Reversibility of Cognitive Effects Associated with Concomitant Gabapentin and Dihydropyridine Calcium Channel Blocker Use

Background: Gabapentin prescriptions have increased 123% since 2010, reaching 59 million annually and 15.5 million patients. Recent evidence indicates that concomitant use of gabapentin and dihydropyridine calcium channel blockers (DHP-CCBs) amplifies dementia risk through a dual neuronal calcium signaling blockade mechanism. Whether these cognitive effects are reversible upon discontinuation, and whether the combination accelerates decline in patients with established dementia, remains unknown. Methods: We conducted two complementary studies using the Rutgers Clinical Research Data Warehouse (CRDW; 2015-2024). Study 1: A self-controlled case series (SCCS; N=3,058) comparing cognitive event rates during concomitant gabapentin-DHP-CCB use versus after discontinuation, using strictly duration-matched observation windows. Study 2: A cohort study (N=320) of patients with established dementia initiating gabapentin, comparing outcomes between DHP-CCB, non-DHP-CCB, and no-CCB users. Findings were externally replicated in the NIH All of Us Research Program Controlled Tier (N=8,853). Results: In the CRDW self-controlled analysis, event rates were significantly higher during combination use versus after discontinuation: falls (RR 1.34, 95% CI 1.11-1.61), cognitive symptoms (RR 1.67, 95% CI 1.38-2.01), and composite cognitive endpoint (RR 1.32, 95% CI 1.09-1.59). Effects were greatest when both drugs were discontinued (cognitive symptoms RR 2.21; falls RR 1.76). Protopathic bias was ruled out by monotonically increasing RRs across 0-, 30-, and 60-day lag conditions. In the dementia acceleration cohort, DHP-CCB use tripled encephalopathy risk (HR 3.18, 95% CI 1.36-7.46), with zero events among non-DHP CCB users. External replication in All of Us confirmed all primary outcomes (falls RR 1.53, cognitive symptoms RR 1.26, composite RR 1.42; all p<0.001). A non-DHP CCB negative control in All of Us confirmed mechanistic specificity: cognitive symptom and encephalopathy reversal signals were absent with verapamil/diltiazem. CKD amplified effects in both datasets, consistent with gabapentin accumulation through impaired renal clearance. Conclusions: Cognitive effects associated with concomitant gabapentin-DHP-CCB use appear substantially reversible upon discontinuation, replicated across two independent datasets. The DHP-specific pattern, confirmed through a pharmacological negative control, supports a neuronal L-type calcium channel mechanism. Clinicians should review gabapentin-DHP-CCB combinations in patients with cognitive complaints or falls, as deprescribing - particularly of both agents - may produce meaningful improvement.