Reply to Gattuso et al.: “Comments on ‘Striking long-term beneficial effects of single-dose psilocybin and psychedelic mushroom extract in the SAPAP3 rodent model of OCD-like excessive self-grooming’ by Brownstien et al. (2024)”

Abstract

We thank Gattuso and colleagues [1] for their kind comments about our paper [2]. However, we wish to note several inaccuracies in statements made about our research and respond to some of their observations:

1. 1)

   The contention that we did not take sex into account in our analyses is incorrect. On the contrary, we compared self-grooming and head-body twitches in male and female SAPAP3-KO mice as the first step in our data analysis. We then analyzed the effect of psilocybin treatment on these variables in males and females separately. The results are shown in Supplementary Tables 1 and 2. There were no differences between males and females at baseline, nor in the effect of psilocybin treatment. Therefore, males and females were combined for further analyses. Sex was also taken into account in our analysis of the behavioral tests.

2. 2)

   Our study was designed and executed as would a clinical trial in patients. In patients with OCD and other disorders, clinical trials do not include an arm in which individuals who do not suffer from the disorder receive the treatment. Therefore, the non-inclusion of such an arm in our study cannot be seen as a shortcoming. Furthermore, compulsive behaviors are, frequently, normal behaviors carried out in an exaggerated way. This is true of the excessive self-grooming of SAPAP3-KO mice. It is of interest that in their own paper on the effect of psilocybin on self-grooming, Gattusso et al. [3] found evidence for a reduction of self-grooming in wild type mice administered psilocybin. However, the absence of a wild type group treated with psilocybin does not detract from the validity of our findings. In the same way, finding that fluoxetine reduces the frequency of hand-washing in individuals without OCD does not in any way detract from a finding that fluoxetine reduces compulsive handwashing.

3. 3)

   Gattuso et al. [1] note that excessive self-grooming increased substantially over the 42 days of our study in SAPAP3-KO mice. A progressive increase in self-grooming after the age of 6 months is by no means idiosyncratic as Gattuso et al. [3] appear to imply and has been noted by other authors. Thus, Glorie et al. [4] examined SAPAP3-KO mice from 6–9 months and reported an “increase in grooming duration with ageing.” Similarly, Manning et al. [5] reported a progressive increase in self-grooming up to the age of 8 months.

4. 4)

   Comments made by Gattuso et al. [1] regarding our study, rest significantly on the findings of their own study on the effect of psilocybin on self-grooming in SAPAP3-KO mice [3]. We are gratified that this work replicated our findings reported in Brownstien et al. [2]. However, we note that in their study Gattuso et al. [3] performed a very limited assessment of self-grooming, quantifying the behavior for only 10 min following 10-min acclimatization. In our study [2] we scored self-grooming over a full hour in each mouse. To determine the validity of a 10-min assessment of self-grooming, we evaluated the correlation between self-grooming scores in the second 10 min of a 1-h assessment and self-grooming scores over the full hour in 60 mice. The results show a positive correlation (r = 0.53, p < 0.0001); however, this falls short of an r of 0.80 which would provide confidence as to the validity of the shorter assessment.

5. 5)

   We fully agree with Gattuso et al. [1] that mechanistic assessments as to the receptors involved in mediating the remarkable effects of psilocybin on excessive self-grooming in SAPAP3-KO mice are highly indicated. Such assessments were not included in their own paper either [3]. In our case, these studies are currently in progress in our laboratory.

The contention that we did not take sex into account in our analyses is incorrect. On the contrary, we compared self-grooming and head-body twitches in male and female SAPAP3-KO mice as the first step in our data analysis. We then analyzed the effect of psilocybin treatment on these variables in males and females separately. The results are shown in Supplementary Tables 1 and 2. There were no differences between males and females at baseline, nor in the effect of psilocybin treatment. Therefore, males and females were combined for further analyses. Sex was also taken into account in our analysis of the behavioral tests.