Lessons From Psychedelics on Receptor Binding and Subsequent Functional Activity

It is 4 AM on a Saturday morning, and you are paged to the emergency department (ED) as the on-call psychiatrist to see a young adult experiencing psychosis whose accompanying friends report this individual’s ingestion of lysergic acid diethylamide (LSD) the previous night. The patient has an active medical record at this ED, with a visit 4 months ago reporting no psychiatric symptoms or treatment and no prescription medications or other medical issues. The psychotic symptoms increase and include visual hallucinations, agitation, and intense fear. Given your expertise in psychopharmacology, you write an order for an atypical antipsychotic (AA) that has high potency as a 5-HT_2A receptor antagonist. Because this is not an established medical treatment and is an off-label use of an AA, you obtain informed consent from the patient’s health care proxy prior to administration. Two hours later, the patient becomes calm, reports feeling safe, and denies any hallucinations.

What molecular dance did you just orchestrate? Spoiler alert: It had nothing to do with the AA dopamine D2 antagonism.

The first step in dissecting this good treatment outcome is to understand what a K_i is.

A Drug’s Binding Affinity

When comparing the potencies of various drugs to bind to a specific receptor, the gold-standard value used by the US Food and Drug Administration (FDA) is the equilibrium dissociation constant, more commonly called the inhibition constant, or simply the K_i. If you look at section 12.2 in any medication’s FDA-approved product insert, which is the section entitled pharmacodynamics, you will find the various K_i’s of that medication for all the relevant receptors with which it interacts. The K_i is the concentration of a drug that it takes to occupy 50% of the receptor’s binding site at equilibrium. Counterintuitively, the lower the K_i for a medication or molecule at a receptor, the more potent it binds to that receptor. The K_i is commonly defined at a nanomolar (nM) concentration, which is 10^-9 moles. This is the concentration range most commonly required for many medications to achieve efficacy at their target receptors in humans.

A drug’s K_i profile across established receptors acts as a fingerprint that predicts the drug’s clinical and adverse effects. If drug A has a K_i of 1 nM at the histamine receptor H1 and a K_i of 100 nM at the dopamine D2 receptor, it will function as an antihistamine at low dosages but will need to be dosed much higher to additionally function as an antipsychotic. Of course, this assumes that drug A antagonizes these 2 receptors (since many other actions on the receptors are possible).

Another common application is to compare K_i values at a specific receptor across 2 or more drugs to approximate their relative potency at this receptor. It is critically important to note that the K_i quantifies how tightly a drug binds to a receptor but does not tell you what the effect of that binding is. This will be discussed in detail in the next section. Additionally, when comparing K_i values, it is imperative to ensure that all variables across assays are identical, as different variables can yield different K_i values for the same drug. Variables include the source of the receptor (organism species, tissue type, anatomical part of the tissue, receptors from a human cloned gene), characteristics of the assay (ions used, pH, temperature), receptor density, and the concentration of the radioactive assay ligand, to name a few.

Psychedelic K_i Values at 5-HT_2A Receptor

Let’s put all these concepts into action and compare the K_i values of LSD, psilocin (the active psychedelic molecule created when the body processes psilocybin, a nonactive prodrug), and mescaline at the primary receptor believed to be necessary for the psychedelic effect of these drugs, the 5-HT_2A receptor. Importantly, all 3 of these psychedelics were studied by Rickli et al in the same study,¹ allowing a direct comparison of K_i values because they were tested in the exact same system with uniform variables and the 5-HT_2A antagonist ketanserin H 3 as the radioligand. The K_i for serotonin is from a different research study² that reported the use of a recombinant human 5-HT2A gene as the receptor source and ketanserin as the radioligand.² Table 1^1,2 provides a summary of the information from these 2 studies. Note that the K_i of LSD is approximately 10 times stronger than serotonin and that psilocin and serotonin are roughly equal.^1,2 Mescaline, on the other hand, binds significantly weaker than any of the 3.^1,2

Clinically Active Psychedelic Doses

A series of high-quality studies in healthy volunteers detailed the pharmacokinetics, acute effects, and subjective psychedelic experiences of varying oral doses of psilocybin, LSD, and mescaline—evaluated both independently and, in 1 study, directly compared.^3-6

The results from these 4 studies are consistent with established oral doses of these 3 psychedelics reported in numerous publications and consistent with doses commonly ingested in recreational use. Table 2^3-6 lists the dosages that produced a psychedelic effect while minimizing adverse effects, including anxiety, an increase in blood pressure, and an increase in heart rate.

Hypothetical Antidote to End a Psychedelic Trip

Going back to our case, although currently no AA is FDA approved for the treatment of an individual experiencing an acute dysphoric psychedelic experience, established published evidence supports the likelihood that this approach may be effective. Ketanserin (the tritiated radioisotope used as the radioligand in the 5-HT_2A agonist K_i studies in Table 1) demonstrated significant post–LSD ingestion effect reversal.⁷ Healthy volunteers were given 100 µg of LSD orally, followed by 40 mg of oral ketanserin 1 hour later. Ketanserin, not currently an FDA-approved medication, is a potent 5-HT_2A antagonist with an established K_i of 3.5 nM at this human receptor⁷; this value is nearly identical to LSD, which is a partial agonist at the same receptor, as are all psychedelics.^8,9 

The ketanserin reversed the visual and acoustic alterations and ego dissolution as well as the LSD-associated cardiovascular effects and mydriasis. It also reduced the subjective LSD effects from the usual 8.5 hours to 3.5 hours. The ketanserin reversal of the LSD was deemed pharmacodynamic and not pharmacokinetic.¹⁰

Most AAs are potent antagonists of the 5-HT_2A receptor and theoretically could bind this receptor and displace a psychedelic in a person who appears distressed by psychedelic intoxication (Table 3).¹¹ The most effective AAs and therapeutic dosing need to be established in well-designed clinical trials.

Psychedelics: Pharmacodynamics and Pharmacokinetics

Collectively, the previous data provide significant insights into basic pharmacological principles. A molecule’s K_i provides an immense amount of information related to which receptors a medication binds to. This information can be used to compare a medication’s binding affinity across a wide range of receptors and to compare the binding affinity of numerous medications across a single receptor. However, as discussed, K_i values are not absolute and should be interpreted in light of numerous factors. Reasonable comparisons can be made when the study conditions are similar, or preferably identical. As Table 1 demonstrates, K_i values allow a general comparison of how the binding affinity of a medication compares with the endogenous neurotransmitter, in this case, comparing various psychedelics to serotonin.

A medication’s dosage range for a meaningful clinical response in humans needs to be well established in the early stages of development, typically during phase 2 clinical trials. Table 2 shows the dose producing the optimal psychedelic effect for 3 psychedelics commonly used recreationally, two of which (psilocybin and mescaline) have been used by humans for thousands of years. The doses represent results from well-designed clinical trials and demonstrate that mescaline requires a dosage 3000 times higher than LSD to achieve roughly the same psychedelic experience in healthy volunteers (100 µg of LSD vs 300 mg of mescaline).^3-6 The psilocybin dose falls between these 2 extremes (20 mg).^3-6

A critical general concept that emerges from psychedelic data is that a molecule’s K_i does not reflect its functional potency or intrinsic activity at the receptor. The K_i is only the beginning of the story. Once bound to a receptor at an orthosteric site, a molecule can function as a full agonist, a partial agonist, an antagonist/partial agonist (controversially often simply called a partial agonist), an antagonist, or an inverse agonist. It is this intrinsic activity at the cell membrane’s receptor that ultimately determines the signal sent across the membrane to orchestrate the consequences of that particular molecule inside that particular cell.

A study by Becker et al provides a useful example of the utility and limitations of a medication’s K_i, clinical dose, and ultimate development of clinical paradigms. Healthy participants were orally administered 100 µg of LSD, which has a K_i of 4 nM at the 5-HT_2A receptor, where it acts as a partial agonist. One hour later, while experiencing psychedelic effects and adverse effects from the LSD, these individuals were orally administered 40 mg of the 5-HT_2A antagonist ketanserin, which has a K_i of 3.5 nM. The K_i of both medications is virtually identical, but the researchers chose to dose the ketanserin 400 times higher than the LSD.¹⁰

Would a significantly lower dosage of ketanserin be equally effective at reversing the LSD activity? The simple answer is that we do not know. However, an experiment could easily be designed to answer this question.

Concluding Thoughts

It appears likely that psychedelics will be joining our psychiatric pharmacopeia, if not in the next 2 years, then certainly within a decade. In the spring of 2026, the FDA fast-tracked the following 3 psychedelics using national priority vouchers¹²:

• Synthetic psilocybin (COMP360; Compass Pathways plc) for treatment-resistant depression
• Psilocybin for major depressive disorder (PSIL201; Usona Institute)
• Methylone, a 3,4-methylenedioxymethamphetamine–line treatment, for posttraumatic stress disorder (TSND-201; Transcend Therapeutics)

Much of the basic science, receptor function, neuronal circuitry, and clinical consequences of ingesting psychedelics is already well established. Stay tuned!

References

1. Rickli A, Moning OD, Hoener MC, Liechti ME. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur Neuropsychopharmacol. 2016;26(8):1327-1337.

2. Mozumder S, Mahesh G, Srinivasan K, et al. Expression and purification of functionally active serotonin 5-HT2A receptor in insect cells using low-titer viral stock. Bio Protoc. 2020;10(15):e3704.

3. Griffiths RR, Johnson MW, Richards WA, et al. Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology (Berl). 2011;218(4):649-665.

4. Holze F, Vizeli P, Ley L, et al. Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology. 2021;46(3):537-544.

5. Klaiber A, Schmid Y, Becker AM, et al. Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects. Transl Psychiatry. 2024;14(1):395.

6. Ley L, Holze F, Arikci D, et al. Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants. Neuropsychopharmacology. 2023;48(11):1659-1667.

7. Herndon JL, Ismaiel A, Ingher SP, et al. Ketanserin analogues: structure-affinity relationships for 5-HT2 and 5-HT1C serotonin receptor binding. J Med Chem. 1992;35(26):4903-4910.

8. McClue SJ, Brazell C, Stahl SM. Hallucinogenic drugs are partial agonists of the human platelet shape change response: a physiological model of the 5-HT2 receptor. Biol Psychiatry. 1989;26(3):297-302.

9. Newton RA, Phipps SL, Flanigan TP, et al. Characterisation of human 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptors expressed in the human neuroblastoma cell line SH-SY5Y: comparative stimulation by hallucinogenic drugs. J Neurochem. 1996;67(6):2521-2531.

10. Becker AM, Klaiber A, Holze F, et al. Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy participants. Int J Neuropsychopharmacol. 2023;26(2):97-106.

11. Meltzer HY, Gadaleta E. Contrasting typical and atypical antipsychotic drugs. Focus (Am Psychiatr Publ). 2021;19(1):3-13.

12. Edwards E. FDA grants quick review for 3 psychedelic drug trials. NBC News. April 24, 2026. Accessed August 21, 2026. https://www.nbcnews.com/health/health-news/fda-psychedelic-drugs-psilocybin-methylone-review-depression-ptsd-rcna341677