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

Authors:
  • University Politecnica delle Marche of Ancona

Abstract and Figures

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.
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Pharmaceuticals 2020, 13, 309; doi:10.3390/ph13100309 www.mdpi.com/journal/pharmaceuticals
Review
Pharmacology of Herbal Sexual Enhancers: A Review
of Psychiatric and Neurological Adverse Effects
Pietro Brunetti 1, Alfredo Fabrizio Lo Faro 1, Anastasio Tini 2, Francesco Paolo Busardò 1,* and
Jeremy Carlier 1,2
1 Unit of Forensic Toxicology, Section of Legal Medicine, Department of Excellence of Biomedical Sciences
and Public Health, Marche Polytechnic University, 60126 Ancona, Italy; pietrobrunetti40@gmail.com (P.B.);
fabriziolofaro09@gmail.com (A.F.L.F.); jerem.carlier@gmail.com (J.C.)
2 Unit of Forensic Toxicology, Section of Legal Medicine, Department of Anatomical, Histological, Forensic,
and Orthopedic Sciences, Sapienza University of Rome, 00198 Rome, Italy; anastasio.tini78@gmail.com
* Correspondence: fra.busardo@libero.it; Tel.: +39-071-5964727
Received: 9 September 2020; Accepted: 12 October 2020; Published: 14 October 2020
Abstract: 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.
Keywords: aphrodisiac; sexual enhancer; plant; pharmacology; toxicology; psychiatry; neurology;
adverse effect
1. 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 drugs during intercourse, i.e., chemsex, is on the rise [2]. Nowadays, sexual
Pharmaceuticals 2020, 13, 309 2 of 52
performance anxiety, which contributes to psychogenic erectile dysfunction, is estimated to affect 9
to 25% of men in the United States, and phytotherapy is often employed as a treatment [3]. In 2007,
approximately 56% of infertile couples had sought medical care worldwide [4] and many of these
couples had opted for supportive complementary and alternative medicines to treat infertility. In
2010, in the United States, approximately 29% of 428 infertile couples had utilized an alternative
treatment after 18 months of observation, 59% of which had taken herbal therapy [5]. Natural
substances are mistakenly believed to be a safer alternative to modern medications with no side
effects. They are also readily accessible on the Internet and specialized markets without a
prescription. Consequently, the use of herbal supplements to enhance sexual drive has become
increasingly popular, and more than 300,000 intoxications were reported to poison control centers
over the last 20 years [6,7].
According to Sandroni, aphrodisiacs can be classified into three categories according to whether
they increase potency (i.e., effectiveness of erection in males), sexual pleasure, or libido (i.e., sexual
desire) [8]. Potency-enhancing substances typically induce vasodilation, often through the nitric
oxide (NO) pathway, inducing hypotension and potentially harmful cardiovascular effects (e.g.,
sildenafil and L-arginine). Sexual pleasure-enhancing substances cause tumescence and lubrication
of the genital mucosa, therefore increasing sensation (e.g., cantharidin). Libido-enhancing substances
alter the concentrations of specific neurotransmitters (e.g., dopaminergic and serotoninergic
pathways) or sex hormones (e.g., pituitary hormones and testosterone) in the central nervous system
(CNS) [8]. For example, methamphetamine is a synthetic illicit psychomotor stimulant affecting the
mesolimbic dopamine pathway, which plays an essential role in motivation and the reward system.
A substantial body of evidence shows that acute methamphetamine use is associated with enhanced
positive sexual experiences and libido, with a greater likelihood of engaging in high-risk sexual
behaviors. Sexual behavior, however, may be impaired due to chronic methamphetamine exposure
[9].
The modulation of neurotransmission is also involved in the mechanisms underlying many
psychiatric and neurological disorders. For instance, although not fully understood, the
dysregulation of monoaminergic systems, especially the decrease in serotoninergic, dopaminergic,
and adrenergic neurotransmissions, seems to be the primary cause of depression [10]. Contrariwise,
mania is believed to be the consequence of an excess of the same monoamines in specific regions of
the brain [11]. Schizophrenia, however, mainly involves dopaminergic and glutamatergic
neurotransmissions [12]. In neurology, a deficit of dopamine due to the death of cells in the substantia
nigra is the primary cause of Parkinson’s disease, while Alzheimer’s disease is due to the
degeneration of the hippocampus and the raphe nuclei, affecting the cholinergic pathway [13]. The
drugs approved to treat psychiatric and neurological conditions mainly target these
neurotransmission pathways.
Considering the mechanism of action of sexual enhancers, psychiatric and neurological adverse
effects associated with their consumption are strongly expected. In 2014, Corazza et al. reviewed the
psychoactive effects of four popular sexual enhancers [6]. In March 2020, Srivatsav et al. reviewed
the efficacy and the safety profile of several common aphrodisiacs used in the treatment of erectile
dysfunction, but the study was not exhaustive and psychiatric and neurological adverse effects were
not addressed [14]. In this review, we aimed to summarize and interpret the findings of cases and
preclinical and clinical studies reporting psychiatric and neurological adverse effects associated with
the use of aphrodisiacs of plant origin. A preliminary screening of the literature allowed for the
identification of several plants with potential psychiatric or neurological complications, which were
therefore included in this review: 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.
Pharmaceuticals 2020, 13, 309 3 of 52
2. 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.
Figure 1. Species-by-species flow diagram of literature search.
Pharmaceuticals 2020, 13, 309 4 of 52
Table 1. Reports of psychiatric and neurological adverse events associated with herbal aphrodisiacs.
Plant/Active
Ingredients Co-Exposure Study, Participants, Age, and Sex Neurological/Psychiatric Effects References
Areca catechu
L.
Fluphenazine decanoate,
procyclidine, flupentixol
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
27–70 (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 16–35, 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]
Pharmaceuticals 2020, 13, 309 5 of 52
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]
Benzodiazepines,
carbamazepine, levetiracetam,
phenobarbital, phenytoin,
sodium valproate, other
medications (not specified)
Observational study on 152 participants
with epilepsy, 50 users with a mean age
of 28.4 (95% CI: 25.3, 31.6) years, 23
males and 27 women; chewed 1–20
nuts/day for more than 5 years
Drowsiness [23]
Tobacco and alcohol-
Epidemiological studies of dependence
on 4031 participants
Case report of two women
Dependence, tolerance, withdrawal,
attentional bias, impaired work, impaired
time perception, and increased arousal
Poor concentration, lethargy,
despondency, and episodes of paranoia (1
individual)
[24]
Tobacco
Survey study on 200 participants, 171
males and 29 females aged 22–45 years;
chewed 4.3 nuts/day
Addiction [25]
Nicotine, arecaidine (1.46
µg/mL in urine), N-
methylnipecotate, cotinine
Cross-sectional survey on 113
participants with a mean (±SD) age of
40.0 (±12.6) years, 104 males and 9
females
Craving for BQ, addiction, depression, and
drowsiness [26]
Arecoline Methscopolamine
Cholinergic REM induction test on 34
participants: 14 bipolar patients with a
mean (±SD) age of 30 (±6.1) years, 6
males and 8 females; 15 HC volunteers
with a mean (±SD) age of 26.8 (±4.4)
years, 8 males and 7 females; and 5
subjects with a personal or family
history of affective disorders, age
ranged between 23 and 35 years, 2
males and 3 females; administered with
0.5 mg of arecoline
Shorter REM latency in patients with
primary affective disorders (1st and 3rd) [27]
Pharmaceuticals 2020, 13, 309 6 of 52
Glycopyrrolate
Pilot dose–response study on 24
participants, 8 bipolar subjects and 16
HC monozygotic twins; administered
with 1 or 12 mg of arecoline IP and 4 or
12 mg SC
Nausea, vomiting, increased anger,
confusion, depression, fatigue and tension,
decreased elation, friendliness, and vigor
[28]
Glycopyrrolate
Arecoline REM induction test on 97
participants: 20 MDD patients with a
mean age of 46.6 years (range 22–83), 8
males and 12 females; 19 MDD+ANX
patients with a mean age of 40.0 years
(range 21–47), 7 males and 12 females;
18 ANX patients with a mean age of
32.2 years (range 22–51), 8 males and 10
females; 14 ANX+MDD patients with a
mean age of 32.8 years (range 23–38), 4
males and 10 females; and 26 healthy
controls with a mean age of 36.4 years
(range 20–87), 11 males and 15 females;
administered with 0.5 mg of arecoline
Rapid REM induction in MDD and
MDD+ANX patients compared to healthy
controls
[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 65.5
years (range 54–79), 4 males and 8
females; administered with 0.5 and 12
mg/h of arecoline for 1 to 6 h
Decreased knowledge memory,
psychomotor retardation, dysphoria, and
difficulty with verbal expression
[31]
Glycopyrrolate
Arecoline REM induction test on 30
participants: 10 with atypical
depression with a mean (±SD) age of
33.5 (±7.8) years, 4 males and 6 females,
and 20 HC with a mean (±SD) age of
34.5 (±13.8) years, 10 males and 10
Rapid REM induction in atypical
depressives without a history of panic
attacks or anxiety disorders compared to
HC
[32]
Pharmaceuticals 2020, 13, 309 7 of 52
females; administered with 0.5 mg of
arecoline
Glycopyrrolate
Catecholamine and ACTH responses to
an arecoline study on 31 participants: 15
MSA patients with a mean (±SD) age of
57.9 (±1.8) years, 8 males and 7 females;
6 PAF patients with a mean (±SD) age
of 52.3 (±1.8) years, 2 males and 4
females; and 10 HC with a mean (±SD)
age of 58.5 (±4) years, 7 males and 3
females; administered with 0.3 mg of
arecoline
Mild vertigo, nystagmus, nausea,
exacerbation of tremor, and alteration in
mood
[33]
Glycopyrrolate
Randomized, double-blind, placebo-
controlled study on 111 participants: 40
placebo-receiving subjects, including 20
depressed patients with a mean (±SD)
age of 39 (±12) years and 20 HC with a
mean (±SD) age of 28 (±6) years; 38
subjects receiving 0.5 mg of arecoline,
including 21 depressed patients with a
mean (±SD) age of 38 (±9) years and 17
HC with a mean (±SD) age of 28 (±6)
years; and 33 subjects receiving 1.0 mg
of arecoline, including 18 depressed
patients with a mean (±SD) age of 42
(±11) years and 15 HC with a mean
(±SD) age of 34.5 (±13.8) years
Shorter REM latency in depressed patients [34]
-
Cholinergic REM induction test on 48
participants: 33 MDD children with a
mean (±SD) age of 10.5 (±1.5) years, 26
males and 7 females and 15 HC
children with a mean (±SD) age of 10.2
(±1.6) years; administered with 0.5 mg
of arecoline over 60 min
Shorter REM latency in depressed children [35]
Pharmaceuticals 2020, 13, 309 8 of 52
-
Animal study on 63 male albino Wistar-
derived rats; administered with 0.5, 1.5,
or 3.5 mg/kg of arecoline SC before test
Accelerated decay of memory after chronic
administration [36]
-
Animal study on 96 female Sprague
Dawley rats; administered with 40 or 80
µg of arecoline
Decreased locomotory activity [37]
Citrus aurantium
L.
Chlordiazepoxide, valproic
acid, diazepam, sodium
pentobarbital, d-limonene
Animal study on 176 adult male Swiss
mice; administered with 0.5 or 1.0
mg/kg of EO (90.4% of d-limonene) and
1.0 mg/kg of four different fractions of
leaves extract orally
Increased hypnotic effect and enhanced
sleeping time induced by pentobarbital [38]
-
Randomized, triple-blind, clinical study
on 156 postmenopausal women: 52 CA-
receiving women with a mean (±SD)
age of 53.65 (±3.55) years, 52 lavender-
receiving women with a mean (±SD)
age of 54.21 (±3.86) years, and 52
placebo-receiving women with a mean
(±SD) age of 52.12 (±3.49) years; took 2 ×
500 mg/day of CA powder for 6 weeks
Headache, nausea, and hypnosis [39]
-
Randomized, triple-blind, clinical study
on 156 postmenopausal women: 52 CA-
receiving women with a mean (±SD)
age of 53.65 (±3.55) years, 52 lavender-
receiving women with a mean (±SD)
age of 54.21 (±3.86) years, and 52
placebo-receiving women with a mean
(±SD) age of 52.12 (±3.49) years; took 2 ×
500 mg/day of CA powder for 6 weeks
Headache and nausea [40]
Rosa damascena Mill.
Randomized, double-blind clinical
study on 99 female students with a
mean (±SD) age of 22.33 (±2.38) years,
equally parted into two intervention
Headache, nausea, and vomiting [41]
Pharmaceuticals 2020, 13, 309 9 of 52
groups and a control group; inhaled EO
of CA blossom at 0.5%
Mitragyna
speciosa Korth.
-
Cross-sectional study on 433
participants with a mean (±SD) age of
45.7 (±13.6) years, 350 males and 83
females; 149 regular users chewed 12
leaves/day, 168 occasional users
chewed 4 leaves/day, and 116 controls
Dizziness, freshness, sprightliness, fatigue,
shaking hands, headaches, decreased sexual
drive, poor concentration, distractedness,
difficulty sleeping, irritability, poor thinking
ability, impaired memory, laziness, and
social withdrawal
[42]
Modafinil
Case report of a kratom intoxication of
a 43-year-old male with chronic pain
and opioid withdrawal; took kratom tea
four times daily for 3.5 years
Withdrawal, drowsiness, and generalized
tonic-clonic seizure [43]
Datura stramonium L.,
cannabinoids, tricyclic
antidepressants, oxycodone
Case report of a kratom intoxication of
a 64-year-old male, found with 167 ± 15
ng/mL of mitragynine in urine
Seizures and coma [44]
heroin, cannabis, amphetamine,
methamphetamine,
mitragynine (67.5–75 mg/day)
Cross-sectional survey on 136
participants: 72 short-term users and 64
long-term users, age range = 36–65
years, 135 males and 1 female; took 3 ×
250 mL/day of kratom tea for 3.5 years
Loss of weight, tiredness, dose-dependent
stimulation/sedation, intense craving,
withdrawal, chronic fatigue, insomnia,
frequent sweating, and sudden nerve pain
[45]
-
Case report of a 44-year-old kratom
addicted male with a previous history
of alcohol and cocaine dependence;
took from 2 × 4 g/day to 4 × 10 g/day for
3 years
Wellbeing, euphoria, increased
productivity, industriousness, relaxation,
tolerance, withdrawal symptoms of
cravings, anxiety, restlessness, and itch
[46]
-
Cross-sectional study on 530 MS users,
528 males and 2 females (age not
reported); took MS tea 1–10 times daily
for 4–5 years
Increased alertness, dizziness, sedation, hot
sensation, hallucination, vomiting, hostility,
aggression, excessive tearing, inability to
work, aching of muscles and bones, jerky
movement of limbs, loss of appetite, weight
loss, insomnia, malaise, and restlessness
[47]
Amphetamine, haloperidol,
diphenhydramine,
Retrospective study on 52 participants
with a median age of 30.5 years (range:
Seizure, nausea, alteration of consciousness,
contraction, confusion, headache, dizziness, [48]
Pharmaceuticals 2020, 13, 309 10 of 52
codeine, depressants, unknown
chemical substance
2 days–81 years), 84.6% males and
15.4% females
syncope, myalgia, insomnia, fatigue, loss of
appetite, agitation, tremor, ataxia, dystonia,
and neonatal withdrawal
Wild dagga, wormwood,
alprazolam, synthetic
cannabinoid, synthetic
tryptamine, alcohol,
methamphetamine, risperidone
14 kratom exposures reported to the
Texas Poison Center Network of 11
males and 3 females aged between 18
and 48 years
Agitation, nausea, vomiting, confusion,
tremor, diaphoresis, drowsiness,
hallucinations, mydriasis, and abdominal
pain
[49]
Alcohol
Qualitative study on 34 male
participants: 22 regular users chewed
10–80 leaves/day for 3–50 years; 6
occasional users chewed 1–20
leaves/day for 1–6 years; 3 non-users;
and 3 ex-users
Loss of appetite, craving to eat kratom,
withdrawal, compulsion, impaired control,
preoccupation, loss of weight,
muscle/bone/back/joint aches,
cramps/numbness, anxiety, depressed
mood, dysphoria, moodiness, annoyance,
restlessness, irritability, autonomic nervous
system hyper/hypoactivity, chills, sneeze,
cough, illness/catch cold, sleepy, yawning,
watering eyes, runny nose, sticky mouth,
disturbances of behaviors and cognitive
functions, and fatigue
[50]
Mitragynine (291.9 mg/day)
Cross-sectional survey on 293 male
kratom users with a mean age of 28.9
years, 153 medium-term users and 140
long-term users; up to ≥3 × 350 mL/day
of kratom fresh juice
Sleeping difficulty, decreased appetite,
nausea, vomiting, muscle spasm, sweating,
fever, abdominal pain, headaches, hot
flashes, hiccups, shakiness or tremors,
severe muscle
pain and cramps, nervousness, sadness,
restlessness, anger, tension, depressed
mood, and craving
[51]
-
Qualitative study on 168 kratom users:
109 males, 13 females, and 44 others
(sex not specified)
Warmth/tingling, nausea/stomachache,
alternating chills/sweats,
dizziness/unsteadiness, vomiting, itching,
numbness in mouth/throat, visual
alterations, and sedation
[52]
Pharmaceuticals 2020, 13, 309 11 of 52
Alcohol, other botanicals,
benzodiazepines, narcotics,
acetaminophen
660 calls about kratom exposure
received by U.S. poison centers, the
median age was 28 years (range = 2
months–69 years, data available for 604
subjects), 472 males and 186 females
(data available for 658 subjects)
Agitation, irritability, drowsiness, and
nausea [53]
-
Cross-sectional study on 526 kratom
users with a mean age of 51.8 years;
took 3–17 leaves/day
Craving-fatigue syndrome, mood
symptoms, insomnia, and physical sickness [54]
Tramadol, codeine, morphine
Case reports of two kratom-addicted
subjects, a 60-year-old female who took
0.25 ounces of kratom every 4 h for
several months, and a 57-year-old male
Dependence, tolerance, irritability,
increased pain, anxiety, edginess, and leg
shaking
[55]
-
Retrospective study on 150 male
participants with a mean (±SD) age of
34.4 (±11.2) years; took up to ≥4 × 350
mL/day of kratom fresh juice
Withdrawal symptoms, anxiety, and
depression [56]
Morphine
Case report of a maternal (a 29-year-old
female) and neonatal kratom exposure;
took 3 × 18-20 g/day of kratom powder
Anxiety and maternal and neonatal
withdrawal [57]
-
Case report of a female infant’s NAS,
her mother took 3–4 kratom teas/day
during her pregnancy
Excessive sucking, irritability, sleeplessness,
and withdrawal [58]
-
Case report of a kratom overdose and
management of withdrawal of a 24-
year-old man with Asperger syndrome,
depression, and long-term substance
dependence; took 600 mg/day of
kratom
Unresponsiveness, seizures, and
withdrawal [59]
Lisdexamfetamine
Case report of a kratom intoxication of
a 19-year-old male with ADHD; took
several pills (2–8 g) per day for several
months
Seizures [60]
Pharmaceuticals 2020, 13, 309 12 of 52
Benzodiazepines
Case report of a 52-year-old kratom-
addicted female with a long-standing
history of MDD; took 1 tablespoon 4–6
times per day for 9 months
Increased depression, anxiety, suicidal
thoughts, exacerbation of chronic pain
issues, dysphoria, nausea, muscle aches,
sweating, goose bumps, and insomnia
[61]
-
Cross-sectional study on 95 male
participants: 70 kratom users with a
mean (±SD) age of 28.8 (±5.3) who took
3 glasses of kratom tea/juice daily, and
25 healthy controls with a mean (±SD)
age of 25 (±7.6)
Visual memory and new learning
impairment [62]
-
Cross-sectional study on 150 male
kratom users with a mean (±SD) age of
34.4 (±11.2) years; took up to ≥3
glasses/day for more than 6 years
Auditory, visual, tactile, and olfactory
hallucinations, persecutory, reference,
control and grandiose delusion thought
broadcasting, and withdrawal
[63]
Alcohol, clonazepam, cocaine
Brief report on 2321 kratom exposures,
of which 4 cases of NAS and 2 deaths
were reported, and 4 deaths for which
kratom was listed as a cause or
contributing factor to the death
Agitation, drowsiness, confusion, seizure,
withdrawal, hallucinations, respiratory
depression, coma, and cardiac or respiratory
arrest
[64]
Alcohol, other unknown
substances
Case reports of kratom intoxications
with 4 males with a mean age of 43.5
years (range = 44–67); case 2 took 4 × 10
g/day of kratom over 24 h
Seizure, sedation, withdrawal symptoms,
and dependence syndrome [65]
Opiate, methamphetamine,
methadone
Cross-sectional survey on 163 regular
kratom male users with a mean (±SD)
age of 37.1 (±10.9) years; took 1–3
glasses/day of kratom tea for more than
6 years
Weight loss, physical pain, loss of appetite,
fatigue, craving for opioid, insomnia, and
depression
[66]
-
Case reports of two kratom
intoxications: a 27-year-old male with
bipolar disorder and schizophrenia
who took 5 g/day of kratom for 3 years,
and a 26-year-old female with no
Restlessness, generalized body aches,
overwhelming anxiety, thoughts of suicide,
hallucinations, and withdrawal symptoms
[67]
Pharmaceuticals 2020, 13, 309 13 of 52
history of mental health disorders who
took 2–3 pills/day (20–30 g of
kratom/day) for 2 years
Dextroamphetamine
Case report of a 22-year-old male with
ADHD and kratom use disorder; took
kratom tea every 2 h daily (30 g at
maximum dosage) for 2 years
Tolerance, irritability, and withdrawal
symptoms [68]
Diphenhydramine
Case report of a 27-year-old male with a
history of ANX, ADHD,
benzodiazepine, and opioid use
disorders; took up to 4 × 8 mL/day
bottles of kratom for 1.5 years
Tonic-clonic seizures [69]
Alcohol, antidepressants,
benzodiazepines, cannabis,
cocaine, hallucinogens, opioids
(prescribed or illicit), tobacco
Online anonymous cross-sectional
survey on 2798 kratom users with a
mean(±SD) age of 40.2(±11.8) years,
1099 males and 1699 females; took up to
3 × 1–6 g/day of kratom
Sickness, dizziness, alertness, anxiety,
sleepiness, and withdrawal symptoms [70]
-
Cross-sectional quantitative study on
356 participants, 137 kratom users and
219 non-users aged between 18 and ≥37
years, 212 males and 144 females
Addiction, withdrawal symptoms, and
impaired social functioning [71]
Mitragynine
Scopolamine
Animal study on 36 male mice from the
ICR strain: 18 mitragynine-treated mice
administered with 5, 10, or 15 mg/kg IP
of for 28 days; 6 scopolamine-treated
mice; and 12 HC
Impaired working memory function and
reduction in locomotory activity [72]
7-hydroxymitragynine (0.15
mg/L in blood, 2.20 mg/L in
urine), zopiclone, citalopram,
lamotrigine
Fatal mitragynine intoxication of a
middle-aged male, found with 1.06 and
3.47 mg/L of mitragynine in blood and
urine, respectively
CNS depression [73]
Morphine, methamphetamine,
Animal study on male C57BL/6 mice;
administered with 1, 5, 10, or 20 mg/kg
IP 30 min before or immediately after
Decreased activity in the δ, θ, and β, but not
α band in the hippocampus and withdrawal [74]
Pharmaceuticals 2020, 13, 309 14 of 52
locomotor and consolidation tests, 30
mg/kg IP for 14 days for the withdrawal
induction and for 28 days for the
chronic study
Morphine, penicillin G
procaine, propofol, xylazine,
ketamine, naltrindole,
naloxonazine
Animal study on 39 male Fischer 334
rats; administered with 25, 50, 100, or
150 µg of mitragynine and 2.5, 5, 10, or
20 µg of 7-hydroxymitragynine
Increased morphine self-administration
after 7-hydroxymitragynine treatment [75]
Morphine, urethane, xylocaine
Animal study on 60 male Sprague
Dawley rats and other set of animals
used for in vivo electrophysiological
studies; administered with 1.0, 5.0 and
10.0 mg/kg of mitragynine IP
Impaired acquisition of spatial learning and
significant synaptic depression in the
hippocampal region at high mitragynine
doses
[76]
Panax ginseng C.
A. Mey
Fluvoxamine, venlafaxine
Case report of a 47-year-old female with
chronic depression; took 200 mg of
ginseng extract within 24 h
Hypomania [77]
-
Case report of a 26-year-old male with
history of suicidal thoughts; took 250
mg/day of Chinese ginseng for two
weeks
Restless, insomnia, agitation,
disorganization [78]
Contraceptive pill, ginsenosides
(4%)
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]
Pharmaceuticals 2020, 13, 309 15 of 52
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 (27–30%)
Single-blind, placebo-controlled clinical
study on 14- and a 17-year-old ADHD
males; administered with 2 × 250
mg/day of ginseng extract
Mild sedation [83]
Rg1, Rb1, Rg3, Re, Rc, Rb2, Rd,
Rf, Rh1, Rg2s, other minor
ginsenosides, escitalopram,
venlafaxine, paroxetine,
duloxetine, citalopram,
bupropion, fluvoxamine,
imipramine, trazodone
Open-label study on 35 MDD females
with a mean (±SD) age of 45.1 (±9.5)
years; administered with 2 g at day 1 of
red ginseng extract titrated at 3 g/day
for 4 weeks and maintained for another
4 weeks
Headache, insomnia, and hypersomnia [84]
Cannabis
Case reports on two ginseng
intoxications of 23- and a 79-years-old;
took ginseng ≅ 15 and ≅ 20 g/day,
respectively
Racing thoughts, anxiety, irritable mood,
labile affect, disorganized thought process,
constant distraction, and auditory
hallucinations,
[85]
Chemotherapies, ginsenosides,
malonylginsenosides
Open-label study on 30 patients with
cancer-related fatigue and under
chemotherapy with a median age of 58
(range = 48–68) years, 15 males and 15
females; administered with 2 × 400
mg/day ginseng root extract for 4 weeks
Pain, nausea, cognitive disturbance, and
seizure [86]
Pharmaceuticals 2020, 13, 309 16 of 52
Multivitamins, herbal
supplements
Case report of a 42-year-old female with
no history of psychiatric issue or illicit
drug use
Psychosis and confusion [87]
- Case report of a ginseng intoxication
(age, sex, and dose not specified) Mania [88]
Methadone
Randomized, double-blind, placebo-
controlled clinical study on 74 opioid-
addicted participants under methadone
maintenance treatment, 48 males with a
mean age of 40.64 years and 26 females
with a mean age of 39.0 years;
administered with 4 × 250 mg of root
powder
Sleepiness and agitation [89]
-
Case report of a 47-year-old male with
no history of psychiatric disorder; took
600 mg/day ginseng to increase energy
and sexual activity
Nervousness, aggressive behaviors,
irritability, increased psychomotor activity,
decreased sleep, and excessive talkativeness
[90]
Eicosapentaenoic acid,
docosahexaenoic acid, Rg1,
Rb1, Rg3
Open-label study on 40 ADHD children
with a mean (±SD) age of 8 (±1.45) years
31 males and 9 females; administered
with 3 mg/day ginseng extract for 12
weeks
Transitory headache (one case) [91]
Panax
quinquefolius L.
Phenelzine, bee pollen, other
natural medications
Case report of a 42-year-old female with
chronic depression, but no history of
manic episodes
Mania and hallucinations [92]
Ginkgo biloba L., ritalin, efamol
Open-label study on 36 ADHD children
with a mean (±SD) age of 10.2 (±3.7);
administered with 2 × 200 mg/day of
ginseng extract for 4 weeks
Increased impulsiveness, hyperactivity and
aggressiveness, headache, and tiredness [93]
Tamoxifen, other estrogenic
botanical supplements
Multicenter, prospective study on 788
with breast cancer; 103 used ginseng
after cancer diagnosis
Fatigue [94]
Pharmaceuticals 2020, 13, 309 17 of 52
Pausinystalia
johimbe (K.
Schum.) Pierre
ex Beille
(yohimbine)
Corynanthine (5, 20 mg/kg)
Animal study on 101 male Sprague
Dawley rats; administered with 5 or 20
mg/kg of yohimbine IP
Decrease in spontaneous locomotor activity,
overreaction to external stimuli, violent
tremors, convulsions, abnormal posture,
and decrease in body temperature
[95]
Xylazine,
Doxapram, 4-aminopyridine
Animal study on 82 red deer (Cervus
elaphus L.), administered with 0.063,
0.124, 0.125, 0.128, 0.189, 0.20, 0.21, 0.23,
0.24, 0.25, or 1.00 mg/kg of yohimbine
IV
Rapid reaction to external stimuli, anxiety,
and nervousness [96]
Desipramine, bupropion,
trazodone
Three case reports of manic symptoms
following yohimbine administration of
three psychiatric patients: a 41-year-old
male who took 10 mg of yohimbine
orally, and 20- and 43-year-old females
who took 20 mg of yohimbine in two
sessions and one session, respectively
Tremors, nausea, generalized restlessness,
diaphoresis, and palpitations [97]
-
Randomized, double-blind, placebo-
controlled study on 59 participants: 39
drug-free patients with agoraphobia
and panic attacks—11 males with a
mean (±SD) age of 36.8 (±8.2) years and
29 females with a mean (±SD) age of
38.8 (±10.1) years; and 20 HC—9 males
with a mean (±SD) age of 33.3 (±7.3)
years and 11 females with a mean (±SD)
age of 43.3 (±7.4) years; administered
with 4 × 5 mg of yohimbine capsules
Anxiety, nervousness, hot and cold flashes,
restlessness, tremors, and piloerection
[98]
Acetylsalicylic acid
Case report of an acute yohimbine
intoxication of a 16-year-old female;
took 250 mg of powdered yohimbine
Weakness, generalized paresthesia, loss of
coordination, dissociative state, severe
headache, dizziness, tremors, decreased
hearing, nausea, diaphoresis, and
intermittent palpitations
[99]
Pharmaceuticals 2020, 13, 309 18 of 52
-
Randomized, double-blind, placebo-
controlled study on 88 participants: 68
agoraphobic subjects with panic attacks
or panic disorder—19 males with a
mean (±SD) age of 38 (±9) years and 49
females with a mean (±SD) age of 40
(±1) years; and 20 HC—9 males with a
mean (±SD) age of 34 (±8) years and 11
females with a mean (±SD) age of 43
(±7) years; administered with 4x5 mg of
yohimbine capsules
Increased rate of panic attacks, anxiety [100]
-
Animal study on male hooded Lister
rats; administered with 2.5 or 5 mg/kg
of yohimbine IP for acute exposure
evaluation and 2.5 or 5 mg/kg daily for
5 days for chronic exposure evaluation
Decreased locomotory activity and
increased anxiety [101]
-
Randomized, double-blind, placebo-
controlled study on 65 participants: 45
depressed subjects with a mean (±SD)
age of 41 (±13) years—17 males and 28
females; and 20 HC with a mean (±SD)
age of 39 (±9) years—9 males and 11
females; administered with 4 × 5 mg of
yohimbine capsules
Drowsiness, nervousness, anxiety, fear,
sadness, depression, nausea, tremors, hot
and cold flashes, and muscle aches
[102]
Amitriptyline
Animal study on 12 male Sprague
Dawley rats; administered with 5
mg/kg IP weekly for 6 weeks
Profound hypothermia [103]
-
Animal study on six unrestrained
bonnet macaques (Macaca radiata É.
Geoffroy); administered with 0.10, 0.25,
0.50, or 0.75 mg/kg (0.93–9.74 mg) of
yohimbine orally
Distress symptoms, freezing behaviors,
clonic jaw movements, excessive yawning,
and sexual arousal
[104]
Pharmaceuticals 2020, 13, 309 19 of 52
Clonidine
Randomized double-blind placebo-
controlled study on 53 participants: 38
subjects with panic disorders with a
mean (±SD) age of 35 (±2) years—11
males and 27 females; and 15 HC with a
mean (±SD) age of 30 (±3) years—5
males and 10 females; administered
with 0.4 mg/kg of yohimbine over 10
min
Anxiety and panic attacks [105]
Glyburide, alcohol
Case report of an acute yohimbine
intoxication of a diabetic 63-year-old
man; took 100 × 2 mg of yohimbine
tablets in about 90–120 min
Anxiety and alertness [106]
Tolazoline, xylazine
Animal study on four healthy horses—
three mares and one gelding;
administered with 0.025 mg/kg of
yohimbine every 2 min until a maximal
dose of 2.0 mg/kg
Agitation, muscular tremors, mild
excitement, and reduction in xylazine-
mediated sedation
[107]
-
Clinical study on eight narcoleptic
participants, four males with a mean
age of 43.5 years (range 22–64) and four
females with a mean age of 26 years
(range 21–39); administered with 2.7,
5.4 mg of yohimbine tablets twice daily
up to 16.2 mg/day
Insomnia, tremors, and flushing [108]
Fluoxetine, TCAs, propranolol,
benzodiazepines
Four case reports of a 44-, two 45-, and
a 53-year-old males with PTSD; took
“high” quantity of over-the-counter
yohimbine
Sexual arousal, sweating, shaking, panic
attacks, and flashbacks [109]
[15O] H2O
PET scans in a single-blind fixed-order
study on nine participants with a mean
age of 30.7 years—three males and six
females; administered with 0.15 mg/kg
Panic attack (one subject) and increased
anxiety [110]
Pharmaceuticals 2020, 13, 309 20 of 52
up to a maximum dose of 10 mg of
yohimbine over 3 min
Morphine, U-50,488, SNC80
Animal study on 318 male OF1 mice
and male Sprague Dawley rats;
administered with 2 and 4 mg/kg of
yohimbine IP
Blockage of opioid-mediated spinal
antinociception [111]
benzodiazepines, [11C]
flumazenil
Animal study on three adult male
rhesus monkeys; administered with 0.4
mg/kg of yohimbine
Increased binding potential for BDZ
receptors in the hippocampus and anxiety [112]
-
Randomized, double-blind, placebo-
controlled study on 17 participants: 8
methadone-maintained subjects with a
mean (±SD) age of 38 (±2.6) years—6
males and 2 females; and 9 male HC
with a mean (±SD) age of 30 (±3.7)
years; administered with 4 mg/kg of
yohimbine over 10 min
Precipitation of withdrawal and craving
symptoms in methadone patients [113]
Xylazine, ketamine,
buprenorphine, gentamicin,
methamphetamine
Animal study on 73 male Long–Evans
rats; administered with 1.25 or 2.5
mg/kg of yohimbine IP after extinction
and 0.625 mg/kg after 21–51 days of
withdrawal
Reinstatement of extinguished
methamphetamine seeking behavior [114]
Cocaine, clonidine, RS-79948,
flupenthixol
Animal study on 14 adult squirrel
monkeys (Saimiri sciureus L.);
administered with 0.1 and 0.56 mg/kg
of yohimbine IP before the
reinstatement test
Reinstatement of extinguished cocaine
seeking behavior [115]
-
Randomized double-blind placebo-
controlled study on 13 male
participants with a mean (±SD) age of
24.9 (±2.2) years; administered with 0.4
mg/kg of yohimbine IV, procedure
repeated after 14 days
Increased restlessness, anxiety, and
impaired mood [116]
Pharmaceuticals 2020, 13, 309 21 of 52
Pentobarbital
Animal study on 12 adult male Sprague
Dawley rats; administered with 0.1, 1.0,
or 10.0 mg/kg of yohimbine IP
Suppression of P13 and N40 auditory
circuitry components at high doses and
increment of amplitude at low/moderate
doses
[117]
-
Case report of an acute yohimbine
intoxication of a 37-year-old male body
builder; took 5 g of yohimbine, found
with 5240, 2250, 1530, and 865 ng/mL in
blood 3, 6, 14, and 22 h, respectively,
after ingestion and 50 mg/L in urine at
admission
General malaise, vomiting, loss of
consciousness, and tonic-clonic seizures [118]
-
Randomized double-blind placebo-
controlled study on 24 claustrophobic
participants, 12 yohimbine-receiving
subjects and 12 placebo-receiving
patients, 79% females with a mean
(±SD) age of 24.46 (±8.65) years (males
not reported); administered with 2 × 5.4
mg of yohimbine pills, procedure
repeated after 14 days
Significant improvement in peak fear at the
one-week follow-up behavioral assessment [119]
Xylazine, ketamine,
pentobarbital, chloral hydrate,
cefazoline, heparin, heroin
Animal study on 22 male Sprague
Dawley rats; administered with 1.25
and 2.5 mg/kg of yohimbine IP 30 min
before reinstatement sessions
Stress and reinstatement of extinguished
heroin seeking behavior [120]
-
Randomized, double-blind, placebo-
controlled study on 24 male
participants: 12 athletes with an average
age of 29 years and 12 untrained HC
with an average age of 29.5 years;
administered with 0.4 mg/kg of
yohimbine IV
Anxiety [121]
Nicotine, acamprosate Randomized, double-blind, placebo-
controlled study on 35 participants: 12 Increase in alcohol craving symptoms [122]
Pharmaceuticals 2020, 13, 309 22 of 52
acamprosate-receiving subjects with a
mean (±SD) age of 44.4 (±1.6) years—11
males and 1 female; and 13 placebo-
receiving patients with a mean (±SD)
age of 44.1 (±1.9) years—11 males and 2
females; administered with 0.4 mg/kg
of yohimbine IV
Clonidine, 2-[18F]-fluoro-2-
deoxy-D-glucose
Randomized, double-blind, placebo-
controlled study on 22 participants, 11
patients with IBS with a mean (±SD) age
of 40.5 (±12.9) years and 11 HC with a
mean (±SD) age of 37.3 (±10.6) years;
administered with 40 mg of yohimbine
tablet
Increased anxiety and reduced brain activity
in the anterior cingulate cortex, amygdala,
dorsal brainstem, and posterior insula
[123]
Nicotine, ketamine, xylazine,
buprenorphine, bupivacaine,
penicillin
Animal study on 84 Long–Evans
juvenile rats; administered with 0.3 and
0.6 mg/kg of yohimbine IP before
operative sessions
Increased nicotine self-administration [124]
Alcohol, d-Phe CRF
Animal study on 60 rats (strain not
reported); administered with 1.25
mg/kg of yohimbine IP before alcohol
self-administration and reinstatement
sessions
Increased alcohol self-administration and
reinstatement of alcohol seeking behavior [125]
Caffeine, diphenhydramine,
alcohol
Two fatal case reports of acute
yohimbine intoxication of 23- and 37-
year-old males; found 7400 ng/mL in
iliac blood and 5400 ng/mL in heart
blood, respectively
Seizures, elevated vitals, and death [126]
Pioglitazone, naltrexone,
alcohol
Animal study on 193 genetically
selected msP male rats; administered
with 1.25 mg/kg of yohimbine IP 1 h
after naltrexone and before the
reinstatement session
Reinstatement of alcohol seeking behavior [127]
Pharmaceuticals 2020, 13, 309 23 of 52
Nicotine, caffeine,
Randomized, double-blind, placebo-
controlled study on 119 participants: 62
cocaine-dependent subjects with a
mean (±SD) age of 41.1 (±10.0) years—
32 males and 30 females; and 57 HC
with a mean (±SD) age of 33.1 (±12.6)
years—32 males and 30 females;
administered with 21.6 mg of
yohimbine capsule
Increase in anxiety and craving in cocaine-
dependent subjects [128]
-
Animal study on 768 AB strain wild
zebrafish larvae, 640 yohimbine-
receiving animals; administered with
10, 25, 50, 100, or 200 mg/L of
yohimbine solution, and 128 HC
anxiogenic at high concentrations [129]
MDMA, SCH-23390, atropine,
ketamine, xylazine
Animal study on 67 male Sprague
Dawley rats; administered with 2.0
mg/kg before reinstatement test and 5.0
mg/kg daily for 10 days for chronic
treatment
Anxiogenic effects and reinstatement of
extinguished MDMA seeking behavior [130]
naltrexone
Double-blind, placebo-controlled study
on 16 healthy women aged between 18
and 32 years: 5 yohimbine + naltrexone-
receiving patients, and 11-placebo-
receiving patients; administered with 16
mg of yohimbine orally alone and co-
administered with 50 mg of naltrexone
orally
Agitation, restlessness, anxiety, headaches,
nausea, light-headedness, vomiting,
weakness, lethargy, tremors, blockage of
analgesia in ipsilateral forehead, and
increase in electrically evoked pain in
forearm
[131]
Nicotine, THC
Randomized, double-blind, placebo-
controlled study on 95 participants: 39
cocaine-dependent subjects with a
mean (±SD) age of 41 (±1.7) years—12
males and 27 females; and 56 HC with a
mean (±SD) age of 33 (±1.7) years—32
Increased impulsivity in HC and slower hit
reaction time in female cocaine-dependent
subjects
[132]
Pharmaceuticals 2020, 13, 309 24 of 52
males and 34 females; administered
with 21.6 mg of yohimbine prior to two
cocaine exposure sessions
Hydrocortisone
Randomized, double-blind, placebo-
controlled study on 103 participants
with a mean (±SD) age of 24.79 (±0.36)
years—51 males and 52 females
randomly assigned to four
experimental groups (placebo,
yohimbine, hydrocortisone, yohimbine
+ hydrocortisone); administered with 20
mg of yohimbine orally
Decreased memory generalization in
females (both yohimbine and yohimbine +
hydrocortisone groups)
[133]
Naltrexone
Randomized, double-blind, placebo-
controlled study on 39 participants: 13
yohimbine-receiving patients and 10
placebo-receiving patients—13 males
and 10 females aged between 18 and 52
years; 5 yohimbine + naltrexone-
receiving females and 11 placebo-
receiving females aged between 18 and
32 years; administered with 16 mg of
yohimbine alone and co-administered
with 50 mg of naltrexone orally
Nausea, headache, malaise, pain, anxiety,
and sexual arousal [134]
-
Randomized, double-blind, placebo-
controlled study on 42 health
participants with a mean (±SD) age of
21.29 (±3.27): 21 yohimbine-receiving
subjects and 21 placebo-receiving
subjects—19 males and 23 females;
administered with 20 mg of yohimbine
orally 45 min before behavioral test
Anxiety, nervousness, nausea, decreased
motor and temporal impulsivity, and
increased reflection impulsivity
[135]
Alcohol, kavain (450.1 mg/L),
dihydrokavain (456 mg/L)
Alternated, double-blind, placebo-
controlled study on 24 participants with
Body sway and decreased reaction time
tasks [136]
Pharmaceuticals 2020, 13, 309 25 of 52
Piper
methysticum G.
Forst.
a mean age of 26.7 years (range = 18–
53), 10 males and 13 females; 12 subjects
received 500 mL of kava juice and 12
received placebo
Valerian
Cross-over study on 24 participants
with stress-induced insomnia, 9 males
with a mean age of 43.7 years (range
23–65) and 15 females with a mean age
of 44.6 (range 30–65) years;
administered with 120 mg/day of
standardized kava extract for 6 weeks
Dizziness, vivid dreams, and dry mouth [137]
-
Randomized, double-blind, placebo-
controlled study on 38 participants with
a previous history of GAD and a mean
(±SD) age of 51.7 (±11.6) years—7 males
and 31 females; administered 140
mg/day of standardized kava extract for
1 week and 280 mg/day for the next 3
weeks
Bad taste in mouth, difficulty achieving
orgasm, drowsiness, dry mouth, increased
appetite, muscle twitching, nausea, spasms
or drawing of muscles, sweating, tingling or
numbness, and trembling
[138]
Benzodiazepines, fluoxetine,
sertraline
Case report of a kava intoxication of a
45-year-old female with a family history
of essential tremor; took 65 mg/day of
kava extract for 10 days
Slow saccades, hypophonic speech,
generalized postural and tremor at rest,
severe generalized rigidity in axial and
appendicular muscles, severe akinesia, gait
disturbance with lack of balance, and
inability to walk
[139]
-
Randomized, double-blind, placebo-
controlled study on 141 participants
with neurotic anxiety: 71 subjects with a
mean age of 48.8 (range 18–69) years,
administered with 3 × 50 mg/day of
standardized kava extract for 4 weeks;
and 70 placebo-receiving subjects with
a mean age of 48.2 (range 18–69)
years—36 males and 105 females
Withdrawal, aggravation of anxiogenic
symptoms, and tiredness [140]
Pharmaceuticals 2020, 13, 309 26 of 52
-
Saccade and cognitive study on 28
participants: 11 kava-intoxicated
subjects with a mean (±SD) age of 38.1
(±10.3) years and 17 kava-users with a
mean (±SD) age of 33.1 (±7.0) years;
took 75–375 g of kava powder
Ataxia, tremors, sedation, disorientation,
and blepharospasm [141]
Kavain (55%)
Randomized, prospective, open study
on 68 perimenopausal females: 15 kava-
receiving subjects with a mean (±SD)
age of 51.5 (±1.1) years were
administered with 100 mg/day of
calcium plus kava for 3 months; 19
kava-receiving subjects with a mean
(±SD) age of 51.1 (±0.8) years were
administered with 200 mg/day of
calcium plus kava for 3 months; and 34
HC with a mean (±SD) age of 50.2 (±0.6)
years
Nausea [142]
Flunitrazepam, flumazenil
Animal study on 40 male sleep-
disturbed Wistar rats; administered
with 10, 30, or 300 mg/kg of a 96%
ethanol kava extract
Hypnosis (shorter sleep latency, increase in
the total non-REM time) [143]
-
Case report of an acute kava
intoxication of a 37-year-old male; took
a “too strong” kava tea
Leg weakness, severe vertigo, nausea,
vomiting, diaphoresis, and dizziness [144]
Hypericum perforatum L.,
alcohol, caffeine
Randomized, double-blind, placebo-
controlled study on 24 participants with
MDD and a mean (±SD) age of 42.9
(±8.8) years—20 males and 38 females;
took 3 × 2.66 g/day of herbal kava
tablets for 10 months
One case of withdrawal [145]
Dihydrokavain (26%), kavain
(21%), dihydromethysticin
Randomized, double-blind, placebo-
controlled study on 28 participants with
GAD and a mean (±SD) age of 30.1
Increased females’ sex drive and difficulty
to reach the orgasm in males [146]
Pharmaceuticals 2020, 13, 309 27 of 52
(18%), methysticin (14%),
yangonin (13%),
Desmethoxyyangonin (8%)
(±12.4) years—7 males and 21 females;
administered with 120 and 240 mg/day
of kavalactones in 3 g tablets of
standardized extract of kava roots
Dihydrokavain (26%), kavain
(21%), dihydromethysticin
(18%), methysticin (14%),
yangonin (13%),
desmethoxyyangonin (8%)
Randomized, double-blind, placebo-
controlled study on 58 participants with
GAD and a mean (±SD) age of 30.1
(±8.8) years, 20 males and 38 females;
administered with 120 or 240 mg/day of
kavalactones in 3 g tablets of
standardized extract of kava roots
Significant reduction in anxiety and
headaches [147]
Anxiolytics, antidepressants,
antinausea, antipsychotics,
painkillers, stimulants,
sedatives, meth/amphetamine,
cannabis, cocaine, ecstasy,
hallucinogens, opiates,
benzylpiperazine, synthetic
cannabis
Survey study on 434 participants with a
mean (±SD) age of 34.54 (±14.62)
years—36.41% males and 63.59%
females, 26 kava-users
Driving-impairment [148]
Kavalactones
Animal study on adult wild-type short-
fin outbred zebrafish with a 1:1 male-to-
female ratio; administered with 10, 20,
or 50 mg/L of water extract from
powdered kava roots for 20 min and 7.5
mg/L for 1 week
Sedation and immobility [149]
Methysticin DMSO
Animal study on 18 AD model mice—
12 APP/Psen1 strain and 6 wild-type
mice; administered with 6 mg/kg of
methysticin once a week for 52 weeks
Reduced movements [150]
Ptychopetalum
olacoides Benth.
Diazepam, pentylenetetrazol
Animal study on CF1 strain male adult
mice parted in eight groups (15–30
animals); administered with 30, 100, or
300mg/kg of ethanolic extract for 30
min
Reduced locomotion [151]
Pharmaceuticals 2020, 13, 309 28 of 52
MK801, DMSO, scopolamine,
physostigmine
Animal study on 66 CF1 strain male
adult albino mice; administered with 50
or 100 mg/kg of standardized ethanolic
and 100–800 mg/kg once a day for 21
weeks
Impairment of both short- and long-term
memories [152]
Sceletium
tortuosum (L.) N.
E. Brown
-
Randomized, double-blind, placebo-
controlled study on 21 participants with
a mean (±SD) age of 54.6 (±6.0), 9 males
and 12 females; administered with 25
mg/day of standardized extract
(Zembrin®) for 3 weeks
Headache, blurred vision, poor hearing,
nausea, vomiting, appetite increase, muscles
rigidity, drowsiness, confusion,
concentration difficulty, memory problems,
depression, anxiety, and ataxia
[153]
AD—Alzheimer’s disease; ADHD—attention deficit and hyperactivity disorder; ADD—attention deficit disorder; BQ—betel quid; CA—Citrus aurantium; CNS—
central nervous system; CPZ—cuprizone; EO—essential oil; HC—healthy controls; IBS—irritable bowel syndrome; IP—intraperitoneally; IV—intravenously;
MDD—major depressive disorder; MS—Mitragyna speciosa; MSA—multiple system atrophy; NAS—neonatal abstinence syndrome; NPDS—United States National
Poison Data System; PAF—pure autonomic failure; PTSD—post-traumatic stress disorder; REM—rapid eye movement; SSRIs—selective serotonin reuptake
inhibitors; SNRIs—serotonin and noradrenaline reuptake inhibitors; ST—Sceletium tortuosum; SUD—substances use disorder; TCA—tricyclic antidepressant;
TeCA—tetracyclic antidepressant.
Pharmaceuticals 2020, 13, 309 29 of 52
3. Discussion
3.1. 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
[160–163]. 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 [164–166], 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 [181–183]. However, it was also demonstrated that areca
alkaloids reduce GABA affinity for the GABAA 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].
3.2. Citrus
a
urantium 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
Pharmaceuticals 2020, 13, 309 30 of 52
have been used for centuries to treat tachycardia, rheumatism, insomnia, anxiety, epilepsy, and
gastrointestinal disorders and to enhance sexual desire [187–189].
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 [38,39,198–201]. 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-HT1A) 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 α- and 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.
3.3. 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 κ- and 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-HT2A receptors and the postsynaptic
stimulation of α2 adrenergic receptors 2R) in the CNS [212]. Recently, LaBryer et al. hypothesized
that kratom may have restored testosterone, luteinizing hormone (LH), follicle-stimulating hormone
Pharmaceuticals 2020, 13, 309 31 of 52
(FSH), and prolactin levels in a patient with hypogonadotropic hypogonadism [213]. Mitragynine
also binds adenosine A2A receptors, dopamine D2 receptors, and serotonin receptors 5-HT2C and 5-
HT7, 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).
3.4. Panax
g
inseng C. A. Mey (Asian Ginseng) and Panax
q
uinquefolius 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 GABAA receptors and Rc is also an agonist of GABAB
receptors. These modulations of several neurotransmission pathways may have an effect at different
Pharmaceuticals 2020, 13, 309 32 of 52
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].
American and Asian ginseng present a good safety profile with a few cases of mild
gastrointestinal and sleep disorders. Psychiatric and neurological side effects are rare, and causality
is difficult to ascertain [77,79,80,82–87,89–94]. In fact, most clinical studies with ginseng or
ginsenosides reported no psychiatric or neurological side effects or statistically insignificant effects
compared to placebo, and were not included in Table 1 [223–227]. A few cases of headache following
ginseng administration were reported without placebo control [84,91]. Insomnia, agitation, and
fatigue were more frequent [82–84,89,94], but still uncommon. More interestingly, several cases of
manic-like effects, such as confusion, agitation, irritation, nervousness, anxiety, and bizarre behavior,
without history of psychiatric disorder, were reported following ginseng use
[77,78,81,85,87,88,90,228]. These cases, however, were isolated and generally resulted from high
ginseng doses or with the concomitant use of other substances (e.g., phenelzine, cannabis, herbal
supplements); mania was not reported in clinical studies using ginseng alone or in combination. In
fact, ginseng toxicity mainly comes from drug interactions with cytochromes P450 (CYPs) CYP3A4
and CYP2D6 inhibitors and serotoninergic drugs, intensifying sedative effects or inducing cognitive
disorders or a serotonin syndrome [229–231].
3.5. 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 α2R antagonist with weaker α1R antagonist activity that blocks the presynaptic
feedback inhibition of noradrenaline release, prolonging the excitatory effects of noradrenaline at
postsynaptic α1R 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 α2R [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 α2R 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].
Pharmaceuticals 2020, 13, 309 33 of 52
3.6. 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 GABAA 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].
3.7. 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].
Muirapuama root bark produces a volatile oil containing α-pinene, α-humulene, β-pinene, β-
caryophyllene, camphene, and camphor. 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).
Pharmaceuticals 2020, 13, 309 34 of 52
3.8. 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 [267–269]. 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 GABAA, δ2-opioid, µ-
opioid, cholecystokinin-1, E4-prostaglandin, and melatonin-1 receptors at high doses, and shows
antinociceptive effects in animal models [266,270–273]. 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].
3.9. 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
Pharmaceuticals 2020, 13, 309 35 of 52
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].
3.10. 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.
3.11. 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.
Pharmaceuticals 2020, 13, 309 36 of 52
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].
4. 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:
A. catechu: “Areca catechu”, “areca palm”, “areca nut palm”, “betel palm”, “Indian nut”, “Pinang
palm”, arecaidine, or arecoline;
A. Mexicana: “Argemone mexicana”, “Mexican poppy”, “flowering thistle”, sanguinarine,
dihydrosanguinarine, dehydrocorydalmine, jatrorrhizine, columbamine, or oxyberberine;
C. aurantium: “Citrus aurantium”, “bitter orange”, “Seville orange”, “bigarade orange”, or
“marmalade orange”;
E. longifolia: “Eurycoma longifolia”, “tongkat ali”, “pasak bumi”, “Malaysian ginseng”,
eurycomanol, eurycomanone, or eurycomalactone;
L. meyenii: “Lepidium meyenii”, maca, or “Peruvian ginseng”;
M. speciosa: “Mitragyna speciose”, kratom, biak, mitragynine, or hydroxymitragynine;
P. ginseng and P. quinquefolius: “Panax ginseng”, “Panax quinquefolius”, ginseng, or
ginsenoside*;
P. johimbe: “Pausinystalia johimbe”, yohimbe, ajmalicine, allo-yohimbine, corynantheine,
pseudoyohimbine, raubasine, yohimbine;
P. olacoides: “Ptychopetalum olacoides”, “muira puama”, or muirapuamine;
S. tortuosum: “Sceletium tortuosum”, kanna, channa, kougoed, mesembrine, mesembrenone,
mesembrenol, or tortuosamine;
T. diffusa: “Turnera diffusa”, damania, or damianin;
V. Africana: “Voacanga africana”, voacamine, or voacangine;
W. somnifera: “Withania somnifera”, ashwagandha, “Indian ginseng”, or “poison gooseberry”.
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
Pharmaceuticals 2020, 13, 309 37 of 52
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.
5. 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.
Acknowledgments: In this section you can acknowledge any support given which is not covered by the author
contribution or funding sections. This may include administrative and technical support, or donations in kind
(e.g., materials used for experiments).
Conflicts of Interest: The authors declare no conflict of interest.
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... Native Khoi and San tribes of South Africa have been traditionally using "Kanna" plants as a pain reliever by chewing the plant material directly and smoking the residue after chewing [12,66,70]. However, recently, this chewable plant has been prepared in various forms such as capsules, gel caps, resin, teas, and tinctures, which can be used as a snuff and smoked [70][71][72]. Despite the extensive documented history of the psychological and biological effect, few studies have proved that the Sceletium plant possesses useful analgesic properties [10,28,66,70]. ...
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Upon stimulation with LPS, the activated MAPKs mediate the signaling cascades leading to the activation of NFκB in activated macrophages [4, 5]. Further, LPS-mediated splenocyte activation can initiate oxygen uptake to drive oxidative stress-induced inflammation in the immune cells leading to ROS production [6]. Mulder et al. suggested that in response to activation with interferon-γ (IFN-γ) and lipopolysaccharide (LPS), spleen-derived macrophages readily acquired a proinflammatory status (M1 type) indicated by the upregulation of nitric oxide (NO) production, prostaglandin E2 (PEG2), tumor necrosis factor-α (TNF-α), and interleukins through NFκB activation [7, 8]. These proinflammatory molecules participate in the development of inflammatory reactions [9, 10]. The expression levels of cytoprotective enzymes, which are a response to oxidative stress, are primarily regulated at the transcriptional level. The Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress and inflammation [11]. Nrf2 is an important protein that participates in the coordination of transcriptional induction for various antioxidant enzymes, which also protects them from LPS-stimulated inflammation [12]. Nrf2 is a member of the basic leucine zipper (bZIP) family of transcriptional activator proteins, and it is activated by endogenous products of oxidative stress. Nrf2 is bound to Keap-1 and stays in the cytoplasm. Due to the ‘inducers,’ Nrf2-Keap1 complex disrupts and Nrf2 undergoes rapid translocation to the nucleus, binds to antioxidant response elements (ARE), and induces the expression of antioxidant and phase II enzymes, such as heme oxygenase-1 (HO-1), NAD(P)H-quinone oxidoreductase-1 (NQO-1), gamma-glutamylcysteine synthetase (γ-GCLC), glutathione (GSH), and glutathione S-transferase A2 (GST-A2) [13]. This group of enzymes has cytoprotective, antioxidant, and anti-inflammatory effects in endotoxin-induced macrophages. Several new and natural compounds and crude herbal extracts of medicinal herbs induced the expression of phase II detoxifying enzymes in different cell types has been reported. A few of these reports, Nrf2-mediated genes employ antioxidant and anti-inflammatory activities [14]. Therefore, an effective strategy would be to reverse the negative effects of LPS-induced ROS generation through the exogenous supplementation of antioxidants. Kava-kava, scientifically known as Piper methysticum, is a shrub belonging to the pepper family Piperaceae. It is widely cultivated in various parts of the world, mainly in the Pacific islands. The aqueous root extract of kava has been consumed as a drink that has a strong odor and a pungent taste with sedative, anesthetic, and euphoriant properties. Kavalactones and chalcones are two major phytochemical ingredients present in this plant. The chalcones are derived from flavonoids with a basic molecular structure of two aromatic rings linked by an unsaturated three-carbon bridge. Chalcones in the kava plant can be recognized by their yellow appearance and are named flavokawains. Flavokawain A (FKA) is the major constituent of chalcones (0.46%) derived from kava extracts [15]. Splenocytes consist of a variety of cell populations such as T and B lymphocytes, monocytes, and macrophages, which have different immune functions and release different factors in response to the inflammatory and anti-inflammatory agents. A previous study indicated that FKA suppresses iNOS and COX-2 expression via blockade of NFκB and AP-1 activation in RAW 264.7 macrophages [16]. However, little is known about the anti-inflammatory activity of FKA in splenocytes. In this study, we further demonstrated the molecular signaling pathways associated with FKA-mediated antioxidant and anti-inflammatory properties in primary splenocytes isolated from the BALB/c mice that were challenged to the LPS-induced inflammation. 2. Materials and Methods 2.1. Reagents and Antibodies This study bought Roswell Park Memorial Institute (RPMI)-1640, fetal bovine serum (FBS), Dulbecco’s Modified Eagle’s medium (DMEM), and penicillin/streptomycin/amphotericin from Gibco BRL/Invitrogen (Carlsbad, CA, USA). We obtained LPS (from Escherichia coli 055: B5), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and 2,7-dihydrofluorescein-diacetate (DCFH2-DA) from Sigma-Aldrich (St. Louis, MO, USA). We purchased flavokawain A (FKA, %) from LKT Laboratories, Inc. (St. Paul, MN, USA). We obtained the antibodies for p65 NFκB, histone H3from Cell Signaling Technology Inc. (Danvers, MA). We purchased antibodies against iNOS, COX-2, Nrf2, NQO-1, and β-actin from Santa Cruz (Heidelberg, Germany). We procured mouse monoclonal antibodies against TNF-α, and IL-1β from Abcam (Cambridge, UK). We obtained anti-γ-GCLC and HO-1 antibodies from Gene Tex Inc. (San Antonio, TX, USA). We obtained all other chemicals and general lab equipment from either Merck & Co., Inc. (Darmstadt, Germany) or Sigma-Aldrich (St. Louis, MO, USA). 2.2. Laboratory Animals We purchased 6–8-week-old female BALB/c mice (20-25 g) from the National Animal Center (Taipei, Taiwan). They were maintained in a pathogen-free set up with a 12-h/12-h light/dull cycle. There was free access to water and rat chow (Oriental Yeast Co. Ltd., Tokyo, Japan) for all mice [17]. In accordance with “The Guidelines for the Care and Use of Laboratory Animals” suggested by the Chinese Society of Animal Science, Taiwan, all animal experiments in this study were performed as indicated. The animal conventions were endorsed by the Institutional Animal Care and Use Committee (IACUC) of China Medical University. 2.3. Primary Splenocyte Preparation Primary splenocytes were aseptically isolated from the 8–12-week-old female BALB/c mice and kept in the RPMI-1640 medium. This medium was supplemented with 0.1% of the penicillin-streptomycin-amphotericin solution and 2% of 50x tissue culture medium (TCM, a serum substitution purchased from Protide Pharmaceuticals, Inc., Lake Zurich, IL) [18]. Suitable cell numbers were evaluated using the trypan blue exclusion method and a hemocytometer. Segregated splenocytes from every animal were acclimated to a cell density of cells/mL of the RPMI-1640 medium. We procured RAW264.7 (the murine macrophage cell line) from the American Type Culture Collection (ATCC, Rockville, MD, USA). It was then cultured in 1% penicillin-streptomycin, DMEM containing 2 mM glutamine, and 10% heat-inactivated FBS at 37°C in a humidified atmosphere with 5% CO2. 2.4. In Vitro Stimulation Assays The primary splenocyte or RAW264.7 macrophage cultures were pretreated with FKA for 2 h. After incubation, PBS washed cells were exposed to the fresh medium supplemented with or without LPS (prepared in pH 7.2 PBS). Liu et al. reported that higher concentrations of (5–20 μg/mL) LPS cause significant cytotoxicity to the cells [19]. Also, Kwon et al. demonstrated the inflammation studies in RAW267.4 macrophages by using 1 μg/mL of LPS [16]. Based on this 2.5 μg/mL and 1 μg/mL concentrations of LPS were used for splenocytes and RAW264.7 cells, respectively, in the entire study. For the measurement of TNF-α, IL-1β, IL-2, IL-6, or IL-10 levels in the cell culture medium, approximately cells/well of splenocytes were cultured in a 12-well plate. These cells were either treated with FKA (0-30 μM, 72 h) to measure the effect of FKA on cytokine secretion (or) pretreated with FKA (0-30 μM, 2 h) followed by LPS (2.5 μg/mL, 72 h) to measure the protective effect of FKA on cytokine secretion from LPS-stimulated cells using the ELISA method. The cytokines, TNF-α, IL-1β, IL-2, IL-6, or IL-10 were quantified by their respective ELISA kits (R&D Systems, Minneapolis, MN, USA) using the manufacturer’s protocols [20]. 2.5. MTT Assay MTT colorimetric assay measured the effect of FKA on cell viability [21]. Splenocytes ( cells/mL in 96-well plate) or macrophages ( cells/mL in 12-well plate) were pretreated with FKA for 2 h, followed by treatment with or without LPS (2.5 or 1 μg/mL) for 72 h. After treatment, MTT (0.5 mg/mL) was added to each well and incubated at 37°C for 4 h. After the incubation period, using the 400 μL DMSO, MTT formazan crystals were dissolved and the absorbance (A570) was measured through an ELISA microplate reader (μ-Quant, Winooski, VT, USA). The cell viability was expressed as a percentage using the following formula: . 2.6. Measurement of Intracellular ROS Accumulation The intracellular ROS accumulation was measured by the DCFH2-DA fluorescence dye method [22]. Briefly, cells/mL were seeded in a 6-well plate (primary splenocytes) or cells/mL were seeded in a 12-well plate (RAW 264.7 macrophages) and then pretreated with different concentrations of FKA (for 2 h) followed by treatment with or without LPS. After incubation, 10 μM of DCFH2-DA was added to the culture medium and the incubation was continued for 30 min at 37°C. The intracellular ROS, as indicated by the dichlorofluorescein (DCF) fluorescence intensity, was measured using a Becton-Dickinson FACSCalibur flow cytometer for suspended primary splenocytes (Becton Dickinson, NJ) or fluorescence microscopy for adherent RAW 264.7 macrophages (200x magnification, Olympus, Center Valley, PA, USA). The ROS levels were measured by comparing the exhibited fluorescence intensity from any treated cells compared to the vehicle-treated cells and were assigned to 1-fold arbitrarily. 2.7. Preparation of Cell Extracts and Western Blot Analysis Approximately cells/mL of primary splenocytes (seeded in 60 mm dish) or cells/mL of RAW264.7 macrophages (seeded in a 100 mm dish) pretreated with different concentrations of FKA (2.5–30 μM) for 2 h followed by exposing to LPS (2.5 or 1 μg/mL) at different time points (1–24 h). The untreated cells were the control cells. After treatment, the cytoplasmic, nuclear fractions of the proteins were harvested using protein extracting reagents (Pierce Biotechnology, Rockford, IL, USA). The concentrations of extracted protein fractions were measured using the BCA protein assay method (Bio-Rad, Hercules, CA, USA). Equal quantities of denatured proteins (50 μg) were resolved on 8–15% gradient SDS-PAGE, followed by transfer on to PVDF membranes. Blocking buffer was used to block these (5% nonfat dry milk for 30 min) and then incubation with various primary antibodies overnight. On the next day, membranes were washed and incubated with secondary antibodies for 2 h. After the incubation, PBS-washed membranes were developed and the protein bands were visualized using a chemiluminescence substrate (Pierce Biotechnology, Rockford, IL, USA). Using AlphaEase (Genetic Technology Inc. Miami, FL, USA) densitometric analysis was carried out and the protein expression data were represented as fold over control. Throughout the western blot experiments, either β-actin (for cytosolic proteins) or histone (for nuclear proteins) proteins were considered internal protein controls [23]. 2.8. In Vivo Demonstration of Pro- and Anti-inflammatory Cytokine Levels in Control-, LPS-, or Con A-Stimulated Splenocytes Isolated from the FKA-Administered BALB/c Mice Eight BALB/c mice were randomly segregated into two groups of four mice each. These mice were orally administered with 0 (control) or 30 mg/kg of FKA (solubilized in 0.1% DMSO) for 4 h. At the end of the incubation period, all mice were sacrificed and primary splenocytes were aseptically isolated as per the procedure described above [18]. Primary splenocytes were seeded in 12-well plates ( cells/mL) and were stimulated with control (saline), LPS (2.5 μg/mL), or concanavalin A (Con A, 2.5 μg/mL) for 72 h. After the incubation period, the concentrations of secreted TNF-α, IL-1β, IL-2, IL-6, or IL-10 levels in the control-, LPS-, or Con A- stimulated cell culture medium were measured using the ELISA kits (R&D Systems, Minneapolis, MN, USA) in accordance with the manufacturer’s protocol. 2.9. Determination of Serum Lipase Concentrations in Cholecystokinin-8- (CCK-8-) Induced Experimental Pancreatitis of BALB/c Mice Twenty BALB/c mice were randomly placed into five different groups and each group was made up of four mice. The mice were administered either oral administration of FKA (in 0.1% DMSO) and/or intraperitoneal (IP) injections of cholecystokinin-8 (CCK-8). The treatments were as follows: (a) vehicle (0.1% DMSO), (b) 100 μg/kg of CCK-8 alone, (c) 15 mg/kg of FKA+100 μg/kg of CCK-8, (d) 30 mg/kg of FKA+100 μg/kg of CCK-8, and (e) 30 mg/kg of FKA alone. In the case of groups ‘c’ and ‘d,’ CCK-8 was injected into the mice for 0.5, 1.5, 2.5, and 4 h after the oral administration of FKA [22]. After the CCK-8 injections, the blood samples for the mice were collected from the retroorbital sinus and the serum lipase levels were measured by using a commercial serum lipase ELISA kit (R&D System, Minneapolis, MN, USA). 2.10. Statistical Analyses In this study, data were represented as () of three or more independent experiments. All data were analyzed using analysis of variance (ANOVA), followed by Dunnett’s test for pairwise comparison. Statistical significance was assigned as , , and compared to the untreated control cells and #,##, and ### compared to the LPS-treated group. 3. Results 3.1. FKA Mediated Differential Secretion Patterns of Pro- and Anti-inflammatory Cytokines in Primary Splenocytes We first determined the subtoxic dosage of FKA (Figure 1(a)) on primary splenocytes derived from the BALB/c mice. Primary splenocytes were treated with increasing concentrations of FKA (1 to 60 μM) or 2.5 μg/mL of LPS for 72 h. After incubation has concluded, an MTT assay was conducted to determine cell viability. The data showed that compared with control cells, splenocytes exposed to FKA did not enhance the proliferative state of splenocytes and did not induce any significant toxicity as well [24]. Based on these observations, 30 μM FKA has been used as the maximum concentration in the entire study (Figure 1(b)). Later, we tested the effect of FKA concentration on the secretion patterns of pro- and anti-inflammatory cytokines in the FKA-stimulated primary splenocyte cell culture medium. ELISA data showed that FKA dose dependently and significantly suppressed the release of proinflammatory TNF-α, IL-1β, and IL-2 but upregulated the release of anti-inflammatory IL-10 from primary splenocytes (Figures 1(c)–1(f)). This data suggested that FKA showed anti-inflammatory properties in primary splenocytes. (a)
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Introduction Erectile dysfunction (ED) is the inability to attain or sustain an erection for sexual intercourse. Affected men endorse difficulties with intimacy and feelings of guilt and shame. Although medical treatments are available, patients are reluctant to discuss ED with physicians and often use dietary supplements to attempt to treat their ED. As such, there is a need to better understand the effects of ingredients used in nutraceuticals for ED treatment. Objectives To summarize the literature on the efficacy and safety of the most common ingredients used in ED supplements. Methods 10 of the most common ingredients in ED supplements were reviewed using PubMed-indexed literature to assess their efficacy and safety in treating ED. Key findings were summarized to include historical use, active ingredients, prior animal studies, human studies, and toxicity. Results Nutraceuticals used in ED treatment include a variety of ingredients. Although L-arginine is a safe supplement with clinical data supporting improved erectile function, limited data exist on the efficacy of other ingredients in the treatment of ED. Conclusion Despite the growing use of supplements for treatment of sexual dysfunction, ED supplements remain poorly studied, with limited data demonstrating efficacy of individual ingredients. Further study is required to definitively determine the efficacy of nutraceuticals in ED treatment. Srivatsav A, Balasubramanian A, Pathak UI, et al. Efficacy and Safety of Common Ingredients in Aphrodisiacs Used for Erectile Dysfunction: A Review. J Sex Med 2020;XX:XXX–XXX.