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Fig. 3. Sample participant responses to pulse administration in R1 and R2 are shown. Panel A is a chronic participant who overall did not respond to psilocybin in R1 but had a sustained response over the diary period in R2. Panel B shows a chronic participant who had an increase in attack frequency after receiving placebo in R1 and a decrease after psilocybin in R2. Panel C shows a chronic participant whose good response to psilocybin was longer lasting in R2 than in R1. Panel D shows an episodic participant who had reduced burden in but not termination of their cluster cycle in R1 with placebo but had an earlier termination in R2 with psilocybin (dosing in both rounds took place one month into their cycle). Open circle, placebo in R1 (B, D); closed circle, psilocybin in R1 (A, C); closed square, psilocybin in R2 (all participants).

Figure 3 Sample participant responses to pulse administration in R1 and R2 are shown. Panel A is a chronic participant who overall did not respond to psilocybin in R1 but had a sustained response over the diary period in R2. Panel B shows a chronic participant who had an increase in attack frequency after receiving placebo in R1 and a decrease after psilocybin in R2. Panel C shows a chronic participant whose good response to psilocybin was longer lasting in R2 than in R1. Panel D shows an episodic participant who had reduced burden in but not termination of their cluster cycle in R1 with placebo but had an earlier termination in R2 with psilocybin (dosing in both rounds took place one month into their cycle). Open circle, placebo in R1 (B, D); closed circle, psilocybin in R1 (A, C); closed square, psilocybin in R2 (all participants).

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Fig. 2. Weekly attack frequency is shown at baseline and over the 3-week period in individual episodic participants (A; n = 4) and over the 8-week period in individual chronic participants (B; n = 6). Open symbols denote participants randomized to placebo in R1; closed symbols denote participants randomized to psilocybin in R1. An effect of time was observed for ‘overall drug effects’ on all three dosing days [Day 1 F(8, 232) = 36.3; Day 2 F(8, 232) = 28.4; Day 3 F(8, 232) = 31.5; all p < 0.0001] but these effects did not differ across days (interaction: F(16, 232) = 1.02, p = 0.440; Supp! Table 3). Psilocybin induced maximal ‘overall drug effects’ between 90 and 120 min with an average maximum rating of 2.8 (0.08) on a 0-3 NRS. Given that 7 out of 10 participants gave the highest rating for this measure (3; i.e., ceiling effect), an average score was calculated wherein ratings were considered along with duration of effect. This average score for ‘overall drug effects’ did not correlate with changes in attack frequency (r = —0.190; p =
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