Tolerance, Tachyphylaxis, and Psychedelic Drug Action

Understanding this interplay is essential in psychedelic drug research.


Psychedelic drugs are a unique class of compounds. They affect sensory processing, perception, and cognition. But these effects can be blunted with repeated dosing, causing tolerance.

Tolerance vs. Tachyphylaxis

Tolerance is when higher doses of a drug are required to produce a given response.1 Behavioral tolerance to a drug can be rapid or chronic. Rapid tolerance means tolerance develops within 24 hours and chronic tolerance develops over a longer stretch of time like days or weeks. Psychedelics typically produce rapid tolerance that dissipates within a few days while other drug classes have a chronic tolerance.2 For example, a typical recreational dose of lysergic acid diethylamide (LSD) is 100-250 micrograms (µg). If a person took 200 µg one day and then within the next few days wanted to take another 200 µg dose, this dose may have less of an effect or none at all, and a higher dose is needed to produce the same behavioral or perceptual response. It has been shown that most people can build up a complete tolerance to the same dose within a week.3

Tachyphylaxis describes a rapid decrease in response to repeated doses of a drug over a short period of time.4 This is similar to rapid tolerance. One study by Buchborn and colleagues investigated the tolerance and tachyphylactic effects of 25CN-NBOH* on the head twitch response (HTR) in mice. They applied the drug twice at 1 and 1.5-hour intervals and found a rapid loss of responsiveness to the second injection, which is thought to be attributed to cellular signaling mechanisms.5 This is comparable to other studies with DOI**, where HTR frequency decreased following repeated injections between 2-8 hours.6

* 4-[2-[(2-hydroxyphenyl)methylamino]ethyl]-2,5-dimethoxybenzonitrile 

** 2,5-Dimethoxy-4-iodoamphetamine

The Neuroscience Behind Tachyphylaxis and Tolerance

These phenomena are common with many pharmacological classes of compounds. The development of this rapid tolerance and tachyphylaxis is thought to be due to changes in the receptors that compounds activate.7,8 In the case of psychedelics, it’s the serotonin 2A receptor (5-HT2AR).

Internalization, down-regulation, and desensitization are all ways these receptors are altered to produce less of an effect. Desensitization involves phosphorylation of the 5-HT2ARs at a specific area that diminishes evoked responses and typically happens within milliseconds to minutes of drug exposure.9,10 This makes it so the receptor can’t keep producing a signal with more agonist exposure. Internalization and down-regulation occur after a longer exposure to the agonist. Internalization is when a receptor is taken from the surface of the cell via a process called endocytosis. Following internalization, the receptor is either recycled back into the cell surface for activation or is degraded and no longer active. The down-regulation of receptors is when the total number of receptors decreases due to that degradation. The changes in the receptors alter the ability of psychedelics to activate the 5-HT2AR to exert their effects

Implications in Therapeutics

The development of rapid tolerance with psychedelics is also important for further development as treatments for psychiatric disorders. Unlike other pharmacotherapies like selective serotonin reuptake inhibitors (SSRIs), psychedelics cannot be given daily due to the rapid development of tolerance. Although SSRIs also cause internalization and down-regulation of receptors, this is seen over longer periods of administration like weeks to months.11 It is also important to note that even small doses of psychedelics may produce tolerance or tachyphylaxis.

Further research is necessary to figure out how this pharmacological mechanism may play a role in the future of psychedelic medicine.

Alaina is a PhD student in pharmacology at Virginia Commonwealth University. Her research focuses on behavioral changes and circuitry of psychedelics involved in preclinical models of addiction and depression.


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