Traditional, Complementary and Alternative Medicines in the Treatment of Ejaculatory Disorders: A Systematic Review

Background and Objectives: Ejaculatory dysfunction (EjD) is a common male sexual disorder that includes premature ejaculation, delayed ejaculation, retrograde ejaculation, and anejaculation. Although psychological and pharmacological treatments are available, traditional, complementary, and alternative medicine (TCAM) is reportedly used. However, the clinical evidence for TCAM in EjD remains unclear. Therefore, this study aims to systematically review human clinical trials investigating the use of TCAM to treat EjD. Materials and Methods: A systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted by searching Scopus and PubMed databases. Controlled clinical trials investigating a cohort of male patients diagnosed primarily with EjD and undergoing any TCAM intervention compared to any comparison group were included. Quality of the studies was assessed using the Cochrane Risk of Bias tool for randomized controlled trials. Results: Following article screening, 22 articles were included. Of these, 21 investigated TCAM in premature ejaculation, and only 1 investigated TCAM in retrograde ejaculation. Different TCAM categories included studies that investigated lifestyle, exercise and/or physical activities (n = 7); herbal medicine supplements (n = 5); topical herbal applications (n = 4); acupuncture or electroacupuncture (n = 3); vitamin, mineral and/or nutraceutical supplements (n = 1); hyaluronic acid penile injection (n = 1); and music therapy (n = 1). Only 31.8% (n = 7) of the included studies were found to have a low risk of bias. The available studies were widely heterogenous in the TCAM intervention investigated and comparison groups used. However, the included studies generally showed improved outcomes intra-group and when compared to placebo. Conclusions: Different TCAM interventions may have an important role particularly in the management of PE. However, more studies using standardized interventions are needed.


Introduction
Ejaculatory dysfunction (EjD) is a multidimensional psych-neuro-uro-endocrine pathological condition characterized by the disruption of the ejaculatory cascade that results in a failure of normal ejaculation [1].Sub-categories commonly include expulsion phase disorders such as premature ejaculation (PE), delayed ejaculation (DE) and anejaculation; emission phase disorders such as retrograde ejaculation (RE); and orgasm disorders such as anorgasmia [2].Due to the overlap of neuromuscular control, these disorders are grouped as EjD but may have a different etiology, pathology, diagnosis and management [2].
Data on the epidemiology in the general population of EjD as a heterogenous sexual disorder are scant [2].The most common form of EjD in the general population is PE, affecting up to 20-30% of the male adult population [2,3], where RE is considered the second most common type of EjD and an important cause of infertility [4].Other types of EjD such as DE and anejaculation are estimated to affect 1-4% of sexually active men [5].However, EjD is reported in 1.8% of males with infertility, with RE the most common (0.7% males), followed by PE (0.5%) and anejaculation (0.4%) [6].
Lifelong PE has been defined as ejaculation that nearly always occurs within or around 1 min following vaginal penetration since the first sexual experience, whereas acquired PE is a significant reduction in latency time of 3 min or less [7].The intravaginal ejaculation latency time (IELT/ELT) is widely used in clinical trials to assess ejaculation delay in men with PE [8].IELT/ELT is recommended to be performed through stopwatch measurement from vaginal intromission to the start of intravaginal ejaculation [8].In the general population, the median (range) IELT is 5.4 (0.55-44.1) min, with a significant decrease for 51 years and older compared to 18-30 years of age [8].In addition to the IELT, numerous questionnaires have been validated for PE.These include the Premature Ejaculation Profile (PEP) [9], Premature Ejaculation Diagnostic Tool (PEDT) [10], Arabic Index of Premature Ejaculation (AIPE) [11], Chinese Index of Premature Ejaculation-5 (CIPE-5) [12], Male Sexual Health Questionnaire-Ejaculatory Disorder (MSHQ-EjD) [13], Checklist for Early Ejaculation Symptoms (CHEES) [14], Index of Premature Ejaculation (IPE) [15] and Multiple Indicators of Premature Ejaculation [14].RE is due to the lack of closure of the internal urethral sphincter (bladder neck) that results in the reflux of semen into the bladder (hypospermia or aspermia) [16], and typically presents with absent or intermittent seminal emission with orgasm and spermatozoa identified in post-coital urine samples [17].DE and anorgasmia are described in men with a delay or absence of orgasm that is ongoing or recurrent [18].Although no formal cut-off is defined, DE is proposed to occur with ejaculation latencies of >20 or 30 min [5,19].
Selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, phosphodiesterase type 5 (PDE5)-inhibitors and/or topical anesthetics are recommended in the management of primary PE.In contrast, acquired PE management is typically dependent on the underlying etiology [3,20].SSRIs, such as dapoxetine and paroxetine, have strong clinical evidence for delaying ejaculation in acquired and lifelong PE [21].Management of RE is primarily aimed at the underlying cause, and alpha-agonists have been used off-label without supporting evidence [20].Pharmacological treatments for DE, anejaculation and anorgasmia, however, remain limited, with few large-scale studies showing limited efficacy and/or significant adverse events [22], although psychotherapy and addressing underlying causes are recommended [18].In addition, traditional, complementary and alternative medicine (TCAM) is widely used for various male sexual dysfunctions in the general population, yet is poorly investigated for clinical efficacy [23][24][25][26].
Traditional knowledge reflects the interaction between individuals and societies with nature, and has the potential to contribute significantly to the healthcare of local people, as well as to scientific knowledge and drug discovery through documentation of traditional medicine and local ethnobotany [27][28][29].As broadly reported by the WHO [30] and Cochrane collaboration [31], TCAM incorporates numerous treatment modalities, including nutritional medicine; dietary supplements; lifestyle changes; exercise therapies; herbal medicines; traditional Chinese medicine and acupuncture; physical therapies such as massage, cupping and acupressure; homeopathy; music therapy; breathing therapy; energy medicine (such as reiki); mind-body techniques (such as meditation and yoga); and psychotherapy and counselling [30][31][32].Although numerous TCAM approaches are used for male sexual function, there are few human clinical studies on ejaculatory disorders and TCAM [23][24][25][26].Therefore, this study aims to systematically review human clinical trials investigating the use of TCAM to treat EjD using validated outcome measures.

Materials and Methods
A literature search was conducted on 22 September 2022 using Scopus and PubMed databases, with no time limit, and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [33].
The following inclusion criteria were used for eligibility of studies: (i) a cohort of male patients diagnosed with any recognized EjD; (ii) any sole TCAM intervention in at least one intervention group; (iii) controlled clinical trials with any comparison group as study type; (iv) any relevant outcome measures for EjD; (v) English, Spanish and Italian full-text articles.The following exclusion criteria were used for eligibility of studies: (i) no control group; and (ii) observational studies, review studies, case reports, conference proceedings, pre-prints, and any other grey literature.
After searching the databases with keywords and removal of duplicates, a preliminary literature screening was performed based on the title and abstract by authors (C.S.O., F.M., R.F.), followed by full-text retrieval of the remaining articles for eligibility analysis based on the inclusion and exclusion criteria.Any disagreement was solved after discussing with the first author (K.L.).Data were collected using an Excel sheet and included the study design, a description of the patient and control cohorts, the dosage and duration of the intervention used, a report of the outcomes and any adverse effects.To simplify the results and discussion, included studies were presented grouped in macro-areas based on the type of intervention used: herbal medicine supplements; topical herbal applications; vitamin, mineral and nutraceutical supplements; acupuncture and electroacupuncture; lifestyle, exercise and/or physical therapy; penile injections; and music therapy.Each included study's quality was evaluated using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) [34].

Discussion
Although there is reportedly an extensive use of TCAM for the management of male sexual dysfunction, including EjD [23][24][25][26], the extent of the available clinical trials of TCMA for EjD has remained unclear.Following a PRISMA-guided systematic literature

Discussion
Although there is reportedly an extensive use of TCAM for the management of male sexual dysfunction, including EjD [23][24][25][26], the extent of the available clinical trials of TCMA for EjD has remained unclear.Following a PRISMA-guided systematic literature search, only a few controlled clinical trials (n = 22) were identified that investigated a wide range of different interventions that can be considered TCAM (Table 1).Furthermore, most (n = 21) of these studies investigated TCAM in PE only, which can be explained as PE is considered the most common and significant EjD affecting the general adult population [2].These results further suggest that there is an under-representation of TCAM investigations in other clinically important forms of EjD, with only one study investigating the use of vitamin B12 in retrograde ejaculation, and no studies investigating other forms of EjD.
No previous similar systematic review to investigate different TCAM interventions on EjD has been identified in the literature.Previously, a 2017 systematic review on the use of CAM in PE included 10 studies in the final analysis, predominantly consisting of herbal medicine and acupuncture [80].This present systematic review included 4 of the 10 studies that were previously reported in 2017 [69,71,72,74], while we excluded 6 of these studies due to Chinese language full text (n = 2) [81,82], combination treatment with conventional medicine (n = 3) [83][84][85] and no inter-group comparison (n = 1) [86].Our systematic review on TCAM for EjD expanded on the previous review in 2017 [80] by widening the definition of TCAM and including all types of EjD, which further identified three additional studies published prior to the 2017 review [80].Specifically, this included herbal medicine [65], yoga [58] and physio-kinesitherapy, biofeedback therapy and electrical stimulation of the perineal floor [60].

Lifestyle, Exercise and/or Physical Therapy
Most TCAM systems have lifestyle, exercise and/or physical therapy components as part of patient management, although these practices may vary widely [32].Physical inactivity is considered a risk factor for PE [20].Only one study included in this review investigated moderate physical exercise (running > 30 min 5 days per week), which improved IELT and PEDT intra-group as effectively as dapoxetine and more effectively than intra-group improvements from minimal physical activity (walking < 30 min 5 days per week) [59].
The pelvic floor is important in male sexual function, particularly for erection and ejaculation control.Pelvic floor therapy may be useful for males with sexual dysfunction, including EjD such as PE, as it is suggested to contribute to the broader bio-neuro-musculopsycho-social approach in the management of EjD [87].Kegel exercises consist of regularly repeated pelvic floor muscle exercises, first developed in 1948 and used in urinary incontinence.Subsequently, electrical stimulation was developed to manage pelvic floor dysfunction, and written and audio perineal re-education techniques were developed.Together, these contribute to the management of urinary incontinence, sexual dysfunction and anorectal canal dysfunction [88].One study included in this systematic review found that physio-kinesitherapy, biofeedback therapy and electrical stimulation of the perineal floor (PFM) as rehabilitation therapy improved IELT as did dapoxetine, although dapoxetine had a significantly better effect on IELT than PFM [60].Another study found that penile root masturbation (PRM) and Kegel exercise increased IELT and decreased PEDT, where PRM was significantly better than Kegel exercises [62].PRM is further supported in an earlier, small uncontrolled study of nine patients, where regular PRM was shown to increase IELT and decrease PEDT, suggesting that PRM has a short-term beneficial effect for PE [50].In another study included in this systematic review, sphincter control training with a masturbation device (GWD) improved IELT similarly to sphincter control training with the addition of a masturbation device (GWtD) [63].
Yoga is an ancient Ayurvedic practice that has increased in popularity globally over the last two decades [89], associated with improved psychosocial attributes such as better coping, mindfulness and support [90].Yoga is increasingly used for male sexual dysfunction, including PE [89].Training in males undergoing a yoga camp for 12 weeks significantly improved sexual function, including libido, sexual satisfaction, sexual performance and confidence, partner satisfaction, erection, ejaculatory control and orgasm intensity based on the Male Sexual Quotient [91].In this systematic review, one study reported that 12 weeks of yoga increased IELT, although fluoxetine was more effective than yoga with more adverse effects [58].Proposed mechanisms for the benefit of yoga in PE are improved neuro-psycho-physiological functioning, hormonal regulation, reduced sympathetic and increased parasympathetic activity, increased serum serotonin levels, pelvic floor muscle strengthening, improved body awareness (and ejaculatory control), and management of underlying psychological or physical risk factors [92].Furthermore, yoga has positive effects in relieving depression, anxiety and stress [93,94].
Psychotherapy and behavior modification are commonly used in the treatment of PE, although there is a lack of evidence-based trials [20].One study in this systematic review investigated a combination of psychotherapy with physical exercises for strengthening the pelvic floor muscles and cognitive exercises for sexual failure distancing, which led to a decrease in PEDT and an increase in PEP [61].There was a concomitant improvement in intercourse satisfaction and overall satisfaction, alongside decreased depression scores.Furthermore, this study found that the application of a mobile training app for exercises was more effective than written and verbal instructions [61].One study investigated mindfulness meditation as a psycho-neuro technique for PE, where mindfulness meditation with vibrator-assisted start-stop exercises and (VSS+) improved CHEES significantly better compared to only vibrator-assisted start-stop exercises (VSS) and no treatment [64].

Herbal Medicine Supplements
Herbal medicines have been used for millennia to prevent and treat disease, with a large proportion of modern pharmaceuticals based on medicinal plant isolates [27][28][29]95,96].Extractions of herbal medicines contain secondary plant metabolites that can work synergistically or as isolates on human physiology [95].Herbal medicine is commonly used to enhance or improve male sexual function, with over 700 species used traditionally for this purpose [23,24].Hypericum perforatum L. (Saint John's wort) is used traditionally in Chinese, Greek and Islamic medicine systems and is a popular medicinal herb globally, prominently as an anti-depressant treatment [27,28,97].This was the only herbal medicine investigated as a single herb with a standardized extract (hypericin).IELT increased significantly compared to the placebo control for Hypericum perforatum L., and improved intercourse satisfaction and orgasmic function [65].In the treatment of mild, moderate and major depression, Hypericum perforatum L. is as effective as SSRIs, with lower side-effects and fewer trial dropouts compared to SSRI treatment groups [98,99], particularly through hypericin and hyperforin as well established active constituents [97].
OLNP-05 is an Ayurvedic polyherbal combination of Mucuna pruriens L., Cynara cardunculus L., Trigonella foenum-graecum L., Withania somnifera L. and L-arginine [67].IELT increased significantly compared to placebo for OLNP-05, with an increased PEP and clinical global impression-improvement scale [67].This formula is proposed to increase testosterone, dopamine, serotonin and nitric oxide (NO), and inhibit phosphodiesterase-5, although these mechanisms were not investigated in this study [67].However, dopamine, serotonin and NO are critical mediators of ejaculatory control, and PDE5-inhibitors are commonly used in the pharmacological management of PE [20].
Gu-jing-mai-si-ha (GJMSHT) is a traditional Uighur medicine polyherbal combination of Radix anacycli pyrethri, Mastiche, Fructus cardamomi, Rhizoma Cyperi, Stigma Croci, Semen Myristicae, Radix Curcumae, Folium Syringae oblatae, Radix et Rhizoma Nardostachyos, Fructus Tsaoko and Flos Rosae rugosae [69].GJMSHT increased IELT alongside CIPE10 and CIPE5 scores compared to a group with no treatment, with an increased Sexual Partner's Satisfaction Rate and Wish Fulfillment Rate [69].The increase may be mediated through NO and prostaglandin-F2α (PGF2α) [69].NO levels are reduced in males with PE, where increased NO secondary to SSRI treatment improves ejaculation latency through a central mechanism [100].Although the role of PGF2α in ejaculation is not clear, administration to boars significantly increased ejaculation time [101].
EiacuMev ® is a polyherbal combination of Satureya montana, Tribulus terrestris, Phyllanthus emblica and Cardamomo, with L-tryptophan, ascorbic acid, vitamins B1, B3 and B6 [66].IELT increased significantly, and PEDT decreased significantly for EiacuMev ® compared to counselling and sexual behavioral treatment, with no change in MSHQ-EjD [66].EiacuMev ® also increased FSH compared to counselling and sexual behavioral treatment, with no change for LH and testosterone [66].Although the role of FSH, if any, in ejaculation has not been well investigated, men with PE have been found to have higher levels of FSH compared to healthy controls [102].It is unclear if the increase in FSH with EiacuMev ® is beneficial for patients with EjD, which appears to be a somewhat contradictory result.Satureja montana is widely used in male sexual dysfunction and has been shown to delay ejaculation latency in rats [103].Tribulus terrestris improves sexual behavior in rats through increased mount frequency and penile erection index; however, this also decreased ejaculatory latency and intromission latency [104].
Qiaoshao Formula (QSF) is a traditional Chinese herbal medicine composed of Fructus Forsythiae, Radix Paeoniae Alba, Radix Bupleuri, Radix Astragali seu Hedysari, Morinda officinalis How, Rhizoma Dioscoreae and Rhizoma Acori Graminei [68].Although QSF improved IELT in an intra-group analysis, dapoxetine was significantly better than QSF [68].However, the Chinese Medicine Symptoms Score decreased, and the sex life satisfaction score increased significantly more than dapoxetine alone [68].In a separate excluded study, the combination of QSF and dapoxetine improved IELT in a sub-group of men (baseline IELT < 1 min and age < 30 years) significantly better than dapoxetine alone [57].Furthermore, QSF has been shown to increase low baseline levels of NO and serotonin and decrease high baseline levels of testosterone and oxytocin in PE patients, with no effect on FSH, LH, prolactin and thyroid-stimulating hormone [105].

Topical Herbal Applications
Topical anesthetics, prominently lidocaine and prilocaine, have been widely used as a medical treatment to reduce glans sensitivity for PE [20].In this review, four studies involved the application of the formula and washing off 30-60 min prior to intercourse [70][71][72][73].The application of a Traditional Chinese Medicine Spray (TCMS) improved IELT and CIPE-5 intra-group but not significantly better than desensitization therapy (DT).However, the combination of TCMS and DT was significantly better than either of these interventions alone [70].TCMS is composed of Herba Asari, Syzygium aromaticum, Ootheca Mantidis, Radix Aconiti, Galla Chinensi, Fructus Rosae Laevigatae, Fructus Rubi and Pericarpium Zanthoxyli [70].The benefit of PE may be mediated through local anesthetic and analgesic effects (Herba Asari; Pericarpium Zanthoxyli; Galla Chinensis), relaxation of the corpus cavernosum (Syzygium aromaticum) and vasodilation (Radix Aconiti), although this has not been investigated [70].Similarly, the application of the traditional Chinese medicine Secret Severance (SS) cream was shown to improve IELT in a dose-dependent manner compared to the control in two studies [71,72].Furthermore, in a previous uncontrolled pilot study, SS-Cream improved IELT compared to baseline and seemed effective in PE and PE combined with erectile dysfunction [106].SS-Cream is composed of Ginseng Radix alba, Angelicae gigantis Radix, Cistanchis Herba, Torilidis Semen, Caryophylli Flos, Cinnamoni Cortex, Zanthoxyli Fructus, Asiasari Radix and Bufonis Veneum [71,72].Although the mechanisms of action of SS-Cream have yet to be determined, it is proposed that the active constituents of the included herbs act as desensitizing agents on the glans penis, smooth muscle relaxation and increased local blood flow that may be mediated through the activation of NO/guanosine monophosphate pathways [107].However, the application of a Persian medicine polyherbal formula (Nigella sativa seed oil, Olea europea oil and oleo-gum-resin of Boswellia sacra Flueck) did not show any benefit intra-group or compared to placebo for IELT or PEDT [73].

Acupuncture and Electroacupuncture
Acupuncture is a practice based on traditional Chinese medicine that involves inserting and manipulating needles into specific points of the body to manipulate meridians (energy channels) [108,109].This meridian system is considered the core basis for therapies such as acupuncture and electroacupuncture, where acupuncture points (acupoints) on the skin guide "qi" energy from somatic meridians to internal organs [110].In two studies, acupuncture increased IELT and decreased PEDT intra-group and compared to sham acupuncture in patients with PE.Although acupuncture was found to be as effective as paroxetine in one study [74], dapoxetine was found to be more effective than acupuncture in a separate study [76].The application of electroacupuncture using the Zhongji point (−) and Sanyinjiao points (+) was found to improve IELT compared to baseline and more effectively than Longdan Xiegan [75].Furthermore, electroacupuncture reduced serum testosterone significantly post treatment, as effectively as Longdan Xiegan [75].However, the mechanisms by which acupuncture or electroacupuncture may be effective in the treatment of PE remain unknown and uninvestigated [74][75][76].The insertion of needles or electric stimulation is proposed to activate local receptors, which deliver neuronal signals to the central nervous system that may mediate physiological activity [111].At the acupoint level, this involves triphosphate (ATP) stimulation and transient receptor potential vanilloid (TRPV) channels.Centrally, acupuncture modulates neurotransmitters, including serotonin, dopamine, norepinephrine, opioids and endocannabinoids.Peripherally, acupuncture may reduce cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) [111,112].Acupuncture has been shown to reduce pain and mediate analgesia, which is proposed through the modulation of various mechanisms such as increased serotonin centrally and peripherally, and the modulation of opioid peptides, enkephalin and dynorphin in the spinal cord [112,113].NO may also mediate the benefit of acupuncture, where NO and NO synthase are increased around acupoints and meridian lines [114].Alongside analgesia, acupuncture is beneficial for anxiety and depression through the modulation of serotonin [113].

Vitamin, Mineral and Nutraceutical Supplements
Vitamins, minerals and nutraceuticals were primarily investigated in just one study included in this review [77].Furthermore, this study was the only study that investigated RE [77].Sperm is recoverable in 69% of males with RE from post-orgasm urine samples for artificial reproductive techniques [6], alongside anticholinergics, sympathomimetics, surgery and electroejaculation [16].In a crossover randomized open-label trial, amoxapine was found to increase the rate of antegrade ejaculation significantly higher compared to vitamin B12 [77].Only 8% (n = 2) of 25 patients were improved due to vitamin B12, compared to 88% (n = 22) of patients taking amoxapine.Vitamin B12 is primarily involved in various physiological processes, including producing red blood cells and maintaining nerve function.Its deficiency can lead to anemia and neurological symptoms [115].While retrograde ejaculation can be associated with certain neurological conditions or nerve damage, there is no established connection between RE and vitamin B12 deficiency.However, based on the information available, no scientific evidence suggests that vitamin B12 is used for the treatment of any EjD, specifically RE.

Hyaluronic Acid
Hyaluronic acid (also known as hyaluronan or hyaluronate) is a naturally occurring non-sulphated glycosaminoglycan found predominantly in the extracellular matrix that has diverse roles in human physiology, most notably tissue repair and regeneration through cell signaling and cell migration [116].It is sourced from animal and bacterial sources for human health and disease [117] and used in bone and joint pathology, cartilage regeneration, ophthalmology, wound healing and dermatology [116].
In andrology, gland penis augmentation using hyaluronic acid has been applied to Peyronie's disease and PE [118,119].Although it is increasingly investigated for medical application, hyaluronic acid is not reported as a conventional treatment for PE [20] and is included as a TCAM treatment in this review.Of the included studies, just one investigated it as an intervention in a controlled clinical trial.The injection of hyaluronic acid into the glans penis and urethral meatus showed a significant improvement in IELT and AIPE following treatment compared to saline injection in a small study sample [78].Previously, in an uncontrolled study, hyaluronic acid injection into the base of the penis increased IELT significantly from baseline scores [47].This has been further supported in prospective studies, where hyaluronic acid may be safe and effective for PE and may improve satisfaction for up to 5 years [120][121][122][123]. Gland penis augmentation using hyaluronic acid is proposed to act as a bulking agent that blocks accessibility and inhibits tactile stimulation of the dorsal nerve receptors to improve ejaculatory control and ejaculation latency time [119].

Music Therapy
Music therapy is the application of personally tailored music interventions that involve music listening and/or music making.This is differentiated from music medicine, which does not include a personalized music intervention [124].In this review, one study investigated music therapy as an intervention compared to dapoxetine.Using music therapy 45 min before sexual intercourse improved IELT and reduced PEDT compared to baseline and was as effective as dapoxetine [79].Music therapy may particularly be valuable in stress and anxiety and for mental health benefits [124], which may explain the potential benefit of music therapy on PE.Furthermore, in obsessive-compulsive disorders, music therapy combined with SSRIs significantly improved obsessive compulsive disorder symptom scores alongside anxiety and depression scores compared to SSRI alone [125].In adolescents and children with depression associated with attention deficit and hyperactivity disorder, music therapy increased serotonin secretion and reduced cortisol, blood pressure and heart rate [125].In stressed rats, music therapy increased serotonin in the hippocampus and frontal cortex [126].It may therefore increase serotonin and reduce anxiety in patients with PE.

Strengths and Limitations
This systematic review used the PRISMA guidelines to improve validity and reliability.The keyword search strategy and eligibility were based on the Population, Intervention, Comparison, Outcomes and Study Design (PICOS) framework and aligned with the aim of this study.As this review focused on a broad definition of TCAM, the interventions included for analysis are heterogeneous.The review identified a small number of studies included for EjD (n = 22), with the majority of these investigating PE.Therefore, the effects of TCAM in EjD remain unclear and under-investigated.The eligibility criteria did not limit to a specific outcome related to EjD.However, most of the included studies investigating PE used the IELT as a standardized measure, with or without a validated self-reported questionnaire, improving the validity of the included studies.The included studies focused on a cohort of patients with primary EjD diagnosis, with most studies on PE.However, there is some variation in the definition of the cohort for PE and inclusion criteria for the different studies.Therefore, the participants in the included PE studies were varied across different forms such as psychogenic organic, lifelong and/or acquired.Although English, Italian and Spanish full-text articles would be included, there is a limitation on other language publications.

Conclusions
The results of this systematic review show that few controlled trials have investigated TCAM as an intervention in EjD.Although the majority of studies used IELT as a standardized outcome in PE, the available studies are widely heterogenous in the TCAM intervention investigated and comparison groups used.They mostly represent PE, and there is an underrepresentation of TCAM investigated in other types of EjD.In PE, most of the studies showed favorable outcomes intra-group and when compared to placebo.Based on these results, various TCAM interventions may have an important role partic-ularly in the management of PE, while this remains unclear for other types of EjD.More standardized interventions need to be investigated in well-designed and controlled studies to confirm the benefit of specific TCAM interventions for EjD.

Medicina 2023 , 20 Figure 2 .
Figure 2. Cochrane Risk of Bias of the Included Studies.D1 = Randomization process; D2 = Deviations from the intended interventions; D3 = Missing outcome data; D4 = Measurement of the outcome; D5 = Selection of the reported result.Mentioned articles are cited in the bibliography as references [58-79].

Figure 2 .
Figure 2. Cochrane Risk of Bias of the Included Studies.D1 = Randomization process; D2 = Deviations from the intended interventions; D3 = Missing outcome data; D4 = Measurement of the outcome; D5 = Selection of the reported result.Mentioned articles are cited in the bibliography as references [58-79].

Table 1 .
Characteristics of the studies included in this systematic review.
•CHEES decreased significantly intra-group for both groups, and it was lower for VSS+•The Sexual Distress Scale, STAI and Brief Symptom Inventory-18 (Anxiety) scales decreased significantly intra-group for the VSS+ group.
Abbreviations: AIPE = Arabic Index of Premature Ejaculation; CGI-I = Clinical Global Impression-Improvement Scale; CHEES = Checklist for Early Ejaculation Symptoms; CIPE = Chinese Index of Sexual Function for Premature Ejaculation; CMSS = Chinese Medicine Symptoms Score; FSH = Follicular Stimulating Hormone; IELT = Intravaginal Ejaculatory Latency Time; IIEF = International Index of Erectile