Stesura Seveso Archivio Italiano di Urologia e Andrologia 2025; 97(3):13931 1 ORIGINAL PAPER INTRODUCTION Khat (Catha edulis Forsk.), a flowering evergreen shrub of the Celastraceae family, contains psychoactive alkaloids structurally and pharmacologically related to ampheta- mines (1, 2). This stimulant is culturally entrenched in East Africa and the Arabian Peninsula, particularly Yemen, where it is traditionally consumed during social occasions to enhance alertness and productivity (3, 4). Globally, an estimated 20 million individuals use khat, with Yemen exhibiting particularly high prevalence: approximately 60% of adult males and 35% of females consume 100-200 g of fresh leaves daily (1). Although the adverse physical and psychological effects of khat are well documented, its impact on male repro- ductive health remains inadequately characterized (1). A recent narrative review identified significant knowledge gaps concerning khat’s reproductive toxicity in humans (5). Emerging meta-analyses suggest associations between khat use and detrimental reproductive outcomes, includ- ing reduced semen volume and increased risks of low birth weight and congenital anomalies (6). However, these findings are based on limited primary data, and mechanistic studies are lacking. Moreover, controlled investigations addressing dose-response effects and reversibility are scarce. Seminal fluid volume is a critical parameter influencing male fertility, providing nutritional and protective func- tions essential for sperm viability during transit through the female reproductive tract (7). In 2021, the World Health Organization defined hypospermia as ejaculate volumes consistently below 1.4 mL (8). Etiologies of reduced semen volume include psychological factors, col- lection artifacts, and pathological conditions affecting accessory sex glands or ejaculatory ducts (9). Khat chewing is widespread among Yemeni men of repro- ductive age, and accumulating evidence implicates it in male infertility (5, 10). For example, El-Shoura et al. report- ed that khat-dependent individuals exhibited significantly reduced semen volume, sperm motility, and sperm counts compared to non-users (11). These findings align with other studies demonstrating khat’s negative effects on sperm quality and testosterone levels (10, 12, 13). However, most research has been conducted outside Background: Khat (Catha edulis) chewing is a culturally ingrained practice in Yemen and has been associated with potential impairment of male reproduc- tive function. However, rigorous quantitative assessments of its effects on seminal parameters are limited. This study investi- gates the relationship between khat consumption and semen characteristics and examines the reversibility of any adverse effects following cessation. Methods: A prospective two-phase study was conducted at Dr. Najat Al-Malas IVF Center in Sana’a, Yemen (2019-2024). Phase 1 compared semen volume and related parameters across four age-, BMI-, education-, and socioeconomic-matched cohorts: infertile khat chewers (n = 91), infertile non-chewers (n = 60), fertile khat chewers (n = 91), and fertile non-chewers (n = 32). Phase 2 involved a three-month supervised khat cessation inter- vention among infertile chewers. Semen samples were obtained via standardized collection methods. Associations between khat use and seminal parameters were analyzed using univariate and multivariate regression models. Results: Khat chewers demonstrated significantly reduced semen volumes compared to non-chewers in all comparisons. Infertile chewers had lower volumes (1.94 ± 0.48 mL) than fertile chew- ers (2.36 ± 0.52 mL; P < 0.001, d = 0.85) and infertile non- chewers (3.07 ± 0.74 mL; P < 0.001, d = 1.72). Pooled analysis indicated that chewers (n = 182) had 29.6% lower semen vol- umes than non-chewers (n = 92) (2.15 ± 0.89 mL vs. 3.04 ± 0.76 mL; P < 0.001). Notably, cessation of khat chewing led to a 35% increase in volume among infertile chewers (from 1.94 ± 0.48 mL to 2.62 ± 0.52 mL; P < 0.001, d = 1.21). Hormonal analysis (n = 15) showed increased testosterone and decreased prolactin post-cessation (P < 0.05). Conclusions: Khat chewing is significantly associated with reduced semen volume and impaired seminal fluid parameters in men. Importantly, cessation of khat use leads to a marked improvement in semen volume and favorable hormonal changes, indicating partial reversibility of its adverse effects. These find- ings highlight khat’s detrimental impact on male reproductive health and underscore the potential benefits of quitting khat for fertility restoration. KEY WORDS: Catha edulis; Semen volume; Semen parameters; Male infertility; Substance-related disorders; Reproductive health; Yemen. Submitted 27 April 2025; Accepted 10 May 2025 Effects of Khat (Catha edulis) chewing on seminal fluid parameters: Findings from a fertility clinic cohort and cessation trial Mohammed Noman 1, Ebraheem Al-Nawd 2, Faisal Ahmed 3 1 Department of Dermatology, Venereology, and Andrology, Faculty of Medicine and Health Sciences, Sana’a University, Sana'a, Yemen; 2 Department of Biochemistry, Faculty of Laboratory Medicine, Jiblah University for Medical and Health Sciences, Ibb, Yemen; 3 Department of Urology, Ibb University, Faculty of Medicine, Ibb, Yemen. DOI: 10.4081/aiua.2025.13931 Summary Archivio Italiano di Urologia e Andrologia 2025; 97(3):13931 M. Noman, E. Al-Nawd, F. Ahmed 2 Yemen, where genetic and environmental factors differ. Given Yemen’s high khat prevalence and cultural normal- ization, there is an urgent need for population-specific data. This study aims to evaluate the effects of khat on seminal parameters and hormonal profiles in Yemeni men, pro- viding locally relevant evidence to inform clinical practice and public health strategies. The findings will contribute novel insights into khat’s reproductive toxicity and its potential reversibility, with implications for fertility man- agement in endemic regions. MATERIALS AND METHODS Study design This study employed a dual-phase approach. The first phase was a prospective cross-sectional study comparing seminal parameters across frequency-matched groups of fertile and infertile men, stratified by khat chewing status. The second phase consisted of a prospective interven- tional cohort study assessing the impact of khat cessation on infertile khat chewers. The study was conducted at Dr. Najat Al-Malas IVF and ART Center in Sana’a, Yemen, over a five-year period from 2019 to 2024. Participants A total of 330 Yemeni men aged 20 to 40 years were ini- tially recruited, with 274 completing the study, yielding an 83% retention rate. During the study period, 56 partic- ipants were excluded: 52 withdrew prematurely, primari- ly due to discontinuation of the khat cessation interven- tion in Group A, and 4 were excluded for protocol viola- tions, specifically unplanned khat cessation during Phase 1. The final analytic sample comprised 274 participants, as detailed in the CONSORT flow diagram (Figure 1). Participants were allocated into four frequency-matched groups to ensure comparability: infertile khat chewers (Group A, n = 91), infertile non-chewers (Group B, n = 60), fertile khat chewers (Group C, n = 91), and fertile non-chewers (Group D, n = 32). Matching criteria includ- ed age (± 3 years), body mass index (BMI, ± 2 kg/m²), edu- cational attainment (primary, secondary, tertiary), and socioeconomic status, assessed via the Hollingshead Index tertiles. This matching strategy was designed to minimize confounding influences related to demographic and lifestyle factors. Inclusion criteria Participants were classified as fertile or infertile based on established definitions. Fertile men (Groups C and D) had documented natural conception of at least one child within the preceding 24 months and were voluntarily recruited as comparative (control) groups. Infertile men (Groups A and B) met the World Health Organization’s criteria for infertility, defined as failure to conceive after 12 months of regular unprotected sexual intercourse (14). Regular khat chewers (Groups A and C) were those consuming 100-200 grams of fresh Catha edulis leaves daily, with chewing sessions lasting a minimum of three hours, sustained for at least 12 months. Khat use was ver- ified through family interviews and standardized meas- urement of khat bundle weights. Figure 1. Participant flowchart depicting recruitment, allocation, and study phases. Of 330 men assessed for eligibility, 274 were allocated into four frequency-matched groups: infertile khat chewers (n = 91), infertile non-chewers (n = 60), fertile khat chewers (n = 91), and fertile non-chewers (n = 32). Phase 1 involved cross-sectional semen analysis of all groups. Phase 2 consisted of a three-month supervised khat cessation intervention in Group A, with semen volume reassessment in all participants and hormonal profiling conducted pre- and post-cessation in a subset of 15 individuals. Archivio Italiano di Urologia e Andrologia 2025; 97(3):13931 3 Effects of Khat chewing on seminal fluid parameters Exclusion criteria All participants underwent thorough andrological evalua- tions to exclude confounding conditions. Exclusion crite- ria included tobacco use exceeding five cigarettes per week, positive urine toxicology for recreational drugs, and endocrine disorders such as hypogonadism (serum testosterone < 2.5 ng/mL measured by liquid chromatog- raphy tandem mass spectrometry). Men with congenital reproductive tract anomalies (e.g., ejaculatory duct obstruction confirmed by transrectal ultrasound and absent seminal fructose), chronic metabolic diseases (dia- betes mellitus with HbA1c > 6.5%, hypertension with blood pressure > 140/90 mmHg), or use of medications affecting semen quality or sexual function (including 5α- reductase inhibitors, α/β-blockers, antipsychotics) were excluded. Additionally, individuals with active inflamma- tory conditions (urethritis, prostatitis, and seminal vesi- culitis diagnosed by NIH-CPSI score > 14 and positive Meares-Stamey test) were excluded. Sample size calculation Sample size was calculated using a two-sample t-test framework based on prior data indicating a mean semen volume of 2.5 ± 1.0 mL (15). To detect a clinically mean- ingful difference of 0.6 mL between groups with 90% power at α = 0.05, 80 participants per group were required. Anticipating a 20% attrition rate, recruitment targets were set at 100 participants per primary compari- son group (chewers vs. non-chewers). Post-hoc power analysis of our study confirmed that the final sample size exceeded 90% power to detect observed effect sizes, with Cohen’s d > 0.8. Semen collection and analysis Participants provided semen samples following a stan- dardized abstinence period of four days (range: 2-7 days), maintained consistently across collections. Two collec- tion methods were employed: condom-protected inter- course with immediate post-ejaculatory withdrawal, and masturbation into pre-weighed sterile containers (Sarstedt AG), conducted seven days apart. The mean semen vol- ume from both methods was calculated to enhance meas- urement reliability. Semen analyses were performed with- in 60 minutes of collection at 37°C by a technician blind- ed to participant group allocation, following WHO 2021 guidelines (16). While semen volume was the primary parameter, additional semen quality indices (sperm con- centration, total sperm count, progressive motility, mor- phology) were recorded for exploratory analyses using samples obtained by masturbation only. Hormonal eval- uation (total testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH], and prolactin) was per- formed for all patients at baseline and for a subset of Group A participants after the khat cessation period. Intervention protocol (Group A) Group A participants underwent a supervised three- month khat cessation program. Compliance was moni- tored monthly using validated craving and withdrawal scales (e.g., Khat Withdrawal Scale, reference). Bimonthly random salivary cathinone measurements were per- formed via high-performance liquid chromatography-mass spectrometry (HPLC-MS) with a detection threshold of 5 ng/mL to objectively verify abstinence. Missing or incon- sistent compliance data were addressed through sensitiv- ity analyses. Post-intervention semen analyses employed identical collection protocols to ensure comparability. Outcome measures The primary outcome comprised comparative analyses of semen parameters among fertile and infertile khat chew- ers and non-chewers. The secondary outcome focused on evaluating changes in semen parameters before and after khat cessation within infertile khat chewers (Group A). Statistical analysis Data were analyzed using IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA) and R software, Version 4.0 (R Foundation for Statistical Computing, Vienna, Austria). The distribution of continu- ous variables was assessed for normality using the Kolmogorov-Smirnov test. For normally distributed data, parametric tests including independent samples t-tests and one-way analysis of variance (ANOVA) with Tukey’s post hoc comparisons were employed. When normality assumptions were violated, appropriate non-parametric alternatives were utilized. Within-subject changes follow- ing khat cessation were evaluated using paired t-tests. Effect sizes were calculated using Cohen’s d and inter- preted according to conventional thresholds: small (0.2), medium (0.5), and large (0.8). To adjust for potential confounding variables such as age, body mass index (BMI), and abstinence duration, multivariate linear regression models were constructed. Correction for multiple com- parisons was performed using the Bonferroni method to control the family-wise error rate. Both intention-to-treat and per-protocol analyses were conducted to ensure robustness of findings. Statistical significance was set at a two-tailed p-value < 0.05. RESULTS Intergroup comparisons of semen parameters among study participants Our analysis demonstrated statistically significant differ- ences in seminal volume between khat chewers and non- chewers across all study groups. Infertile khat chewers exhibited significantly lower semen volumes (1.94 ± 0.48 mL) compared to fertile khat chewers (2.36 ± 0.52 mL; mean difference -0.42 mL, 95% confidence interval [CI] - 0.77 to -0.07; P < 0.001; Cohen’s d = 0.85) and infertile non-chewers (3.07 ± 0.74 mL; mean difference -1.13 mL, 95% CI -1.55 to -0.71; P < 0.001; Cohen’s d = 1.72). When pooling all khat consumers (n = 182), seminal vol- ume was significantly reduced (2.15 ± 0.89 mL) relative to non-consumers (n = 92; 3.04 ± 0.76 mL; mean differ- ence -0.89 mL, 95% CI -1.21 to -0.57; P < 0.001; Cohen’s d = 1.07). Notably, no significant difference was observed between fertile and infertile non-chewers (mean difference 0.07 mL, 95% CI -0.52 to 0.66; P = 0.811; Cohen’s d = 0.04), underscoring khat consumption as the principal factor associated with reduced seminal vol- ume (Table 1). Archivio Italiano di Urologia e Andrologia 2025; 97(3):13931 M. Noman, E. Al-Nawd, F. Ahmed 4 Multivariate linear regression analysis of factors influencing semen volume Adjusting for age, BMI, and abstinence duration, multi- variate linear regression identified khat chewing as the strongest independent predictor of diminished semen volume (β = -0.92, 95% CI -1.15 to -0.69; P < 0.001), explaining 28% of the variance (partial η² = 0.28) (Table 2). The regression model exhibited excellent fit (R² = 0.41, adjusted R² = 0.39) and no multicollinearity issues (variance inflation factors < 1.2). Effect of Khat cessation on seminal fluid volume and hormonal profile Following a supervised three-month khat cessation pro- gram, infertile khat chewers demonstrated a significant 35% increase in seminal volume, rising from 1.94 ± 0.48 mL to 2.62 ± 0.52 mL (mean difference 0.68 mL; 95% CI 0.49-0.87; P < 0.001), with a large effect size (Cohen’s d = 1.21). This improvement surpassed the World Health Organization’s minimal clinically important difference for semen volume and restored values comparable to those of untreated fertile individuals (p = 0.12), indicating reversibility of khat’s detrimental effects on male repro- ductive function. Additional semen quality parameters – including total sperm count, progressive motility, and normal morphology – also exhibited statistically signifi- cant improvements, with effect sizes ranging from medi- um to large (Table 3 and Figure 2). Table 1. Intergroup comparisons of semen volume among frequency-matched participant groups. Comparison Group 1 Group 2 Statistical test Mean difference P-value Effect size (Mean ± SD) (Mean ± SD) (95% CI) (Cohen’s d) Khat chewers (Fertile vs. Infertile) Fertile chewers (Group C) 2.36 ± 0.52 – Independent t-test 0.42 (0.25 to 0.59) < 0.001 0.85† Infertile chewers (Group A) – 1.94 ± 0.48 Non-chewers (Fertile vs. Infertile) Fertile non-chewers (Group D) 3.00 ± 0.78 – Independent t-test -0.07 (-0.42 to 0.28) 0.69 0.09 Infertile non-chewers (Group B) – 3.07 ± 0.74 All chewers vs. all non-chewers Chewers (Groups A + C) 2.15 ± 0.89 – Independent t-test -0.89 (-1.12 to -0.66) < 0.001 1.07† Non-chewers (Groups B + D) – 3.04 ± 0.76 Multi-group comparison (ANOVA) Fertile chewers (C) vs. Fertile non-chewers (D) 2.36 ± 0.52 3.00 ± 0.78 One-way ANOVA (Tukey) -0.64 (−0.98 to -0.30) < 0.001 0.94† Infertile chewers (A) vs. Infertile non-chewers (B) 1.94 ± 0.48 3.07 ± 0.74 -1.13 (−1.45 to -0.81) < 0.001 1.72† † Large effect size (d ≥ 0.8). *Statistical adjustments for age, BMI, and abstinence duration were performed via multivariate linear regression. P-values: *P < 0.01, **P < 0.001. Table 2. Multivariate linear regression analysis of factors affecting semen volume. Predictor Unstandardized β Standardized β P-value VIF Partial η2 (95% CI) Khat chewing (Yes vs. No) -0.92 (-1.15 to -0.69) -0.53 < 0.001 1.12 0.28 Age (years) -0.02 (-0.05 to 0.01) -0.08 0.18 1.08 0.03 BMI (kg/m2) -0.03 (-0.07 to 0.01) -0.10 0.12 1.05 0.04 Abstinence duration (days) 0.11 (0.06 to 0.16) 0.22 < 0.001 1.04 0.12 Model summary: R² = 0.41, Adjusted R² = 0.39, F(4, 269) = 32.7, P < 0.001. VIF = Variance Inflation Factor (all values < 2 indicate absence of multicollinearity). Continuous predictors were centered prior to analysis. Table 3. Semen parameter changes after 3-month Khat cessation in infertile chewers (Group A, n = 91). Parameter Pre-cessation Post-cessation Mean difference P-value Effect size (Mean ± SD) (Mean ± SD) (95% CI) (Cohen’s d) Volume (mL) 1.94 ± 0.48 2.62 ± 0.52 0.68 (0.52 to 0.84) < 0.001 1.21† Total Sperm Count (×10⁶) 45.2 ± 12.1 58.7 ± 15.3 13.5 (9.8 to 17.2) < 0.001 0.98† Progressive Motility (%) 32.5 ± 8.4 41.2 ± 9.7 8.7 (6.2 to 11.2) < 0.001 0.89† Normal Morphology (%) 4.2 ± 1.8 5.9 ± 2.1 1.7 (1.1 to 2.3) 0.003 0.72‡ † Large effect size (d ≥ 0.8). ‡ Medium-large effect (d > 0.5). Statistical test: Paired t-test. Terminology reflects alpha-adrenergic mediation of seminal emission. Archivio Italiano di Urologia e Andrologia 2025; 97(3):13931 5 Effects of Khat chewing on seminal fluid parameters Hormonal assessment in a subset of 15 participants revealed a significant increase in serum testosterone lev- els accompanied by a modest but statistically significant decrease in prolactin concentrations. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels remained unchanged. These findings collectively suggest that khat cessation positively influences both seminal parameters and select hormonal profiles, supporting its beneficial impact on male reproductive health (Table 4). DISCUSSION This study investigated the impact of khat (Catha edulis) chewing on male reproductive parameters, with a specific focus on semen volume, and assessed the reversibility of these effects following supervised khat cessation. Our findings indicate that chronic khat chewing is significant- ly associated with impaired semen quantity and quality, including reductions in semen volume, total sperm count, progressive motility, and normal morphology. Encouragingly, these adverse effects showed substantial improvement after three months of cessation, concurrent with favorable hormonal changes – increased testosterone and decreased prolactin levels. Chronic khat chewing is increasingly recognized as a con- tributor to male infertility. Studies consistently associate it with reduced semen volume, sperm concentration, motility, and increased abnormal sperm morphology (6, 11). These alterations often coincide with lower testos- terone and altered prolactin secretion, potentially dis- rupting spermatogenesis and sperm function (5). The underlying pathophysiology appears multifactorial. Khat's primary psychoactive alkaloids, cathinone and cathine, act as potent stimulants. This activity may trigger oxidative stress and heighten sympathetic nervous system activity, leading to increased reactive oxygen species (ROS) that damage sperm DNA and cellular membranes, com- promising viability and motility (17-19). Furthermore, khat's adrenergic effects could impair seminal emission, potentially through receptor desensitization or neuro- transmitter depletion, thereby reducing semen volume. While some animal studies suggest dose-dependent or biphasic effects, the prevailing evidence points to khat disrupting endocrine regulation and inducing oxidative damage within the seminal environment (5, 6, 19, 20). Collectively, these findings suggest khat-related infertility arises from a complex interplay of hormonal changes, oxidative stress, and impaired seminal fluid dynamics. Khat shares sympathomimetic toxicodynamic pathways with other substances (e.g., indirect sympathomimetic activity, monoamine modulation, α-adrenergic receptor overstimulation), contributing to reproductive toxicity (17). However, khat's natural alkaloid profile and phar- macokinetics may lead to distinct, potentially biphasic, dose-dependent hormonal effects not always observed with synthetic sympathomimetics (13, 21). Ejaculation comprises two main phases: emission (sympa- thetically controlled movement of seminal fluid into the Table 4. Hormonal profile changes after Khat cessation (Subset Cohort, n = 15). Hormone Pre-cessation Post-cessation Mean difference P-value Statistical (Mean ± SD) (Mean ± SD) (95% CI) test Testosterone (ng/dL) 412 ± 98 438 ± 105 26 (12 to 40) 0.012 Paired t-test FSH (IU/L) 5.2 ± 1.8 5.0 ± 1.6 -0.2 (-0.6 to 0.2) 0.35 Paired t-test LH (IU/L) 4.8 ± 1.5 4.9 ± 1.4 0.1 (-0.3 to 0.5) 0.62 Paired t-test Prolactin (ng/mL) 15.3 ± 4.2 14.1 ± 3.9 -1.2 (-2.0 to −0.4) 0.021 Wilcoxon signed-rank test* Non-normal distribution (Shapiro-Wilk P < 0.05). FSH = Follicle-stimulating hormone; LH = Luteinizing hormone. Figure 2. Changes in semen parameters following three months of khat cessation in infertile khat chewers (Group A). Significant improvements were observed in semen volume, total sperm count, progressive motility, and normal morphology (p < 0.05, p < 0.01). Archivio Italiano di Urologia e Andrologia 2025; 97(3):13931 M. Noman, E. Al-Nawd, F. Ahmed 6 urethra) and expulsion (muscle contractions propelling fluid outward) (22). Khat may interfere with both phases, particularly emission, by potentially inhibiting acetyl- choline release and smooth muscle contraction via pre- junctional α2 adrenergic and 5-HT7 receptors (6, 23-25). Our results demonstrate that khat chewing is independ- ently associated with reduced semen volume in both fer- tile and infertile men. This aligns with the pharmacology of cathinone and cathine, potent norepinephrine releasers and reuptake inhibitors (26, 27). Alpha-adrenergic stimu- lation is critical during emission for coordinating contrac- tions in the vas deferens, seminal vesicles, and prostate (28, 29). Chronic adrenergic overstimulation from khat may lead to receptor desensitization or neurotransmitter depletion, impairing seminal emission and reducing vol- ume (5, 20, 30). Reduced contractility in accessory sex glands due to α-adrenergic dysregulation may also decrease seminal fluid volume and alter viscosity, mirror- ing effects seen with α1-blocker medications known to impair fluid release and contribute to infertility (12, 31). These mechanisms suggest the observed reduction in semen volume among khat chewers is more likely due to impaired emission than impaired production. Our findings of reduced semen parameters among khat chewers align with previous studies. El-Shoura et al. reported significantly lower semen volume, sperm motil- ity, and concentration in khat users (11). Hakim et al. also found correlations between long-term khat chewing and changes in seminal fluid, including decreased volume, count, and motility, though statistical significance varied (20). Additional studies link khat chewing with reduced libido and possible erectile dysfunction, highlighting the need for further causal research (32, 33). A key observation is the reversibility of khat's adverse effects on semen parameters following cessation. Infertile chewers who abstained for three months showed substan- tial improvements in semen volume, total sperm count, progressive motility, and normal morphology. The recov- ery in volume supports the hypothesis that alpha-adrener- gic dysfunction caused by chronic khat chewing is, at least partially, reversible as receptor sensitivity and neurotrans- mitter balance recover (26, 34). Concurrent improve- ments in other semen parameters suggest khat's detrimen- tal impact extends to spermatogenesis and sperm matura- tion, potentially through oxidative stress, impaired testic- ular vascular function, or hormonal disruption (11, 32, 33). While the cross-sectional design limits definitive causal claims, the pattern of reversibility provides sup- portive evidence. These findings highlight the potential for recovery of male reproductive function with cessation and underscore its relevance for clinical counseling. Hormonal profiling in a subset of participants revealed modest increases in total testosterone and decreases in pro- lactin levels after khat cessation, while FSH and LH levels remained stable. These shifts are consistent with khat's dopaminergic effects, potentially alleviating hyperpro- lactinemia – a known contributor to hypogonadism and impaired semen quality (3). The stability of gonadotropins suggests that khat's primary impact on fertility may occur peripherally (e.g., testicular and accessory glands) rather than centrally via the hypothalamic-pituitary-gonadal axis. These hormonal changes likely interact with the observed oxidative stress pathways to impair semen quality (5, 17). Dopaminergic modulation could influence prolactin levels and antioxidant defenses, while adrenergic overdrive direct- ly contributes to the generation of oxidative stress (35). Animal studies offer further mechanistic insights, though with nuances requiring careful interpretation. Mohammed et al. and Shulman et al. reported biphasic effects on male rat sexual behavior, with higher doses diminishing per- formance and lower doses sometimes enhancing motiva- tion, potentially linked to testosterone fluctuations (13, 36). Khat administration has reduced epididymal sperm count without consistently altering endocrine gland func- tion in some models, suggesting direct gonadal toxicity (5). Other studies demonstrate khat or cathinone reduc- ing sperm count and motility, increasing abnormal sperm, and inhibiting spermatogenesis, with variable effects on reproductive hormones depending on dose and species (5, 13, 18, 37, 38). Importantly, the observed biphasic effects in animals underscore the complexity of dose-response relationships, which may also exist in humans but remain inadequately characterized due to variations in chewing habits and alkaloid content (5). Furthermore, the stable levels of gonadotropins observed in our human cohort contrast with some animal data showing LH suppression, highlighting species differences and underscoring the need for targeted human research to understand dose-dependent effects and distinguish between central and peripheral actions. Clinical and public health implications Our findings have significant implications for clinical practice and public health, particularly in regions where khat chewing is prevalent. Clinicians should routinely inquire about khat use during infertility evaluations and preconception counseling, given the evidence of its asso- ciation with impaired semen parameters and the potential for reversibility upon cessation. Men presenting with reduced semen volume, abnormal semen parameters, or hormonal disturbances such as low testosterone or ele- vated prolactin should be specifically screened for khat consumption. In reproductive counseling, it is essential to inform men planning conception or concerned about fertility of the potential reproductive risks associated with khat chewing. The demonstrated reversibility of semen impairment following cessation offers an encouraging message and a concrete intervention strategy for affected individuals. From a public health perspective, these results underscore the need for targeted educational cam- paigns that address the reproductive risks of khat along- side its other health consequences. Integration of khat cessation support within existing reproductive health and substance use services could enhance the effectiveness of interventions. Community-based awareness initiatives and the development of practical biomarkers for objective exposure assessment would further strengthen monitor- ing and prevention efforts. Collectively, these strategies could contribute to improved male reproductive health outcomes in populations with high rates of khat use. Study limitations Several limitations warrant consideration. The cross-sec- tional design of much of the data limits causal inference, Archivio Italiano di Urologia e Andrologia 2025; 97(3):13931 7 Effects of Khat chewing on seminal fluid parameters although the observed reversibility provides supportive evidence. Hormonal analyses were constrained by a small sample size, limiting generalizability and emphasizing the need for larger prospective studies. The three-month ces- sation period may not fully capture the timeline of repro- ductive recovery; longer-term follow-up is important. The reliance on self-reported khat consumption intro- duces potential recall bias, and the lack of detailed usage pattern data prevents dose-response analysis. The single- center design and recruitment of fertile controls via vol- unteer sampling may limit generalizability and introduce selection bias. Despite adjustments for key confounders, residual confounding from unmeasured variables (e.g., diet, concurrent substance use, environmental exposures) cannot be excluded. Finally, the precise mechanisms by which khat influences seminal fluid production, especial- ly autonomic regulation of accessory glands, require fur- ther elucidation. Addressing these limitations necessitate multicenter studies employing objective biomarkers, extended longitudinal monitoring, and evaluation of sympathetic nervous system function. CONCLUSIONS This study demonstrates that khat chewing is significant- ly associated with reduced semen volume in both infertile and fertile men, with khat use emerging as a strong inde- pendent predictor of this reduction. Importantly, cessa- tion of khat consumption leads to a substantial recovery in semen volume, accompanied by favorable hormonal changes, including increased testosterone and decreased prolactin levels. These findings corroborate prior evi- dence linking khat use to impaired male reproductive parameters and suggest that the adverse effects on semi- nal fluid volume are at least partially reversible. Given the cultural prevalence of khat chewing in affected regions, these results underscore the need for targeted public health interventions and further research into the mecha- nisms underlying khat’s reproductive toxicity and its potential reversibility. REFERENCES 1. Balint EE, Falkay G, Balint GA. Khat - a controversial plant. 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Short-term effects of high-dose khat on sperm parameters and reproductive hormonal levels in olive baboons (Papio anubis). Gynecol Obstet Invest. 2013; 75:109-14. 13. Mohammed A, Engidawork E. Reproductive parameters are dif- ferentially altered following subchronic administration of Catha edulis F. (Khat) extract and cathinone in male rats. J Ethnopharmacol. 2011; 134:977-83. 14. Zegers-Hochschild F, Adamson GD, de Mouzon J, et al. International Committee for Monitoring Assisted Reproductive DECLARATIONS Ethical approval: Approval for the study protocol and all relat- ed procedures was granted by the Institutional Ethics Committee of Dr. Najat Al-Malas IVF and ART Center in Sana’a, Yemen. The protocol was further approved by the Institutional Review Board of Dr. Najat Al-Malas IVF Center (Reference number 0031MN-2024, dated 21 January 2024). Written informed con- sent was obtained from all participants in accordance with the Declaration of Helsinki, with participants retaining the right to withdraw from the study at any time without penalty. The study protocol was initially established on 1 June 2019 and registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), Japan, under registration number T000009772 (see: https://center6.umin.ac.jp/cgi- bin/ctr_test_e/ctr_view_reg.cgi?recptno=T000009772). Availability of data and material: All data generated or ana- lyzed during this study are included in this published article. Competing interests: The author declares no conflicts of interest. Funding: No funding was received for this study. 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Ejaculation: the Process and Characteristics From Start to Finish. Curr Sex Health Rep. 2023; 15:1-9. 23. Abdulwaheb M, Makonnen E, Debella A, Abebe D. Effect of Catha edulis foresk (khat) extracts on male rat sexual behavior. J Ethnopharmacol. 2007; 110:250-6. 24. Kelly JP. Cathinone derivatives: a review of their chemistry, pharmacology and toxicology. Drug Test Anal. 2011; 3:439-53. 25. Engidawork E. Pharmacological and Toxicological Effects of Catha edulis F. (Khat). Phytother Res. 2017; 31:1019-28. 26. Al-Motarreb A, Al-Habori M, Broadley KJ. Khat chewing, car- diovascular diseases and other internal medical problems: the cur- rent situation and directions for future research. J Ethnopharmacol. 2010; 132:540-8. 27. Toennes SW, Harder S, Schramm M, et al. Pharmacokinetics of cathinone, cathine and norephedrine after the chewing of khat leaves. Br J Clin Pharmacol. 2003; 56:125-30. 28. Michel MC, Vrydag W. 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Metab Brain Dis. 2014; 29:451-8. Correspondence Mohammed Noman noaman670@gmail.com Ebraheem Al-Nawd drnod4all@gmail.com Faisal Ahmed (Corresponding Author) fmaaa2006@yahoo.com Department of Urology, Ibb University, Faculty of Medicine, Ibb, Yemen