2027 · Article · Online 12 November 2026
Botulinum neurotoxin type a exposure and executive functioning: A multinational web-based survey
45,523 participants · 155 countries · 28 survey languages
How to cite this article
Hashemi, F., Hoepner, L., Hashemi, H., et al. (2027). Botulinum neurotoxin type a exposure and executive functioning: A multinational web-based survey. DARU Journal of Pharmaceutical Sciences, 35, Article 7. https://doi.org/10.1007/s40199-026-00681-3.
First published online on 12 November 2026. See the publisher's record for the complete co-author list.
Extended Structured Summary
Introduction
Botulinum neurotoxin type A (BoNT-A) is widely used in clinical practice and aesthetic medicine. Beyond its established therapeutic effects, growing scientific interest has focused on potential associations between BoNT-A administration and various aspects of cognitive and psychological functioning. However, empirical evidence concerning these relationships remains relatively limited.
The present study focuses on executive functions, a complex set of cognitive processes underlying planning, organization, and goal-directed behavioral regulation. Five domains were examined: self-control and response inhibition; emotional self-regulation; self-motivation; self-organization and problem-solving; and time management.
The study assesses self-reported difficulties across these domains, which should be distinguished from objectively established cognitive impairments.
Aim
To investigate the association between botulinum neurotoxin type A administration and self-reported executive-function difficulties in a large multinational sample, examining differences according to injection frequency and assessing the robustness of observed associations after adjustment for measured sociodemographic and behavioral factors.
Materials and Methods
A multinational cross-sectional online survey was conducted among participants from 155 countries. A structured questionnaire translated into 28 languages was used, enabling participation across diverse linguistic and sociocultural settings.
Data from 46,611 individuals were initially screened. Following the exclusion of 1,088 participants according to predefined criteria, the final analytical sample comprised 45,523 respondents. Information was collected on BoNT-A exposure, injection frequency, and self-reported difficulties across five executive-function domains.
Statistical analyses included chi-square tests, analysis of variance (ANOVA), and multivariable linear regression models estimated using generalized estimating equations (GEE). This approach accounted for correlations among observations within countries and allowed adjustment for measured sociodemographic and behavioral factors.
Additional sensitivity analyses were performed to assess the robustness of the observed associations.
Results
Key Study Characteristics
- 45,523 participants in the final analytical sample
- 155 countries represented
- 28 language versions of the questionnaire
- 5 executive-function domains assessed
1. Differences According to BoNT-A Injection Frequency
Among participants reporting BoNT-A exposure, a statistically significant difference in self-organization and problem-solving scores was observed across injection-frequency groups (p = 0.008). Participants receiving annual injections had a mean score of 42.3 ± 12.9, indicating slightly greater self-reported difficulties in this domain compared with the other groups.
The magnitude of this difference was small. No statistically significant differences according to injection frequency were identified in the remaining four executive-function domains (p > 0.05).
Thus, the findings did not demonstrate a consistent association between injection frequency and the severity of difficulties across all assessed domains.
2. Results of the Multivariable Regression Analysis
After adjustment for measured sociodemographic and behavioral factors, small but statistically significant associations were observed between BoNT-A exposure and higher difficulty scores in three executive-function domains:
| Executive-function domain | β | 95% CI | p |
|---|---|---|---|
| Self-control and response inhibition | 0.508 | 0.131–0.886 | 0.008 |
| Emotional self-regulation | 0.508 | 0.238–0.778 | < 0.001 |
| Self-motivation | 0.226 | 0.023–0.428 | 0.028 |
Note: β denotes the regression coefficient; CI denotes confidence interval. Positive coefficients indicate associations with higher difficulty scores on the respective scales, rather than improved executive functioning.
No statistically significant associations were identified for self-organization and problem-solving or time management in the primary adjusted analysis.
3. Robustness of the Observed Associations
Sensitivity analyses yielded broadly consistent results. However, some associations were attenuated or lost statistical significance under alternative analytical specifications.
These findings warrant cautious interpretation, particularly regarding the potential clinical relevance of the observed differences.
Key finding: The observed associations were small in magnitude, restricted to selected executive-function domains, and did not indicate a consistent pattern across all assessed outcomes.
Discussion and Limitations
The findings indicate statistically significant associations between BoNT-A exposure and self-reported difficulties in selected executive-function domains. Statistical significance, however, should not be equated with clinical significance. The small magnitude of the regression coefficients and the absence of significant associations in several domains do not support the hypothesis of generalized executive dysfunction.
A major methodological limitation is the cross-sectional study design, which precludes establishing the temporal sequence between BoNT-A exposure and reported difficulties. Reliance on self-reported data, potential selection bias associated with online recruitment, and the influence of unmeasured factors further constrain the interpretation of the results.
Particular attention should be given to potential confounding by indication. The underlying health conditions and individual characteristics of people receiving BoNT-A may themselves be associated with measures of cognitive functioning. Such influences cannot be fully eliminated through statistical adjustment.
Notable strengths of the study include its multinational scope, large analytical sample, and use of statistical models accounting for both individual-level factors and the clustering of participants within countries. The findings provide a basis for refining research hypotheses and support the need for subsequent longitudinal investigations.
Conclusion
This multinational survey identified small but statistically significant associations between botulinum neurotoxin type A exposure and self-reported difficulties in selected executive-function domains. After adjustment for measured covariates, significant associations were observed for self-control and response inhibition, emotional self-regulation, and self-motivation.
The findings do not establish a causal relationship between BoNT-A exposure and cognitive impairment, nor do they support the conclusion that BoNT-A administration is associated with a generalized deterioration in executive functioning.
Prospective longitudinal studies incorporating more detailed information on clinical indications, participant characteristics, and other potential confounding factors are needed to clarify the robustness and clinical relevance of the observed associations.