heroin, endomorphins, enkephlins, dynorphins
Psychotropics Dopaminergic stimulants (cocaine, amphetamine), Muscarinic psychedelics (Jimson Weed, Amanita), Cannabinoidergic (THC), NMDA antagonists (PCP, Ketamine), Serotonergic psychedelics (LSD, mescaline, psilocybin)

Antianxiety and sedative hypnotics[edit]

Exciting the GABA receptor produces an influx of Chloride ions, which hyperpolarizes it and makes it less likely to give rise to an action potential and decreases a neuron’s firing rate. The GABA receptor can also bind barbiturates and benzodiazepines. Barbiturates binding increases the binding of GABA and benzodiazepines maximizes the time the pore is open, both of these mechanisms allows for an influx of Chloride ions. When these drugs are taken together it is very dangerous because the effects of both are added up since they act on the same receptor, which is why when you have tolerance for one drug in the group you will most likely show cross-tolerance for the other drugs in the group.[3]

Antipsychotic drugs[edit]

These drugs block dopamine receptors and can also block serotonin receptors

Antidepressants and Mood Stabilizers[edit]

A MAO inhibitor allows for more serotonin release by inhibiting enzymes that break down serotonin. Some of the other drugs block the reuptake transporter which takes some of the neurotransmitters back up, and disallows for the neurotransmitter to reach the next synapse.[4]

Opioid analgesics[edit]

These drugs mimic three classes of endorphins, such as endomorphins, enkephalins, and dynorphins. All three of these classes each have their own receptor-mu, kappa, and delta. Opioids will bind to the receptor for the endorphin they are most chemically similar to. Tolerance develops quickly with regular use, with the down regulation of the stimulated receptors to blame.


Amphetamine and cocaine block the reuptake of dopamine. Amphetamine also helps release dopamine from presynaptic membranes. Psychedelic drugs generally act through modulation of serotonin, hence, the high affinity of psychedelics for the 5HT-2A Receptor. Caffeine increases the metabolic activity of cells. It inhibits the enzyme which breaks down cAMP, allowing for further glucose production and therefore, more energy.[5]

Drugs of Different Classifications[edit]

Sometimes cross-tolerance occurs between two drugs that do not share mechanisms of action or classification. For example, amphetamine and amphetamine-like stimulants have been shown to exhibit cross-tolerance with caffeine, and it is likely the mechanism of cross-tolerance involves the dopamine D(1) receptor.[6] Amphetamines also have cross-tolerance with pseudoephedrine, as pseudoephedrine can block dopamine uptake in the same manner that amphetamines do, but less potently.[7]

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.[8] Numerous studies have also suggested the possibility of cross-tolerance between alcohol and cannabis.[9]


  1. ^ Kolb, Bryan, and Ian Whishaw. An Introduction to Brain and Behavior. New York: Worth Publishers, 2014. Print.
  2. ^ The Free Dictionary
  3. ^ Kolb, Bryan, and Ian Whishaw. An Introduction to Brain and Behavior. New York: Worth Publishers, 2014. Print.
  4. ^ Kolb, Bryan, and Ian Whishaw. An Introduction to Brain and Behavior. New York: Worth Publishers, 2014. Print.
  5. ^ Kolb, Bryan, and Ian Whishaw. An Introduction to Brain and Behavior. New York: Worth Publishers, 2014. Print.
  6. ^ Jain R. and S.G. Holtzmann. 2005. Caffeine Induces Differential Cross Tolerance to the Amphetamine-like Discriminative Stimulus Effects of Dopaminergic Agonists. Brain Research Bulletin 65(5): 415-421.
  7. ^ Ruksee N., W. Tonjaroenbuaranga, S. Casallotti, and P. Gobitrapong. 2008. Amphetamine and Pseudoephedrine Cross-Tolerance Measured by c-Fos Protein Expression in Brains of Chronically Treated Rats. BMC Neuroscience 9(99).
  8. ^ Funk D., P. Marinelli, and A. Le. 2006. Biological Processes Underlying Co-use of Alcohol and Nicotine: Neuronal Mechanisms, Cross­tolerance, and Genetic Factors. Alcohol Research and Health 29(3): 186-192.
  9. ^ Pava M. and J. Woodward. 2012. A Review of the Interactions between Alcohol and the Endocannabinoid System: Implications for Alcohol Dependence and Future Directions for Research. Alcohol 46(3): 185-204.