Caffeine has been purported to have anxiogenic and panicogenic properties, specifically salient in patients with panic disorder (PD). However, compilations of the magnitude of the effect of caffeine on anxiety and panic attacks are lacking and potential dose-response relationships have not been examined.
In the present systematic review and meta-analysis, we aimed to examine the acute effects of placebo-controlled caffeine challenge on occurrence of panic attacks and subjective anxiety in patients with PD and healthy controls (HC), including dose-response relationships.
Systematic searches were performed in six databases. We included blinded placebo-controlled studies of acute caffeine challenge on panic attacks and/or subjective anxiety in adult patients with PD.
Of the 1893 identified articles, ten met our inclusion criteria. The 9 studies investigating panic attacks included 237 patients, of which 51.1% had a panic attack following caffeine, but none after placebo. Six of these studies compared 128 patients with 115 healthy controls (HC), finding that patients (53.9%) were more vulnerable than HC (1.7%) for panic attacks following caffeine (log RR: 3.47; 95% CI 2.06–4.87). Six studies investigated subjective anxiety in 121 patients and 111 HC following caffeine, with an overall effect indicating increased sensitivity to the anxiogenic effects of caffeine in the patient group (Hedges' g = 1.02 [95% CI: 0.09–1.96]). The restricted range of caffeine employed [400–750 mg] and few studies (3) not using 480 mg prevented any meaningful analysis of a dose-response relationship.
Of the ten studies included, only 2 reported anxiety data for the placebo condition, precluding a proper meta-analysis comparing anxiogenic effects of caffeine and placebo. The restricted dose range used prevented assessment of dose-response relationships.
The results confirm that caffeine at doses roughly equivalent to 5 cups of coffee induces panic attacks in a large proportion of PD patients and highly discriminates this population from healthy adults. Caffeine also increases anxiety in PD patients as well as among healthy adults at these doses although the exact relationship between caffeine-induced anxiety and panic attacks remains uncertain. The results suggest that caffeine targets important mechanisms related to the pathophysiology of PD.
Future studies should employ a wider range of caffeine doses and investigate contributions of biological and psychological mechanisms underlying the anxiogenic and panicogenic effects of caffeine. In the clinic, patients with PD should be informed about the panicogenic and anxiogenic effects of caffeine, with the caveat that little is known regarding smaller doses than 480 mg.
Panic disorder (PD) is a debilitating anxiety disorder affecting around 5% of the population . The core symptom of PD is re-occurring panic attacks, sudden episodes of intense fear or discomfort along with a number of bodily symptoms, such as palpitations, shortness of breath, numbness, and dizziness . Panic attacks can also occur in other anxiety disorders as well as in depressive disorders , and even occasionally in healthy individuals . To achieve a PD diagnosis however, such attacks need to appear unexpectedly on a regular basis and must result in anticipatory fear of further episodes, alternatively a significant change in behavior .
Results and analyses
A total of 10 studies were included in the review. The systematic database search resulted in 2647 hits out of which 754 duplicate records were identified and removed automatically by the data management program and 1893 passed to the title and abstract screening. Out of these, 1875 were excluded and 18 were screened in full-text for eligibility. After exclusion of studies that did not fulfill our eligibility criteria, ten studies remained for inclusion. Reasons for exclusion included wrong comparator (lack of a placebo-arm in one or more of the participant groups; 3 studies), data not available for the outcome measures of our interest (2 studies), study not presenting original data (1 study), wrong intervention (participants told they were given caffeine and the expected effects of caffeine, regardless if they were given caffeine or placebo; 1 study), and wrong outcomes (1 study) (Table S1). One study  included patients with the diagnosis agoraphobia with panic attacks as diagnosed with DSM-III. Since this diagnosis is considered as panic disorder in later versions of DSM [2,3], we included this study in our review. See flow diagram Fig. 1 for a summary of the study selection process.