Tolerance and Tachyphylaxis in Psychedelic Therapy

This week, the Psychedelic Science Review published a helpful overview of the mechanisms that explain anecdotal evidence of patients rapidly increasing tolerance to psychedelic use.

Put simply:

• Pharmacodynamic tolerance occurs when drugs repeatedly interact with nerve receptors. The brain gets used to the presence of the drug and demands higher doses to feel the effect previously achieved by lower dosage
• Metabolic Tolerance – the drug may be metabolized in the body before it reaches the destination point resulting in tolerance.
• Tachyphylaxis –the consumed drug results in a rapid decrease in efficacy. 

Why does this happen?

The above happens with many pharmacological classes of compounds. The development of rapid tolerance and tachyphylaxis is thought to be due to changes in the receptors that are targeted by the drug- in the case of psychedelics, it’s the serotonin 2A receptor(5-HT_2AR).

"Internalization, down-regulation, and desensitization are all ways these receptors are altered to produce less of an effect. Desensitization involves phosphorylation of the 5-HT_2ARs at a specific area that diminishes evoked responses and typically happens within milliseconds to minutes of drug exposure. 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Following internalization, the receptor is either recycled back into the cell surface for activation or is degraded and no longer active.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-HT_2AR to exert their effects".

It's clear that the above needs to be considered as psychedelic medicine becomes more and more adopted, either by manipulating the molecules involved, or by strategically pacing the psychedelic therapy. It is worth noting though, that a benefit of psychedelics is that daily doses (as in the case of SSRI antidepressants), may not be necessary. Indeed, evidence has repeatedly shown that even one powerful psychedelic trip can alleviate symptoms in even the most treatment resistant patients.

For more updates on the latest psychedelic news and research, visit the psychedelic health professional network homepage.