01 April 2023: Epidemiology
A Narrative Review of the Toxic Effects on Male Reproductive and Sexual Health of Chewing the Psychostimulant, (Khat)Meshari A. Alzahrani 1ABCDEFG*, Majed A. Alsahli2ABDEF, Fasial F. Alarifi2BCEF, Basel O. Hakami 3BE, Fawaz W. Alkeraithe 4BE, Mohammed Alhuqbani2BE, Zyad Aldosari 2BE, Omar Aldosari2BE, Abdalah Emad Almhmd 5BDE, Saleh Binsaleh 6AD, Raed Almannie 6ADF
Med Sci Monit 2023; 29:e939455
ABSTRACT: Khat (Catha edulis Forsk) is a stimulating narcotic grown mainly in East and Southern Africa. The plant has a long history as a popular social behavior within these regions, and its active ingredient, cathinone, has been thought to cause an array of physical, psychological, and mental health complications. In 1980, the World Health Organization (WHO) classified it as an illicit substance due to the potential for psychological dependence. Subsequent investigations have found that its regular consumption can negatively impact the human central nervous system (CNS), systemic blood pressure, genitourinary system, and psychological health. This narrative review aims to discuss the reproductive toxicity and sexual dysfunction (SD) caused by regular khat usage in humans and experimental animals. Animal studies found dose-dependent impacts on male reproductive health: low levels increased testosterone production, whereas high levels had the opposite effects. Moderate intake was associated with reduced luteinizing hormone (LH) levels and heightened cortisol in blood plasma. In human studies, chronic users had dramatically lower semen volume, sperm motility, and count, as well as reduced libido or erectile dysfunction (ED). Khat can have serious implications for male fertility and sexual health: therefore, better understanding of its effects is paramount. This article aims to review the toxic effects on the male reproductive and sexual health of chewing the psychostimulant, Catha edulis (khat).
Keywords: Catha, cathinone, Erectile Dysfunction, Impotence, Vasculogenic, Infertility, reproductive health, Sexual Dysfunction, Physiological
In the Arab world, khat is the popular name of the plant
The fresh khat leaf is usually chewed and placed along the cheek on one side and repeatedly chewed until the active ingredients take effect; other methods of consumption include drying the khat leaves and using it as a tea-like drink . There is high consumption of khat among the population in the Arabian Peninsula and in certain regions of eastern and southern Africa owing to its perceived therapeutic effects against depression and tiredness [5,6]. There has been an increase in the consumption of khat among women . In addition to teratogenic consequences, khat chewing during pregnancy causes problems with sexual function, decreased libido, decreased food intake, decreased utero-placental blood flow, impaired fetal development, and low birth weight . There is also high use in pregnant women whose husbands are struggling with addiction to khat or alcohol ; moreover, they use khat to relieve stress and to gain intimacy with their partner . Addiction to khat can cause psychological, physical, and financial problems, negatively impacting professional and personal life, and may even lead to divorce [9–11]. Khat is a hazardous substance, and its use has recently increased, especially in the Arabian Peninsula and the horn of Africa . There is a widespread erroneous perception that the plant has benefits and lacks harmful effects. This idea is perilous and needs to be corrected by spreading awareness of its social-economic and health consequences.
Khat is believed to affect most organ systems in the human body, including cardiovascular, digestive, hepatobiliary, respiratory, endocrine, ocular, nervous, and genitourinary systems . However, there have been no comprehensive investigations on the effects of khat on human reproductive and sexual health. Khat use was shown to be associated with urinary retention, spermatorrhea, spermatozoa malformations, ED, and altered libido. Furthermore, a negative impact on female reproductive health has been reported, such as low birth weight, stillbirth, and impaired lactation .
This article aims to review the toxic effects on the male reproductive and sexual health of chewing the psychostimulant
Chemical Composition of Khat
Khat contains various chemical components that may have different effects on the human body. The essential active ingredients of khat are cathine (norpseudoephedrine) and cathinone [(S)-2-amino-l-phenyl-l-propanone] .
Only the (−)-enantiomer of cathinone is found in the khat plant . As a result, S-(−)-cathinone has the same absolute configuration as S-(+)-amphetamine . Cathinone is mostly present in the young leaves and shoots of plants. Cathinone is converted during maturation to cathine [(+)-norpseudoephedrine] and (−)-norephedrine . The leaves contain [(+)-norpseudoephedrine] and (−)-norephedrine in a 4: 1.11 ratio. The phenylpentenylamines merucathinone, pseudomerucathine, and merucathine are among the several phenylalkylamine alkaloids discovered in khat leaves. These chemicals appear to contribute less to the stimulating effects of khat .
The chemical structure and biological activity of cathinone are similar to that of amphetamine and it accounts for most of the pharmacological effects of khat chewing . Khat extract and cathinone have been demonstrated to impede ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and protein synthesis in dividing cells, and to suppress cell proliferation, which can cause decreased spermatogenesis [15–17]. Cathine is also responsible for the moderate CNS stimulatory effects associated with khat consumption . In addition, fresh leaves and the young shoots of khat contain the psychoactive substance monoamine alkaloid cathinone [(S)-2-amino-l-phenyl-l-propanone], which has euphoric effects [15,18].
Other chemical elements found in the leaves of khat include alkaloids, flavonoids, and sterols, in addition to more than 40 other alkaloids, glycosides, tannins, and terpenoids . Chemically, the leaves contain vitamin C, niacin, calcium, and iron. Cathinone is one of the psychoactive alkaloid chemicals in khat that stimulates the CNS . Khat is also a biologically active, non-narcotic, habituating compound with severe adverse effects on the CNS, similar to those of amphetamine .
Studies have shown the potentially harmful impact of chronic use of khat on the CNS, systemic blood pressure, urinary system, and psychological health. The psychostimulant component in khat is cathinone, which is responsible for developing addiction . The cognitive and mental impairment caused by khat use can lead to headaches, insomnia, impaired concentration, migraine, fine tremors, and impaired motor function .
Anorexia and insomnia caused by khat chewing have been shown to affect work performance on the following day [23,24]. Another study elaborated on the psychological impact of khat, such as psychological and physical dependence, euphoria, schizophrenia, hallucinations, mild depression, alertness, dizziness, anxiety, and psychosis [25–27]. Manic psychosis and paranoid or schizophrenia spectrum disorder were the 2 main kinds of psychosis induced by chronic khat consumption . Khat-induced psychosis does not typically require antipsychotics, as complete remission follows khat withdrawal [14,28–32]. Elevated diastolic blood pressure is another adverse effect attributed to cathinone, which causes peripheral vasoconstriction due to increased sympathetic activity [33,34]. This elevated blood pressure becomes chronic with long-term use of khat [35,36]. Accordingly, this population has a higher incidence of acute coronary vasospasm and myocardial infarction .
The urological adverse effects of khat abusers include a decrease in the maximum urinary flow compared to the control group, which could be explained by the sympathomimetic action of cathinone α1-adrenergic receptors in the bladder neck . An observational study showed a higher risk of oral cancers in chronic khat users [38, 39]. Nasr et al suggested that the habit of chewing khat was likely to be an essential contributory factor in patients with head and neck squamous cell carcinoma . The association between khat chewing and progressive liver damage has been well documented in the literature. Long-term khat consumption can cause hepatitis, fibrosis, and cirrhosis [40–43].
Effect of Khat on Different Animal Fertility Parameters
Many studies have investigated the effects of khat on different animal species. These studies discussed the main chemical constituents of the khat plant mentioned earlier and their various side effects, with cathinone being the most potent compared to cathine and norephedrine . Furthermore, more than 40 other compounds have been extracted from khat, including alkaloids, glycosides, tannins, and terpenoids . Islam et al (1990)  conducted one of the first animal studies exploring the effect of khat supplementation on different aspects of male infertility. They found that khat supplementation caused a decline in sperm count by 28%, a decline in motility by 22%, a decrease in plasma testosterone level by 50%, and an increase in abnormal sperm number by 53%. Although Islam et al (1990)  attributed these effects to cathinone, subsequent studies suggested variable effects of cathinone or khat, ranging from positive to negative or even both positive and negative effects, on sex hormone levels, sperm morphology, and sperm activity. Adeoya-Osiguwa and Fraser (2005, 2007) [45,46] found that cathine can improve the success rate of
Consumption of khat affects spermatogenesis and plasma testosterone levels, which in turn impacts male rate potency . In a study conducted on baboons , crude khat extract was found to increase plasma testosterone levels while decreasing prolactin and cortisol levels; however, it did not affect the testicular histology, which is in contrast to a previous study in rats  in which administration of cathinone was found to cause interstitial tissue degradation, cellular infiltration, and atrophy of Sertoli and Leydig cells. The cathinone component of khat may be partially or totally responsible for the reproductive toxicity of khat chewers . Mwenda et al (2006)  investigated the serum levels of reproductive hormones in olive baboons after being supplemented with khat. They found a 35% increase in testosterone levels and a 36% decrease in cortisol blood plasma levels after khat supplementation . Another study concluded that the effects of khat were dose-dependent, as low levels of khat caused increased production of testosterone by mouse interstitial cells, while an opposite effect was observed at high khat levels. Moreover, moderate supply caused a decline in LH levels and increased levels of cortisol in blood plasma (Nyongesa et al, 2008) . In the same study, fresh khat extract was found to reduce the plasma levels of LH and testosterone in male rabbits by 24% and 23%, respectively, and it caused a dose-dependent increase in plasma cortisol levels. A report from an animal study found male mice treated with khat extract had lower reproductive rates, while females had post-implantation loss during the first week of pregnancy . Khat has also been found to inhibit spermatogenesis, reduce sperm volume and count, and egg fertilization in roosters , while another study reported an increase in the incidence of abnormal sperm in mice . Cathinone treatment in male rats resulted in a substantial drop in sperm count and motility and an increase in the number of abnormal sperm . A recent study found testosterone had a similar pattern, in that higher doses of khat in rats caused a substantial decrease in testosterone levels, while low doses had no significant effect on testosterone levels; moreover, LH and follicle-stimulating hormone (FSH) levels in all rat groups were not significantly different from those in the control group . In the same study, prolactin level was significantly decreased in low-dose groups while there was no significant change in the high-dose group .
Effect of Khat on Human Male Reproductive and Sexual Health
Penile erection is a complex process involving the cavernous smooth muscles and the arteriolar and arterial smooth muscles. The muscles are tonically contracted in the penile flaccid state . Sexual stimulation results in the release of various neurotransmitters which work together to relax these smooth muscles, resulting in a gush of blood inside the tissue and causing an erection . Infertility is defined as the inability to conceive after at least 1 year of frequent unprotected sexual intercourse . Infertility can be attributed to either the male or female partner. Male infertility contributes to approximately 50% of infertility issues . Many factors, including age, medications, genetic factors, and exposure to toxins can cause male infertility. Many male infertility cases are attributed to primary testicular defects diagnosed with abnormal sperm parameters . Another major cause is ED, defined as the failure to maintain penile erection for enough time to achieve satisfactory sexual intercourse . Khat consumption is one of the many potential factors involved in abnormal male reproductive health and SD.
There are few studies about the effects of khat consumption on human reproductive health . Most studies on the association between khat consumption and poor reproductive and sexual health, including ED, have been conducted on animals.
A study conducted in Saudi Arabia in 1995  compared semen parameters and sperm ultrastructure between people addicted to khat and those who are not. Both groups were matched for age, education, and socioeconomic status and were free of medical disorders that could affect the results of semen analysis. The khat-addicted group had significantly lower semen volume, sperm motility, and sperm count compared to the non-khat-addicted group (mean semen volume: 3.76±1.05 mL and 4.75±0.96 mL, respectively; sperm count: 37.23±19.37×106/mL and 116.04±51.28×106/mL, respectively; sperm motility: 27.83±9.87% and 73.30±11.05%, respectively) . In Ethiopia, a study published in 2002 investigating the influence of khat on seminal fluid analysis among presumed infertile couples also found an association between long-term khat consumption and abnormal seminal fluid profiles . The study revealed decreased semen volume, sperm count, and sperm motility among khat users compared to the control group; however, the results were not statistically significant. The study also found abnormal sperm morphological changes among khat consumers . Another study, conducted in Kenya, reviewed articles published from 1961 to 2002 to study the effect of khat consumption on reproductive function . The study revealed that khat consumption was associated with low libido and possible ED following long-term use and emphasized the need for detailed studies to establish a definite causal relationship .
Regular khat use has been linked to increased mean diastolic pressure . A recent case report describes a patient who developed khat-induced non-ischemic cardiomyopathy despite having no other known cardiovascular risk factors . Its sympathomimetic/vasomotor actions on the heart and coronary arteries are mediated via beta-1-adrenoreceptors, which account for the tachycardia, palpitations, and hypertension that occur . Previous studies have shown a connection between cardiovascular disease and ED . A study conducted in Yemen in 2014 examined penile blood flow using Doppler ultrasonography in patients with ED; out of 190 patients consuming khat, 54 were diagnosed with pathological ED attributed to either arterial disease or venous leakage, while most etiologies of ED were psychological causes 170 (72%) .
Current Gaps in Understanding the Effects of Khat on Male Reproductive and Sexual Health
It is important to note that the therapeutic benefits of khat have not yet been proven. There was sufficient information on this substance to justify a critical review by the WHO. However, the WHO expert committee on drugs and dependency has advised a rigorous investigation of khat use . According to our review of data, the potential for misuse of khat and dependency is growing. In the last 2 decades, available human studies found a negative impact of khat use on male reproductive and sexual health. However, more future studies are warranted.
The amount of misuse and harm to public health may be severe enough to require concerted intervention at the international level. Chronic use of khat causes social and certain health difficulties, and it is proposed that national educational programs be implemented to dissuade usage that can lead to these negative repercussions. The results of our narrative review back up the World Anti-Doping Agency’s (WADA) recent declaration that athletes are no longer permitted to use cathinone and cathine as specific stimulants during sports contests (WADA, 2023) .
Communities where khat usage is widespread across the world have certain health issues associated with khat use. Men who use khat are more prone to perceive reproductive and sexual problems. Health promotion initiatives should be directed at both lowering use in those that are currently using khat and avoiding the commencement of khat use. Health promotion programs should include information not only on the oral, digestive, hepatic, and mental health problems associated with khat use, but also on the potential for reproductive health and SD, as well as information on the assistance and treatment available to those wishing to stop using.
Recommendations for Future Studies on Khat Toxicity
The impact of khat on human reproduction is still an under-researched subject. The potential consequences and processes by which khat may alter reproductive and sexual functions are still being debated. Ethical issues restrict the nature of studies on human subjects. Collaboration between reproductive healthcare providers, including andrologists, endocrinologists, obstetricians, gynecologists, and in vitro fertilization (IVF) physicians, is warranted to identify people who misuse khat and to establish a database registry for follow-up and further evaluation, especially among communities where khat misuse is prevalent.
Khat is a toxic substance linked to human reproductive toxicity and SD according to several studies conducted throughout the world. This harmful effect is brought on by the various chemical components, particularly cathinone. Abnormal semen parameters, sperm ultrastructure, low libido, and ED are the principal reproductive and sexual harmful consequences reported in humans. Further investigation of khat’s effects on sexual and reproductive health in humans requires clinical investigations. Raising public knowledge of the negative consequences of khat chewing is important since this is a significant societal issue in some regions. Social media and educational resources may be used to accomplish this through effective communication tactics.
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