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WTF is a head twitch?!

You may have noticed that a lot of basic psychedelic research revolves around this single assay: the head twitch response (HTR). The purpose of HTR has changed over the years, but most recently can be thought of as a tool for pharmacological characterization of psychedelic compounds. Dr. de la Fuente joined the corresponding episode to discuss his automation of the assay and what the f*** a head twitch really is.

HTR is a behavior noted in rodents in which the animal rapidly rotates the head side-to-side. HTR is mainly studied in rats and mice, but a similar behavioral phenotype described as “wet-dog shakes” has also been noted in other mammals including rabbits, dogs and cats. The first ever recorded drug-elicited HTR was noted following intravenous administration of the psychedelic lysergic acid diethylamide (LSD), in which this behavior was rapidly occurring and sustained. Following the initial discovery of the LSD-induced HTR, the same researchers elicited HTR with the serotonin precursor, 5-hydroxytryptophan (5-HTP), thus proposing the involvement of 5-HT in the behavior. It was later discovered that the 5-HT2 receptors and, specifically, 5-HT2ARs were responsible for psychedelic-induced HTR in rodents.

Work by Dr. de la Fuente and others have corroborated the findings that the psychedelic-elicited HTR can be blocked using 5-HT2AR antagonists such as ketanserin and volinanserin (M100907). HTR is undetected in mice with genetic deletion of 5-HT2AR and the behavior is able to be rescued using genetic tools to rescue expression of 5-HT2AR in frontal cortex pyramidal neurons. Analogous findings have been demonstrated in human subjects where ketanserin was found to prevent the subjective effects of psilocybin and LSD. The potencies of HTR in mice have been correlated with potency of psychedelic's in humans.

Interestingly, in the early to mid-20th century, psychedelic compounds were noted to produce effects similar to symptoms reported by schizophrenia patients and were used by clinical researches to understand the mechanisms underlying psychosis in patients with this and other psychiatric conditions. At first, HTR was thought to be a preclinical model of psychosis, but more recent findings have raised concerns about the translational validity. Despite this change in interpretation, this family of psychoactive compounds did provide key insights into the pathology of schizophrenia mainly through the involvement of serotonin. Additionally, classical psychedelics as a preclinical model of psychosis also served as a tool in the search for new antipsychotics.

Effects of classical psychedelics and other compounds on peak HTR response in mice. Lisuride and TBG both listed as examples of compounds that do not produce HTR. Data pulled from several studies (linked at the end of article).

With the rise of interest in understanding the targets and mechanisms behind the potential therapeutic effects of psychedelics in patients with psychiatric disorders such as depression and post-traumatic stress disorder (PTSD), the HTR behavior has become popularized as a functional tool to characterize psychedelic compounds and novel compounds. As discussed above, it is well established the involvement of 5-HT2AR in the behavioral and cognitive effects of psychedelics as it relates to HTR, but it is not clearly established as to whether the effects of psychedelics on neuroplasticity processes, which may underlie the positive therapeutic effects of psilocybin and other psychedelic compounds, are 5-HT2AR-dependent. The race to create the perfect compound is well underway and HTR is a tool that's been used extensively - automated or not - to determine their psychedelic effects.

Interested in reading some studies? We've linked a ton of good ones throughout the article and below. Feel free to comment or DM us if you need any of the PDFs!

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