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.

The authors have declared no competing interest.

This research did not receive specific grant funding. Computing resources were provided by the Rutgers Office of Advanced Research Computing (Amarel HPC cluster). NIH All of Us Controlled Tier access was provided through the Researcher Workbench. J.G. is supported in part through the Rutgers School of Health Professions doctoral program.

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