Cross-tolerance is tolerance that carries over from one drug to another. A 1961 study at the US Addiction Research Center is titled simply “Cross tolerance between LSD and psilocybin” (Isbell et al., 1961). According to a 2018 review, it gave psilocybin repeatedly to 19 participants for up to 12 days, found diminished effects, and is one of the studies showing that tolerance to psilocybin carries over to LSD and back (Johnson et al., 2018).
Researchers read cross-tolerance as a clue to shared mechanism: if two drugs blunt each other, they probably work through the same target. For the classic psychedelics that target is the serotonin 5-HT2A receptor, where a 2016 review reports a consensus that they act (Nichols, 2016).
The evidence is old and small. The human cross-tolerance studies date from the 1960s, with few participants, and modern trials have not revisited them in depth (Johnson et al., 2018). Cross-tolerance is not a reason to combine drugs; combinations raise risk. This is not medical advice.
Sources
- Isbell et al., 1961, Psychopharmacologia: cross tolerance between LSD and psilocybin
- Johnson et al., 2018, Neuropharmacology (PMC)
- Nichols, 2016, Pharmacological Reviews
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