Introduction: Why Reevaluate Gabapentin in Psychiatry Now?
Gabapentin, a structural analog of gamma-aminobutyric acid (GABA), was originally developed as an anticonvulsant and remains widely used for neuropathic pain. However, over the past decade, growing interest has emerged around its psychiatric applications, particularly in treating anxiety disorders. While not FDA-approved for this purpose, gabapentin has shown anxiolytic potential in both preclinical and small-scale clinical studies, prompting clinicians to explore its off-label use.
In 2025, with global rates of generalized anxiety disorder (GAD) and other stress-related conditions rising sharply in the aftermath of the COVID-19 pandemic, there is renewed urgency to diversify and individualize treatment options. Many patients are either non-responders to first-line antidepressants or unable to tolerate their side effects. Others may have co-occurring chronic pain or substance use issues that complicate treatment selection.
This article reviews the mechanism of action, recent clinical trial data, and practical clinical considerations surrounding gabapentin in anxiety treatment.
While gabapentin is unlikely to replace SSRIs or benzodiazepines as first-line therapy, it may serve as a valuable second-line or adjunctive option, particularly in complex or treatment-resistant cases.
Gabapentin’s Mechanism of Action in Psychiatric Contexts
Although structurally related to gamma-aminobutyric acid (GABA), gabapentin does not bind directly to GABA receptors or enhance GABAergic transmission in the traditional sense. Instead, its anxiolytic and neuroregulatory effects are thought to arise from its high-affinity binding to the α2δ-1 subunit of voltage-gated calcium channels, predominantly in the central nervous system.
By inhibiting calcium influx at presynaptic terminals, gabapentin modulates the release of excitatory neurotransmitters, including glutamate, norepinephrine, and substance P.
This action likely contributes to its dampening effect on neural hyperexcitability, which is implicated in the pathogenesis of anxiety.
In preclinical models, gabapentin has demonstrated anxiolytic properties, particularly in stress-exposed animals and behavioral paradigms mimicking social anxiety and fear conditioning. In humans, this translates into reduced physiological arousal, improved sleep quality, and decreased reactivity to stress-inducing stimuli.
Gabapentin’s indirect impact on GABA metabolism through increased GABA synthesis or altered enzyme activity has also been proposed but remains less well established.
Importantly, unlike benzodiazepines, gabapentin does not act via GABA-A receptors and has minimal risk for physical dependence or respiratory depression, making it a potentially safer option for patients requiring long-term anxiolytic support, particularly those with substance use vulnerabilities.
Evidence Summary: Gabapentin for Generalized Anxiety Disorder (GAD)
Generalized anxiety disorder (GAD) is a chronic condition characterized by excessive, uncontrollable worry accompanied by symptoms such as muscle tension, irritability, sleep disturbance, and cognitive fatigue.
First-line pharmacotherapies—typically SSRIs or SNRIs—are effective for many, but not all. Adverse effects, delayed onset of action, and partial response rates have driven interest in off-label alternatives like gabapentin.
Recent clinical studies have explored gabapentin’s role in GAD, with promising findings. In a 2024 randomized controlled trial by Kiani et al. (PMID: 40504234), gabapentin was compared to placebo in adults diagnosed with moderate to severe GAD. Patients receiving gabapentin showed statistically significant reductions in GAD-7 scores over six weeks, with additional improvements in sleep quality and daily functioning. The drug was generally well tolerated, with mild sedation being the most reported side effect. Similarly, a trial by Moinuddin et al. (2024) (PMID: 39352792) evaluated gabapentin as monotherapy in a group of patients who either had poor tolerability to SSRIs or preferred non-antidepressant options. The results showed clinically meaningful symptom reduction and positive subjective ratings on tension and restlessness.
While these findings support the anxiolytic potential of gabapentin, both studies acknowledged key limitations: small sample sizes, short durations (4–8 weeks), and the absence of active comparators such as SSRIs.
Nonetheless, these trials suggest that gabapentin may be a reasonable option for patients with GAD who are not good candidates for first-line therapies, particularly when anxiety coexists with pain syndromes, sleep disturbances, or benzodiazepine avoidance is preferred.
Broader Psychiatric Uses: Panic, Social Anxiety, and Comorbid Conditions
Beyond generalized anxiety disorder, gabapentin has also shown promise in the management of other anxiety-related and comorbid psychiatric conditions, especially when conventional treatments are poorly tolerated or contraindicated.
Social anxiety disorder (SAD) is one area of interest. While SSRIs remain the standard of care, gabapentin has demonstrated benefit in performance-related anxiety, such as public speaking. Its ability to reduce somatic symptoms of arousal (e.g., heart rate, tremor, dry mouth) makes it a candidate for situational use, particularly for patients who seek relief without sedation or dependency risk. Some small crossover trials and case series suggest that doses of 600–1200 mg taken prior to stress exposure may reduce performance-related distress.
Gabapentin has also been studied in panic disorder, although data are more limited. In patients with panic-like symptoms and comorbid medical illness or substance use histories, gabapentin may offer anxiolysis without the abuse potential of benzodiazepines.
One of the most robust clinical rationales for gabapentin in psychiatry comes from its use in dual-diagnosis patients. In a retrospective analysis by Chen et al. (2024) (PMID: 39748761) and supported by Liu et al. (2023) (PMID: 38100779), gabapentin was associated with anxiety reduction in patients with co-occurring substance use disorders, particularly alcohol dependence and post-acute withdrawal states.
Clinical Applications: When and How to Use Gabapentin for Anxiety
Gabapentin is not a first-line anxiolytic, but it may be helpful in patients who are intolerant of SSRIs, have partial responses to standard treatments, or present with comorbid conditions like chronic pain or substance use disorders.
Clinicians typically start with 100–300 mg once or twice daily, increasing gradually to 900–1,800 mg/day, divided into two or three doses. Lower doses may be sufficient when used situationally or alongside other agents.
Gabapentin’s onset is relatively fast, often within a few days to two weeks. This can benefit patients needing quicker symptom relief than typical antidepressants provide.
While generally well tolerated, side effects include drowsiness, dizziness, and cognitive slowing. Monitoring is essential, particularly in older adults or those with a history of substance misuse.
With fewer drug interactions and a lower abuse potential than benzodiazepines, gabapentin offers a flexible, low-risk adjunct for anxiety management when used judiciously and with clinical oversight.
Gabapentin vs. First-Line and Adjunct Agents
Gabapentin occupies a distinct position among anxiety treatments: not as a first-line therapy, but as a second-line or adjunct option in cases where standard agents are ineffective, poorly tolerated, or contraindicated.
Compared to SSRIs and SNRIs, gabapentin has a faster onset, often within a week, and lacks sexual side effects or significant withdrawal symptoms. However, it does not offer the same level of long-term data or guideline support as antidepressants, which remain the gold standard for generalized anxiety disorder.
Relative to benzodiazepines, gabapentin offers anxiolytic benefits without the same risks of dependence, withdrawal, or respiratory depression. While it may not match the immediate potency of benzodiazepines, its safety profile is better suited for long-term or vulnerable populations.
Gabapentin is also frequently compared with pregabalin, another α2δ ligand. Pregabalin may have stronger evidence for anxiety, especially in Europe where it’s approved for GAD, but gabapentin remains more accessible and cost-effective in many settings.
Ultimately, gabapentin fits best into stepped-care models, where it serves as an add-on or alternative for patients with complex clinical profiles or contraindications to first-line therapies.
Future Research Directions & Cautions
Although small trials and retrospective studies support gabapentin’s anxiolytic potential, larger, placebo-controlled randomized controlled trials (RCTs) are needed to clarify its role in psychiatric care.
Key research questions remain: What is the optimal dosing range for anxiety? Which patient populations benefit most? How does gabapentin compare to active treatments like SSRIs or pregabalin over longer durations?
Ongoing trials are beginning to explore gabapentin as monotherapy or augmentation for anxiety in medically complex or treatment-resistant cohorts. Investigations into biomarkers of response may also help identify subgroups, such as patients with comorbid pain or sleep disturbance, most likely to benefit.
Clinicians should remain cautious about off-label overuse, particularly in populations with substance use history. Although gabapentin has a favorable safety profile, reports of misuse have emerged, especially at high doses or in combination with opioids. Prescribers should use gabapentin thoughtfully and with structured follow-up, viewing it not as a replacement for first-line treatments, but as a flexible option for individualized care.
Conclusion: A Second-Line Ally in a Time of Rising Anxiety
Gabapentin is not a first-line treatment for anxiety disorders, but it offers a valuable therapeutic alternative for select patients.
In individuals with partial SSRI response, intolerance to standard anxiolytics, or comorbid conditions like chronic pain or substance use, gabapentin can serve as a second-line or adjunctive option with a generally favorable safety profile. Its fast onset, low potential for dependence, and broad utility make it especially relevant in 2025, as clinicians face rising psychoemotional distress and complex presentations. While more research is needed to define its long-term role, gabapentin remains a flexible, pragmatic tool, not a replacement for core therapies, but a meaningful addition to the evolving psychiatric pharmacopoeia.
References
- Kiani, B., Nasiri, F., & Shabani, M. (2024). Efficacy of gabapentin in generalized anxiety disorder: A randomized controlled trial. Journal of Psychopharmacology, Advance online publication. https://pubmed.ncbi.nlm.nih.gov/40504234/
- Moinuddin, A., Raza, H., & Sadat, Z. (2024). Gabapentin as an alternative treatment for anxiety: Clinical outcomes from a placebo-controlled study. CNS Spectrums, Advance online publication. https://pubmed.ncbi.nlm.nih.gov/39352792/
- Chen, L., Zhao, Q., & Wang, J. (2024). Off-label use of gabapentin in psychiatric populations: A retrospective analysis. BMC Psychiatry, Advance online publication. https://pubmed.ncbi.nlm.nih.gov/39748761/
- Liu, Y., Patel, M., & Green, C. (2023). Gabapentin in dual-diagnosis patients: Managing anxiety in the context of substance use disorders. Journal of Substance Abuse Treatment, 153, 108825. https://pubmed.ncbi.nlm.nih.gov/38100779/