The Bicuspid Aortic Valve Within the Therapeutic Window of Cannabis, Tryptamines, and Novel Neuroplastogen Analogs: A Mechanistic Risk Analysis Anchored to a Reconstructed openSNP Genotype Cohort

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation and converts the aortic valve and proximal aorta into unusually vulnerable target tissues: a calcification-prone valve seated in front of an aneurysm-prone media governed by transforming growth factor-β (TGF-β) signalling and nitric oxide (NO) homeostasis. We ask where the therapeutic windows of three expanding drug classes — cannabis, tryptamines (psilocybin/psilocin, DMT, 5-MeO-DMT), and non-hallucinogenic neuroplastogen analogues — sit relative to that vulnerability. We integrate receptor pharmacology (CB1/CB2; 5-HT2A/5-HT2B; biased agonism), exposure patterns separating macrodose from microdose regimens, and the convergent effector pathways through which each class could plausibly interact with BAV disease, and we anchor the analysis to a reconstructed genetic resource: the complete archived openSNP phenotype-361 (“Bicuspid aortic valve”) cohort (22 members; 19 with recoverable genotypes across a 17-SNP panel), rebuilt from Internet Archive holdings after the platform closed in April 2025. We propose that the three classes threaten BAV through separable doors — cannabis hemodynamically and vasculopathically, tryptamines through 5-HT2B-mediated valvular fibrosis, and neuroplastogen analogues, by medicinal-chemistry design, through neither — and that cumulative 5-HT2B receptor occupancy above endogenous tone, not binding affinity, is the operative risk variable. Descriptively, most genotyped cohort members carry at least one TGFB1 −509 variant allele and five of eight covered members carry a NOS3 −786C allele, demonstrating that the substrate for pharmacogenomic interaction is common rather than rare. We close with an exposure × phenotype risk-stratification matrix and six falsifiable hypotheses for a registry-scale test. This is a hypothesis-generating mechanistic analysis, not clinical guidance.