Can classic psychedelics cause addiction? (notes of a Pharmacologist)


Active member
Expert Pharmacologist
Jul 6, 2021
Reaction score

To answer the question, we need to define some receptor dynamics and corresponding effects.
It has been established that after a single administration of classical psychedelics there is a massive and prolonged desensitization of 5-HT2a receptors, which leads to the phenomenon of tachyphylaxis - a marked decrease in the expression of the effect when the drug is reintroduced. However, this does not seem to be specific enough, since there are other substances that cause massive desensitization/internalization of receptors (e.g., CB1 agonists).

The focus of attention shifts to pharmacodynamics: classical psychedelics affect the serotonergic system, which in turn regulates both tonic and phasic modes of discharge of dopaminergic neurons in the ventral cap region, as well as modulating the operation of dopamine synapses in the adjoining nucleus.

It has been proven that if the property of "inhibiting dopamine reuptake" is added to that of serotonin reuptake, then the addictive potential and the potential for abuse is reduced by several times. I think this is a fairly utilitarian observation, both for practicing addicts and for people involved in drug development. Surprisingly, no chemical addiction treatment guidebook mentions the use of SSRIs or serotonin releasers, and that's a shame.

Moving on. As we know, different serotonin receptor subtypes have different effects on dopamine levels in the nAcc (adjoining nucleus), and therefore have different effects on drug seeking behavior and its reinforcing properties.

5-HT2a increases dopamine release and adds to the addictiveness of the psychoactive substance. Given the above fact, it is possible to prevent addiction either beforehand (by reducing the density of the 5-HT2a receptor, e.g. with an antipsychotic) or to block the receptor or stop the receptor's own/intrinsic activity using an inverse agonist like eplivanserin. This is a very important and subtle point. The mechanisms of drug addiction disruption are still being studied, there are no ideal approaches to prevent it. However, 5-HT2a may actually be involved. Taking cathanserin greatly reduces the rate of reinstatement (provoking a breakdown under certain conditions), just as an alcoholic breaks down at the sight of a bottle of alcohol.

5-HT2b. There is little data on this receptor, much less on its selective activation. It is true that there is one compound, 6-APB, which is an empathogen whose effects are similar to those of MDMA. It has an affinity for 5-HT2b 100 times higher than 5-HT2a and 5-HT2c. According to reports from and, no special craving or physical dependence on it has been observed.

Finally, the chief guest of the anti-drug program, 5-HT2c! Selective agonists of this receptor reduce craving, self-injection, and other effects of addictive substances, and there are already such heroes on the market - lorcaserin.
This anorectic drug has a powerful anti-addictive potential, and a bonus is that it makes it easier to visualize the wallpaper for psy-trance :)

5-HT2c, by activating GABAergic interneurons in the VTA, inhibits the firing of DA neurons, all prosaic enough, but that's not all. Even if dopamine reaches the nAcc, the 5-HT2c receptor there, through intracellular signaling, inhibits DARPP-32 phosphorylation, and this is a very important aspect of intracellular rearrangement in addiction. Unfortunately or fortunately, dopamine does not drop in the dorsal striatum from 5-HT2c activation.

Our fundamental nAcc-VTA reinforcement circuit has its own feedforward. It consists of so-called middle spiking neurons that send their GABAergic "tentacles" back to the DA neurons of the VTA. The 5-HT2c activates them, but the D1 receptor blocks them. The conclusion is simple: when stimulants increase dopamine levels in the nAcc, they disrupt/break/damage the negative feedback loop, thereby greatly increasing the potential for cellular learning. Let me remind biocachers that super-nootropics lie in the plane of displaced D1 receptor agonists, of which, however, there are plenty in other key areas of learning, such as the hippocampus.


Another electrophysiological precursor point for psychostimulants and 5-HT2c agonists is the change in cell excitability through the effect on potassium channels K.v1.x

What is the answer to today's question?
Classical psychedelics do have anti-addictive properties, but what about selective 5-HT2a agonists - think for yourself.