Pharmacology of Herbal Sexual Enhancers: A Review of Psychiatric and Neurological Adverse Effects

Sexual enhancers increase sexual potency, sexual pleasure, or libido. Substances increasing libido alter the concentrations of specific neurotransmitters or sex hormones in the central nervous system. Interestingly, the same pathways are involved in the mechanisms underlying many psychiatric and neurological disorders, and adverse reactions associated with the use of aphrodisiacs are strongly expected. However, sexual enhancers of plant origin have gained popularity over recent years, as natural substances are often regarded as a safer alternative to modern medications and are easily acquired without prescription. We reviewed the psychiatric and neurological adverse effects associated with the consumption of herbal aphrodisiacs Areca catechu L., Argemone Mexicana L., Citrus aurantium L., Eurycoma longifolia Jack., Lepidium meyenii Walp., Mitragyna speciosa Korth., Panax ginseng C. A. Mey, Panax quinquefolius L., Pausinystalia johimbe (K. Schum.) Pierre ex Beille, Piper methysticum G. Forst., Ptychopetalum olacoides Benth., Sceletium tortuosum (L.) N. E. Brown, Turnera diffusa Willd. ex. Schult., Voacanga africana Stapf ex Scott-Elliot, and Withania somnifera (L.) Dunal. A literature search was conducted on the PubMed, Scopus, and Web of Science databases with the aim of identifying all the relevant articles published on the issue up to June 2020. Most of the selected sexual enhancers appeared to be safe at therapeutic doses, although mild to severe adverse effects may occur in cases of overdosing or self-medication with unstandardized products. Drug interactions are more concerning, considering that herbal aphrodisiacs are likely used together with other plant extracts and/or pharmaceuticals. However, few data are available on the side effects of several plants included in this review, and more clinical studies with controlled administrations should be conducted to address this issue.


Introduction
Sexual drive is influenced by biological, psychological, and social factors, but it can also be affected by medications and medical conditions. Many prescription drugs and narcotics (e.g., antidepressants, anxiolytics, antihistamines, antihypertensives, adrenergic receptor blockers, antipsychotics, and opioids) can negatively impact sexual desire, inhibit erection, ejaculation, or orgasm, and so on. Contrariwise, many aphrodisiac substances can improve sexual performance. In particular, substances of natural origin have been used worldwide for millennia in traditional medicines to boost sexual desire, sexual pleasure, or sexual behavior [1], and the use of psychoactive and/or stimulant

Results
Of 5255 potentially relevant reports, 4758 were excluded because they did not describe psychiatric or neurological adverse effects or because they were not written in English, French, or Italian language. No relevant reports were found for A. Mexicana, E. longifolia, L. meyenii, T. diffusa, V. africana, and W. somnifera, which were therefore excluded from the results. A total of 137 records were included in the final review; species-by-species search results are detailed in a flow diagram in Figure 1. A general description of each species including their traditional and modern uses, active ingredients with their mechanism of action and pharmacokinetics, and general toxicity, is provided in the discussion. Psychiatric and neurological adverse events reported in the literature are displayed in Table 1; study conditions and co-exposures are also detailed.
Pharmaceuticals 2020, 13, x FOR PEER REVIEW 3 of 52 Of 5255 potentially relevant reports, 4758 were excluded because they did not describe psychiatric or neurological adverse effects or because they were not written in English, French, or Italian language. No relevant reports were found for A. Mexicana, E. longifolia, L. meyenii, T. diffusa, V. africana, and W. somnifera, which were therefore excluded from the results. A total of 137 records were included in the final review; species-by-species search results are detailed in a flow diagram in Figure  1. A general description of each species including their traditional and modern uses, active ingredients with their mechanism of action and pharmacokinetics, and general toxicity, is provided in the discussion. Psychiatric and neurological adverse events reported in the literature are displayed in Table 1; study conditions and co-exposures are also detailed.   Case reports of acute intoxications with Areca catechu L. in two schizophrenic men aged 51 and 45; both patients consumed a high quantity of betel nuts for 2 weeks Rigidity, bradykinesia, akathisia, and tremors [15] Tobacco, alcohol, cannabis, amphetamine Survey study on 11 participants aged  (average = 52), 9 males and 2 females; chewed 6 nuts/week (range = 4-6 days) Mood swings, anxiety, irritability, reduced concentration, reduced energy, sleep disturbance, craving, tolerance, and dependence [16] Tobacco, salbutamol, tea, coffee, arsenic Longitudinal pilot study on 100 participants, 26 users with a mean (±SD) age of 40.0 (±9) years, 11 males and 15 women Enhancement of physiological tremor [17] Tobacco, alcohol Cross-sectional study on 310 pregnant women, 292 users, mean age of 26 years (range = 25-27); took 5-10 nuts during pregnancy Addiction [18] Tobacco Survey study on 59 participants, 47 males and 12 females, median age of 43.0 years (range = 12-70); 1-50 years of chewing Craving and dependence [19] Tobacco Cross-sectional study on 851 participants, aged [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]314 users, 242 tobacco + users, and 295 regular cigarette smokers; <6->10 years of chewing Tolerance and withdrawal [20] Tobacco, alcohol Intercountry Asian BQ Consortium study on 2078 participants who took any A. catechu products/day for a minimum of 6 months Tolerance, withdrawal, craving, and dependence syndrome [21] Tobacco, alcohol Survey study on 41 participants with a mean (±SD) age of 40.34 (±9.23) years, 27 males and 14 females; took 5 to more than 31 BQ/day Relaxation, stimulation, addiction, and withdrawal symptoms [22] [29] Methyl atropine Animal study on 265 Sprague Dawley rats; administered with 2 mg/kg of arecoline Decreased locomotory activity [30] Glycopyrrolate Cognitive and behavioral study on 12 participants with AD, mean age of 65 Placebo-controlled, clinical study on 20 participants with (mean (±SD) age of 20.6 (±4.2), 10 males and 10 females; administered with placebo and 5 × 200, 400, or 600 mg of ginseng extract with a 7-day wash-out between administrations Decreased speed attention [79] Ginkgo biloba L., contraceptive pill.
Placebo-controlled, clinical study on 20 participants with a mean (±SD) age of 20.6 (±4.2), 10 males and 10 females; administered with placebo and 5 × 200, 400, or 600 mg of ginseng extract with a 7-day wash-out between administrations Decreased speed attention [80] Clomipramine Case report of ginseng intoxication of a MDD 56-year-old woman; took 300 mg/day of root extract for 2 weeks Hyperactivity, insomnia, dysphoria, and verbal and physical aggressiveness [81] Ginkgo biloba L., vitamins and minerals, cold-liver oil, primrose oil, caffeine, alcohol Randomized, double-blind, placebo-controlled clinical study on 70 post-menopausal females, 12 ginseng-receiving subjects with a mean (±SD) age of 58.4 (±1.0) years and 14 placebo-receiving subjects with a mean (±SD) age of 57.4 (±0.7) years; administered with 2 × 100 mg/day of ginseng extract for 12 weeks Slight depression (one case) [82] Ginsenosides (

Areca catechu L. (Betel Nut)
Betel nut is one of the most widely used addictive substances in the world and represents the fourth most consumed drug after nicotine, ethanol, and caffeine [23,154]. The fruit, obtained from the palm tree, Areca catechu L., is commonly chewed in Southeast Asia and the South Pacific islands [155,156] for its antiparasitic, digestive, euphoric, and aphrodisiac effects [157,158]. There are two main ways to prepare areca nut for chewing: wrapping a split unripe nut with lime paste (calcium oxide) in a betel tree leaf or inserting a piece of Piper betel L. inflorescence with lime paste into an unripe areca nut [22,154,159].
The betel nut contains a variety of active alkaloids responsible for its effects. The content of major alkaloids arecoline, arecaidine, guvacoline, and guvacine in the fresh nut is approximately 0.30-0.63%, 0.31-0.66%, 0.03-0.06%, and 0.19-0.72%, respectively, although it may vary with maturation [160][161][162][163]. Due to the presence of calcium oxide, arecoline and guvacoline are hydrolyzed to arecaidine and guvacine, respectively, in basic conditions [163,164]. Areca alkaloids mediate the autonomic responses of the parasympathetic nervous system and the synaptic transmission in the peripheral nervous system [164][165][166], and impact various aspects of brain function and regulation [167,168]. Arecoline is a partial muscarinic (M) agonist and possesses a higher affinity for M receptors than guvacoline [24,169]. High arecoline doses produce nicotinic cholinergic effects [170]. As tertiary amines, arecoline and, to a lesser extent, arecaidine have a deep brain penetration [165,169]. It was demonstrated that arecoline enhances cognition and memory and significantly improves several behavioral disorders in patients with Alzheimer's disease or schizophrenia, through the activation of postsynaptic M1 receptors [24,162,171]. In addition, improvements in positive and negative symptoms of psychosis have been observed in schizophrenic areca nut chewers [155,172,173]. It is believed that arecoline reduces the dopaminergic hyperactivity underlying the positive symptoms of psychosis throughout the modulation of M1, M2, and M4 receptors, and induces dopamine release in the prefrontal cortex, the striatum, and the ventral tegmental area, ameliorating the negative symptoms [169,174,175]. Furthermore, the release of dopamine and other catecholamines causes stimulant and libido-enhancing effects [3,156,166,176,177]. These effects, coupled with the inhibition of monoamine oxidase A (MAO-A) caused by aromatic phenolic compounds of the plant, may also explain the antidepressant properties of the areca nut [24,169].
High betel nut doses can cause typical muscarinic and extrapyramidal symptoms such as salivation, diaphoresis, diarrhea, gastrointestinal upset, emesis, vertigo, myosis, tremor, hyperthermia, bradycardia, and asthma attacks [156,158,166,168,176,178,179]. Furthermore, if betel nut is taken in high quantities, transient extrapyramidal symptoms including rigidity, bradykinesia, and jaw tremor may occur [24,176,180]. These effects are probably due to guvacine and arecaidine, which are strong inhibitors of γ-aminobutyric acid (GABA) reuptake and contribute to the reduction in spontaneous activity and body excitability [181][182][183]. However, it was also demonstrated that areca alkaloids reduce GABA affinity for the GABA A receptor, and arecaidine and guvacine effects on GABA signaling may cause epileptic seizures [23,169,180,184]. The main risks associated with the chronic consumption of betel nut are related to its metabolism. Indeed, areca alkaloids are converted into DNA alkylating nitrosamines, which cause cell proliferation and oxidative stress-dependent neurotoxicity, leading to oral carcinogenicity and exacerbating neurodegenerative disease symptoms [24,158,183,185]. Albeit its use is culturally well accepted, the betel nut is a strongly addictive substance and multiple adverse effects were reported (Table 1). Tolerance and nicotine/amphetamine-like withdrawal syndrome, characterized by insomnia, mood swings, irritability, and anxiety, may appear after repeated intakes [16,167,179].

Citrus aurantium L. (Bitter Orange)
Citrus aurantium L., also called Seville orange, sour orange, or bitter orange, is a small tree belonging to the Rutaceae family. It is native to Eastern Africa, Arabia, and Syria, but is also cultivated in Spain, Italy, and North America [186]. Bitter orange tree's leaves, flowers, fruits peels, and seeds have been used for centuries to treat tachycardia, rheumatism, insomnia, anxiety, epilepsy, and gastrointestinal disorders and to enhance sexual desire [187][188][189].
The bitter orange tree contains vitamins, minerals, terpenoids, and flavonoids [190]. The most abundant flavonoids are hesperetin and naringenin, which possess, together with terpenoids, carotenoids, and ascorbic acid, a free radical-scavenging ability and inhibit proinflammatory mediators release, exerting a powerful antioxidant activity and reducing tumoral cell proliferation [191,192]. Terpenoids such as d-limonene, α-pinene, β-myrcene, linalyl acetate, and linalool are the main volatile components of the plant [193,194], and are distilled or extracted from blooms, leaves, and orange peel to obtain essential oils (EOs) [195]. These substances, especially d-limonene, modify the cell membrane of microbes and denature enzymes responsible for their germination and sporulation, showing antimicrobic and antifungal properties [191,196]. For these reasons, bitter orange tree's EOs are widely sold as flavoring and preservative agents in foods and drinks [190,197]. Recently, a great interest in these EOs has been observed in the context of alternative medicines such as aromatherapy. It was demonstrated that these substances, after vaporization and inhalation, are effective for treating different forms of anxiety, sleep, and libido, and reduce seizures in animal models [38,39,[198][199][200][201]. The mechanism of action of the plant's ingredients, however, is not fully elucidated. Anxiolytic and hypnotic effects are seemingly due to the combination of the action of the plant's aroma on the limbic system through olfaction and the direct action of terpenes on GABAergic and serotoninergic (5-HT 1A ) receptors [39,202,203].
Adverse effects are mild and transient; psychiatric and neurological effects are reported in Table 1. The US Food and Drug Administration confirmed that oral administration of bitter orange extracts is safe [39], and its derivatives have gained popularity as dietary supplements over the last few years [200,204]. Standardized derivatives containing 4-6% synephrine, an ephedrine-like alkaloid naturally occurring in C. aurantium and possessing αand β-adrenergic properties, are available [3,40,205]. Although synephrine has become one of the most popular stimulants in weight loss products, cardiovascular adverse effects including increased blood pressure, tachycardia, ventricular fibrillation, transient collapse, myocardial infarction, and cardiac arrest have been reported [206]. Headache and gastrointestinal symptoms have also been reported.

Mitragyna speciosa Korth. (Kratom)
Kratom is an herbal preparation obtained from the leaves of Mitragyna speciosa Korth, an evergreen plant of the Rubiaceae family that grows spontaneously in Southeast Asia, mainly in Thailand and Malaysia [207]. In these countries, the plant has been exploited for centuries for its stimulant and narcotic properties and is commonly self-administrated by manual laborers to combat fatigue and improve productivity [51]. Mitragyna leaves are traditionally chewed, smoked, or boiled with hot water and served as a tea [208]. New preparations such as capsules, resins, or tinctures are now available on the Internet and are purchased in Europe and in America for recreational use or as herbal products [209,210].
More than 40 alkaloids were isolated from kratom. The alkaloids' content is variable and depends on plant age, season, and geographical location [211]. Mitragynine is the most abundant active compound and accounts for up to 66% of the total mass of crude alkaloids extract. Other major alkaloids are paynantheine, which is the second most abundant alkaloid (10% of total content), speciogynine, and speciociliatine. Among the various minor alkaloids, 7-hydroxymitragynine is of particular interest due to its important role in mediating the analgesic effect of mitragynine [157]. Both mitragynine and its oxidized metabolite 7-hydroxymitragynine are partial agonists of µ-opioid receptors (MOR) and competitive antagonists of κand δ-opioid receptors (KOR and DOR), which are involved in analgesia. However, mitragynine affinity for opioid receptors is lower than that of morphine, while 7-hydroxymitragynine affinity is approximately 46 and 13 times higher than that of mitragynine and morphine, respectively [212]. The possible stimulant and libido-enhancing effects of mitragynine may be due to the blockade of serotonergic 5-HT 2A receptors and the postsynaptic stimulation of α 2 adrenergic receptors (α 2 R) in the CNS [212]. Recently, LaBryer et al. hypothesized that kratom may have restored testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin levels in a patient with hypogonadotropic hypogonadism [213]. Mitragynine also binds adenosine A 2A receptors, dopamine D 2 receptors, and serotonin receptors 5-HT 2C and 5-HT 7 , but the physiological significance of these interactions is unclear [214]. Data showed that low kratom doses (1-5 g) induce stimulating effects, involving the release of neurotransmitters by reversible blockade of calcium channels. At higher doses (>15 g), it can cause sedative/narcotic effects, and the plant can be used as a general analgesic, as an opium substitute, or to treat opium withdrawal symptoms [215].
Studies have found that 7-hydroxymitragynine is the main contributor to the plant's toxicity and the development of addiction symptoms. In 2014, Singh et al. [51] reported a cross-sectional survey investigating the correlation between frequency and quantity of kratom consumption, and the risk of addiction development and the severity of withdrawal symptoms and craving in regular user [216]. Cessation of kratom use produced physical withdrawal symptoms similar to those of opiate addiction including pain, sleep disorders, muscle spasms, watery eyes, runny nose, hot flashes, fever, decreased appetite, diarrhea, and craving. Psychological withdrawal symptoms reported by users included restlessness, tension, anger, and depression [217] (Table 1).

Panax ginseng C. A. Mey (Asian Ginseng) and Panax quinquefolius L. (American Ginseng)
Ginseng is a perennial herbaceous plant of the family Araliaceae. Over twelve ginseng species were identified, although mainly Asian or Korean ginseng (P. ginseng) and American ginseng (P. quinquefolius) have been used for their therapeutic properties. Asian ginseng grows in East Asian mountains, while American ginseng is an endangered species that grows in deciduous forests of the west half of North America. Asian ginseng is an emblematic plant of traditional Chinese medicine, and is listed in the Shennong Ben Cao Jing, the most ancient Chinese book of herbal medications. A variety of pharmacological effects are attributed to ginseng. For example, it is used to improve intelligence, to treat impotence, to treat hemorrhage, to relax, and to slow aging [218]. American ginseng medical use is more recent and has gained popularity in Western countries over recent decades. Ginseng health benefits were demonstrated in many clinical studies in various fields: it has shown aphrodisiac, anti-inflammatory, anticancer (lung, liver, intestine, and stomach), antidiabetic, cardioprotective, gastroprotective, antiamnestic, and antioxidative (heart and kidney) properties [219]. The fresh root of ginseng can be directly chewed after peeling or soaked in wine for drinking and chewing. In China and Korea, it is boiled with chicken to prepare energy drinks, teas, and candies [218].
Asian and American ginseng contain a variety of pharmacologically active triterpene saponins, named ginsenosides. Ginsenosides are classified into two groups depending on the hydroxylation of their steroid core structure: the 20(S)-protopanaxadiol (PPD) and 20(S)-protopanaxatriol (PPT) groups. Rb1, Rb2, Rb3, Rc, and Rd are the main PPD-type ginsenosides, and Rg1 and Re are the main PPT-type ginsenosides. A total of 32 ginsenosides, including the abovementioned compounds, are found in in both American and Asian ginseng, but the two plants also possess specific ginsenosides. The presence of Rf, a PPD/PPT ratio lower than 2, and a Rb1/Rg1 ratio lower than 5 usually identify Asian ginseng. The content of ginsenosides is affected by seasons, geographical distribution, and processing (fresh ginseng, steamed ginseng or white ginseng, and sun-dried ginseng or red ginseng) [220]. After oral administration, ginsenosides are mainly metabolized in the gastrointestinal tract and the liver, undergoing successive deglycosylations: Rg3 is a metabolite of Rb1, Rb2, Rb3, Rc, and Rd, and is further metabolized to Rh2; Rg2 is a metabolite of Re; and Rh1 is a metabolite of both Rg1 and Rg2. Ginsenosides have low oral bioavailability, owing to their low membrane permeability and their degradation in the gastrointestinal tract [219]. Rg1 induces NO synthesis in endothelial cells and perivascular nerves, and increases vascular smooth muscle sensitivity to NO, prolonging the erection in males and enhancing sexual potency. In addition, P. ginseng was proved to increase testosterone, LH, and FSH in healthy volunteers through Rg1 and Rb1, enhancing libido. Re increases extracellular dopamine and acetylcholine in rat brains, while Rb1 increases choline reuptake at the synapses. Rb1, Rb2, Rc, Re, Rf, and Rg1 are agonists of GABA A receptors and Rc is also an agonist of GABA B receptors. These modulations of several neurotransmission pathways may have an effect at different levels of the hypothalamus-pituitary-testis axis [221]. Mancuso and Santangelo recently reviewed the effects of ginsenosides on the immune system (e.g., modulation of the immune response, anti-inflammatory effects), the nervous system (e.g., regulation of the stress axis, improvement of memory and learning functions), and the cardiovascular system (e.g., improvement of cardiac performance, cardioprotective effects) [222].

Pausinystalia johimbe (K. Schum.) Pierre ex Beille (Yohimbe)
Pausinystalia johimbe (K. Schum.) Pierre ex Beille, also known as yohimbe, is an evergreen tree of the Rubiaceae family that mainly grows in the tropical region of the African West coast, where the bark has been consumed as an aphrodisiac for the treatment of erectile dysfunction [157,232].
The bark of the plant contains several structurally related indole alkaloids, yohimbine being the most abundant one (10-15% of total content), followed by its stereoisomers α-yohimbine, β-yohimbine, ψ-yohimbine, corynanthine, allo-yohimbine, and yohimbic acid [233,234]. Yohimbine is marketed as a pharmaceutical prescribed for the treatment of erectile impotence and has been used in multiple clinical trials as a probe to identify abnormal physiological and affective responses to increased noradrenergic signaling, especially in patients with panic disorders [235,236]. Yohimbine is a potent selective α 2 R antagonist with weaker α 1 R antagonist activity that blocks the presynaptic feedback inhibition of noradrenaline release, prolonging the excitatory effects of noradrenaline at postsynaptic α 1 R and β-receptors [237,238]. Yohimbine has a relatively short half-life due to an extensive hepatic metabolism, which produces two main hydroxylated metabolites, 11-and 10-hydroxyyohimbine, that are rapidly excreted in urine [239,240]. There is increasing interest in botanic dietary supplements containing yohimbine extracts in the context of sexual and body enhancement [241].
Yohimbine readily passes the blood-brain barrier after absorption, causing an increase in sympathetic tone and blood pressure through the blockade of central medullary α 2 R [242], and provokes noradrenergic perturbation in limbic forebrain structures like amygdala and locus coeruleus, leading to mood and behavior alterations (Table 1). Due to these potential cardiac and neurological adverse effects, yohimbine was used in patients with difficulties to reach orgasm, with erectile dysfunction, or with low libido, mainly before the emergence of phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), which present a better safety profile [243,244]. The yohimbine mechanism of action is currently unclear. There is evidence suggesting that yohimbine increases libido by blocking α 2 R in the locus coeruleus, which is involved in the control of the erection. Peripherally, it was suggested that yohimbine enhances NO release from cavernosal endothelial cells, producing a relaxation of smooth muscle cells and consequent erection, increasing sexual potency [3,6,237]. Moderate to severe adverse effects like sweating, flushing, hypertension, tachycardia, palpitations, bronchospasm, chest pain, and atrial fibrillation are reported after deliberate or accidental ingestion, while lethal intoxications are extremely rare [245,246].

Piper methysticum G. Forst. (Kava)
Native to Western Pacific islands where the shrub is traditionally called "ava", "wati", or "yagona", kava (Piper methysticum G. Forst) grows in humid and shaded areas of tropical regions. This is a perennial Piperaceae with a massive rhizome weighing up to a dozen kilograms [19]. Kava is considered as a sacred beverage in Pacific islands [247]. The plant has also been used in traditional medicine, first as a treatment for venereal diseases, then later as a sedative and treatment for anxiety and sleep disorders, to decrease fatigue, and to relieve pain [248].
Eighteen active compounds named kavalactones were identified in kava, but only six, i.e., methysticin, dihydromethysticin, kawain, dihydrokawain, desmethoxyyangonin, and yangonin, have been the focus of kava studies as they account for up to 96% of organic extracts (acetonic or ethanolic extraction). Kava also contains a variety of other non-lactone compounds, i.e., flavokawains A, B, and C, 5,7-dimethoxyflavanone, cinnamic acid bornyl ester, flavanones, fatty acids, and a chalcone. Kava effects may be the result of a synergy of the six major kavalactones [249]. Kava extracts produce a similar activity profile as that of benzodiazepines, which interact with GABA receptors, inhibit the MAO-B, and inhibit dopamine and noradrenaline reuptake in the CNS, inducing libido-enhancing properties [250]. In vitro studies of the hippocampus and other brain regions suggest that the sedative effects of kavalactones may be mediated by an increase in GABA A receptor binding sites [251,252]. It was demonstrated that several kavalactones are potent inhibitors of several CYP metabolic enzymes [253]. Oral pharmacokinetics of kawain (100 mg/kg) were determined in rats with and without co-administration of kava extract (256 mg/kg). The results showed that kawain was well absorbed, and more than 90% of the dose was eliminated within 72 h, mainly in urine [254].
Data on kava's safety profile obtained from clinical trials in patients with anxiety suggest generally good tolerability and safety for short-term use (1-4 weeks) at therapeutic doses. However, the use of kava at frequent and high doses can cause hepatotoxicity through the modulation of various CYP, which is also the cause of potential drug interactions [255], dermopathy [256], and cognitive disorders [257]. Sedation with drowsiness and dizziness is commonly reported in clinical trials with administration of kava or methysticin (Table 1), which may impair driving performances [148].

Ptychopetalum olacoides Benth. (Muirapuama)
Ptychopetalum olacoides Benth. is a popular Amazonian tree belonging to the Olacaceae family. It is also known in Brazil as marapuama or muirapuama [258]. The native communities have used its roots and barks as a treatment for depression, sexual dysfunction, and as a "nerve tonic" [259]. Roots are usually prepared in alcoholic infusion, but other formulations have also been employed (e.g., mixture of extracts, solutions, pills) [260].
Fatty acids such as uncosanoic, tricosanoic, and pentacosanoic acids account for up to 20% of the total lipophilic components of the plant [261]. Other compounds detected in muirapuama are fatty acid esters of sterols, coumarin, free fatty acids, and free sterol; a small quantity of β-sitosterol was also detected [262]. Based on ethnopharmacological data, it can be hypothesized that muirapuama interacts with the dopaminergic system, increasing libido; the noradrenergic system, inducing antidepressant effects; and the serotonergic system, modulating appetite. The antinociceptive effects of the plant were investigated in thermal and chemical models of nociception in mice. Data showed that the maximal effect was reached 6 h after administration of a low dose of muirapuama extract and produces significant and long-lasting (up 12 h) effects in both chemical and thermal tests of nociception in mice. In addition, higher doses, either acutely or subchronically (15 days), did not cause a worsening of adverse effects [263]. A few neurological side effects were reported in preclinical studies, including impairment of both short-and long-term memory and reduced locomotion [151,152] (Table 1).

Sceletium tortuosum (L.) N. E. Brown (Kanna)
Kanna, or Channa, is the traditional name of a succulent, perennial plant belonging to the Aizoaceae family (earlier Mesembrynantheaceae) that is indigenous to South Africa, where it is consumed by local tribes to relieve thirst and hunger and combat fatigue [264,265]. The dried aerial parts of the plant are commonly chewed or consumed as teas, decoctions, and tinctures and sometimes smoked or snuffed [266].
Kanna's main active compounds are mesembrine, mesembrenol, mesembrenol, and mesembrenone, which are synthesized in the plant through the condensation of phenylalanine and tyrosine amino acids. Kanna alkaloids inhibit serotonin reuptake and PDE4A, potentially enhancing sexual potency and libido [267][268][269]. In fact, the plant is widely sold over the Internet and specialized herbal shops to increase sexual performance, although its mechanism of action and effects were not clearly demonstrated. This dual inhibitory effect has been studied for the development of compounds for the treatment of cognition impairment, motor dysfunction, depression, and neurodegeneration [270]. Mesembrenone is the most potent inhibitor of PDE4A, while mesembrine is more selective towards the serotonin receptor. In addition, mesembrine is also an agonist of GABA A , δ 2 -opioid, µ-opioid, cholecystokinin-1, E4-prostaglandin, and melatonin-1 receptors at high doses, and shows antinociceptive effects in animal models [266,[270][271][272][273]. Recently, S. tortuosum has been marketed for the treatment of mild depression and to improve mood [274]. Zembrin ® , a standardized hydroalcoholic extract, was found to be safe and well-tolerated in preclinical studies with mild adverse effects (Table 1) and is widely sold as a dietary supplement [275]. Another commercially available product is Trimesemine™, a highly-concentrated mesembrine extract (3% mesembrine (w/w)) that shows a great upregulation of the expression of vesicular monoaminetransporter-2 (VMAT-2), increasing monoamines release as the primary pharmacological effect [276,277]. Kanna alkaloids are metabolized in the liver to O,N-demethylated or dehydroxylated compounds, which are then excreted as glucuronides or sulfates conjugates [277,278].

Other Plants
Little evidence was found on the psychiatric and neurological side effects of several sexual enhancers that were originally included in this review: A. Mexicana, E. longifolia, L. meyenii, T. diffusa, V. africana, and W. somnifera.
The safety of maca (Lepidium meyenii Walp.) and ashwagandha or Indian ginseng (Withania somnifera (L.) Dunal) is well-documented. Maca is an edible herbaceous plant of the Andes Mountains and has been used for centuries for improving male and female sexual function. A renewed interest for maca has been observed from the 1990s onwards, and pills, capsules, flour, liquor, and extracts are now massively produced and exported [279]. The plant, however, presents a good safety profile [279], and only one case of a manic-like episode following consumption in a patient without history of psychiatric disorders was reported [280]. Ashwagandha is an evergreen shrub of the family Solanaceae, which is cultivated in hot and dry areas of tropical and subtropical regions of the world. Ashwagandha has numerous applications in traditional Indian medicines and has been used for more than 5000 years as an aphrodisiac, antioxidant, antimicrobial, adaptogenic, diuretic, tonic, narcotic, immuno-stimulant, anti-inflammatory agent, anti-stress, antiulcer, among many other purposes. Positive effect in insomnia, anxiety, chronic stress, weight management, thyroid gland function, telomerase, cardio-respiratory endurance, muscle strength, recovery of male and female sexual function, and senescence was demonstrated in preclinical and clinical studies [164]. Excellent tolerability is generally reported after using ashwagandha for weeks at therapeutic doses, with statistically insignificant adverse effects compared to placebo [281,282].
Other plants have been little studied, although some of them are well-known remedies that have been used for many years. Further investigation is necessary to clearly understand the possible neurological and psychiatric effects caused by these plants. For example, damiana (Turnera diffusa Willd. Ex. Schult.), a Central American shrub of the family Passifloraceae, has been traditionally used for centuries as a stimulant and aphrodisiac, to spark male sexual drive and increase performance, and is still widely marketed [283]. Recently, the plant also proved to induce anxiolytic and antidepressant effects in preclinical studies [283,284]. However, no psychiatric or neurological side effects related to damania were reported. Another interesting example is Voacanga africana Stapf ex Scott-Elliot, a shrub/small tree of tropical Africa whose seeds have been recently commercialized as a poison, stimulant, aphrodisiac, and ceremonial psychedelic [285]. Although the plant contains a variety of indole alkaloids related to ibogaine, a well-known psychoactive substance from iboga (Tabernanthe iboga Baill.) that has also been used as an aphrodisiac [286], there is no evidence of positive effects on sexual function. In addition, although Voacanga africana alkaloids may modulate neuronal excitability and have positive effects in Alzheimer's disease [287,288], no neurological or psychiatric complications related to the plant were reported. There is also little information on the side effects of the Mexican poppy (Argemone mexicana L.) and Tongkat Ali (Eurycoma longifolia Jack.).
Other herbal aphrodisiacs that were not included in this literature review are commonly used, but data on their safety profile are also limited [14].

General Discussion
The psychiatric and neurological side effects caused by the consumption of herbal aphrodisiacs are mild, with mostly no consequences at therapeutic doses. Although rare, psychiatric side effects were mostly reported and included anxiety, depression, psychosis, and mania. Neurological effects included seizures, extrapyramidal symptoms, and withdrawal symptoms. Dizziness, sleepiness, fatigue, agitation, insomnia, and headaches were reported. As expected, all the plants involved are libido-enhancing aphrodisiacs altering neurotransmission, although ginseng (P. ginseng and P. quinquefolius) and yohimbe (P. johimbe), and kanna (S. tortuosum) also enhance sexual potency. Kratom (M. speciosa) and yohimbe presented the highest rate of side effects, but yohimbe's general toxicity is mainly cardiovascular, due to its effects on the NO pathway. These mild effects were not anticipated, considering the mechanism of action of these plants. However, they did not come as a complete surprise, because these plants have been used for centuries or millennia in traditional medicines and modern medicine has considerably benefited from these ingredients and preparations [289].
Few clinical reports and few data were found for the side effects of bitter orange (C. aurantium), muirapuama (P. olacoides), and kanna (S. tortuosum), and only preclinical reports were found for muirapuama. There were no reports on the side effects of damania (T. diffusa), the Mexican poppy (A. mexicana), and Tongkat Ali (E. longifolia). Although several of these plants have been used for centuries in traditional medicines, they have not been as extensively studied as the other plants included in this review. Therefore, this result was not surprising. Psychiatric and neurological side effects included headaches and hypnotic effects and were mild. Although the consumption of these plants appears safe, further studies should be conducted to better understand their positive and negative effects.
Herbal aphrodisiacs are readily available on the Internet and specialized shops and markets. Aside from sexual enhancement, these plants often have many other therapeutic applications and can be a part of the everyday diet of individuals. In addition, self-medication is frequent, as they are available without a prescription, and plant extracts provided by retail herbal stores may also be mislabeled or adulterated (e.g., heavy metals, pharmaceuticals) [290]. Consequently, these plants are often taken concomitantly with contaminants, medications, and other herbal therapies or dietary supplements: drug interactions represent the most significant health risks of herbal aphrodisiacs and psychiatric and neurological adverse effects have been reported [230]. Medical doctors should be aware of the potential drug interactions with aphrodisiacs and dietary supplements when prescribing a pharmaceutical drug.

Limitations
Considering the paucity of data and the frequent co-exposure to other psychoactive substances, conclusions can be hardly drawn regarding the psychiatric/neurological adverse effects of several of the plants included in this article. In particular, more clinical studies with controlled administrations, to have a better grasp on doses and co-exposures, should be conducted to address this issue.
Another limitation is the choice of the keywords used for the literature search. The review focused on selected plants and their active ingredients, which were included after a preliminary screening of the literature. Other less common herbal aphrodisiacs might have eluded the search.
Additionally, only articles written in English, Italian, and French were included in the review, and reports written in another language were excluded. This limitation is particularly relevant considering the prevalence of traditional Ayurvedic, Unani, and Chinese medicines in East Asia and diasporas [291].

Materials and Methods
A comprehensive literature search was conducted using the PubMed, Scopus, and Web of Science bibliographic databases to identify scientific reports on the psychiatric and neurological complications associated with the use of A. catechu, A. mexicana, C. aurantium, E. longifolia, L. meyenii, M. speciosa, P. ginseng, P. quinquefolius, P. johimbe, P. methysticum, P. olacoides, S. tortuosum, T. diffusa, V. africana, and W. somnifera. Database-specific search features with truncations (represented by an asterisk in this article) and multiple keywords (represented by quotation marks in this article) were employed. The search terms employed were addict*, anxiety, anxious, "brain disorder *", cognit *, depression, depressive, hallucin *, insomnia *, mania *, manic, mental, panic, "personality disorder *", psychiatry *, psychosis, psychotic, or schizoph * in combination with the following terms for each plant:
Further studies were retrieved from the reference list of selected articles and reports from international institutions such as the World Health Organization (WHO), the US Drug Enforcement Administration (DEA), and the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).
Records reporting the psychiatric and/or neurological adverse effects associated with the use of the selected plant species in humans were included; only articles written in English, French, and Italian were included. Databases were screened up until June 2020 and references were independently reviewed by three of the authors to determine their relevance to the present article.

Conclusions
Most of the sexual enhancers of plant origin included in this review appeared to be safe at therapeutic doses, and few psychiatric and neurological side effects were reported. Yohimbe mainly was involved in intoxication cases, but its cardiovascular toxicity is more concerning than its psychiatric and neurological adverse effects. In addition, causality was often difficult to determine, especially in case reports and self-reports, in which co-administration of other substances and herbal formulations is prevalent. Interactions with pharmaceuticals or other herbal supplements are more common and may pose a significant health threat.
The mechanisms underlying psychiatric and neurological disorders are multifaceted, often involving multiple CNS pathways and receptors, and are not fully understood. Similarly, herbal aphrodisiacs often contain multiple active ingredients with multiple mechanisms of action that are yet to be fully characterized. Consequently, the mechanisms underlying the psychiatric and neurological side effects associated with herbal aphrodisiac use is little-known.
Other sources of aphrodisiacs affecting the CNS are available, such as synthetic or semi-synthetic drugs and natural substances of animal origin, which may also induce psychiatric or neurological effects. Although aphrodisiacs are mainly obtained from plants, these substances may also be worthy of investigation. It is also important to consider that plants that do not induce psychiatric or neurological adverse effects are not necessarily harmless, and could exhibit another type of toxicity (e.g., cardiovascular, hepatic, and renal toxicity), which was not the focus of the present review.
Author Contributions: P.B. and J.C. designed the study; A.F.L.F. and F.P.B. approved the design. P.B., A.F.L.F., A.T. and J.C. collected and organized the data and drafted the manuscript. All the authors contributed to the revision of the manuscript and approved the final content. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.

Conflicts of Interest:
The authors declare no conflict of interest.