The NIH Progesterone Trial prespecified post hoc analysis found that adjunctive cyclic progesterone supplement significantly lessened seizures in WWEC1≥3.  Some treated chronically with BDZ, however, rapidly developed highly distressing anxiety, agitation and increased seizures within days of starting the combination. 

The retrospective chart review data came from 200 WWEC1≥3, outpatients of the Harvard Neuroendocrine Unit between 2008-2020, who were prescribed progesterone as adjunctive treatment for intractable seizures while on chronic BDZ treatment.  100 WWEC1≥3 on chronic adjunctive selective serotonin reuptake inhibitors (SSRIs) without BDZ served as controls.  Outcome was the incidence of apparent BDZ cross-tolerance as manifested by the development of highly distressing anxiety, agitation and increased seizures (≥2x baseline average daily frequency, increased level of severity [simple < complex < generalized] or increased duration) within one week of initiation of the combination.

9 of the 200 WWEC1≥3, (4.5%) experienced an acute (<24 hr) or subacute (<1 week) flare of highly distressing anxiety, agitation and increased seizures within one week of initiation of the combination of BDZ and progesterone (Table 1), whereas none of the 100 controls experienced the flare (Fisher’s Exact Test, p = 0.0319).  A 10^th subject (S10) experienced the flare with the addition of cyclic progesterone to another antiseizure medication that has prominent GABAergic effects. i.e. on chronic primidone, rather than BDZ.  Three of the 9 WWCE1 who gradually tapered off BDZ tolerated the addition of progesterone one month after discontinuation.

The finding of a small minority of WWEC1≥3, 4.5%, who reported a marked increase in anxiety, agitation and seizures within one week of initiation of progesterone while on chronic BDZ but none on SSRIs or after tapering off BDZ, is consistent with cross-tolerance.