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Influence of traditional Turnera diffusa var. aphrodisiaca (Damiana) extract on monoamine-and glutamate receptor-mediated neurotransmission

Authors:
  • Finzelberg GmbH & Co. KG
  • Finzelberg GmbH & Co KG
  • Vivacell Biotechnology GmbH

Abstract

Introduction: Damiana is an aromatic shrub endemic to tropical regions of America. It has been used as aphrodisiac by both genders since pre-Columbian times. Furthermore, commercial products containing 90% ethanolic Damiana leaf dry extract, are marketed as aphrodisiacs. Hydro-ethanolic extracts showed stimulated sexual behaviour in rats [1] and efficacy on mild erectile dysfunction in men [2]. Aromatase and PDE5 inhibition (EtOH 90% extract and single polyphenols) [3,4], and CNS-mechanisms, primarily attributed to apigenin [5], might contribute to sexual stimulation. Our aim was to analyze the traditional Damiana extract (EtOH 90% v/v) concerning effects on neurotransmission. Methods/Results: The influence on the uptake of neurotransmitters into rat synaptosomes was investigated. The Damiana extract inhibited the reuptake with IC50–values of 2.7±0.1 μg/mL (dopamine), 84.3±18.1 μg/mL (noradrenaline), and 237.4±7.9 μg/mL (serotonin), respectively. The ability of Damiana to interfere with glutamate receptors, was tested with hippocampus slice preparations from rats that received 60 mg/kg extract/ placebo daily for one week. The extract reduced glutamatergic neurotransmission provoked by electrical stimulation and antagonized actions of AMPAR and NMDAR agonists (about 1/3 lower amplitudes). Conclusion: We found CNS-effects of the traditional Damiana extract associated with antidepressant/ mood-enhancing and anxiolytic properties. They might contribute to the aphrodisiac activity.
Influence of traditional Turnera diffusa var. aphrodisiaca (Damiana) extract on
monoamine- and glutamate receptor-mediated neurotransmission
Felix Heiner1, Björn Feistel1, Kurt Appel2
1 Finzelberg GmbH & Co. KG, Koblenzer Strasse 48-56, 56626 Andernach, Germany 2 Vivacell Biotechnology GmbH, Ferdinand-Porsche Str. 5, 79211 Denzlingen, Germany
Introduction
Conclusions
References
Bonn Polyphenols 2018: 12th World Congress On Polyphenols Applications September 25 - 28, 2018, Bonn
Damiana (Turnera diffusa var. aphrodisiaca, Passifloraceae) is an aromatic, up to 2 m high
shrub endemic to tropical regions of America: Caribbean, Mexico, South America. Its dried
leaves have been used as an aphrodisiac by indigenous peoples of Mesoamerica since pre-
Columbian times (both genders). Besides essential oil, terpenes, and phytosterols, the
plant contains polyphenolic compounds such as flavonoids and tannins. Commercial
products in form of tablets, containing a 90% ethanolic Damiana dry extract with a DER
native of 57:1, are marketed as aphrodisiacs (THMP).
Pharmacological evidence and plausibility are delivered by several studies. Hydro-
ethanolic Damiana extracts had shown to stimulate sexual behaviour in rats [1] and
demonstrated a time-dependent efficacy on mild erectile dysfunction in men [2]. A variety
of mechanisms may contribute to the increase of sexual potency: 90% EtOH extract and
single polyphenols showed in vitro-inhibition of aromatase which might lead to higher
testosterone levels, having an impact on the libido of both genders [3,4]. Vasorelaxant
activity through NO-pathway and inhibition of PDE-V enhances blood flow in Corpus
cavernosum penis and clitoridis [4,5]. Also, central nervous actions, primarily attributed to
apigenin, may be part of the sexual stimulation [6].
Following this idea, the aim of our investigations was to analyze the traditional Damiana
leaf extract (EtOH 90% v/v; 50% native; manufactured by Finzelberg GmbH) concerning
effects on neurotransmitter receptors and uptake.
Monoamine neurotransmitter reuptake
The influence on dopamine, serotonin, and
noradrenaline uptake into rat synaptosomes by
the Damiana extract was measured.
The assays were initiated by addition of [³H]-
dopamine, [³H]-serotonin, or [³H]-norepine-
phrine to isolated rat synaptosomes and
graded concentrations of the extract in
incubation buffer. After incubation for 15 min
at 37 °C in the dark, samples were transferred
onto GF/C-filter plates and filter-bound
radioactivity was determined by a microplate
reader. The compounds GBR 12909 (DA),
imipramine (5HT), and protriptyline (NA)
served as reference inhibitors to approve the
suitability of the methods.
The calculated IC50-values revealed that the
Damiana extract is an outstanding inhibitor of
dopamine reuptake. Furthermore, noradrena-
line uptake was considerably inhibited and a
moderate inhibition of serotonin uptake could
be observed.
Neuro-
transmitter
Dopamine
(DA)
Noradre-
naline
(NA)
Serotonin
(5HT)
IC50 ±
SEM
[µg/mL] 2.7 ± 0.1
84 .3
±
18.1
237.4
±
7.9
AMPA and NMDA receptor modulation
The ability of the Damiana
extract to interfere with
glutamate receptors, was
tested ex vivo with
hippocampus slice prepa-
rations.
Midsections of the hippo-
campi from 8 adult male
Sprague-Dawley rats that
received daily administration
of 60 mg/kg Damiana extract
or placebo for 7 days were
excised. Electrical stimulation
of Schaffer collaterals lead to
release of glutamate, result-
ing in excitation of the
postsynaptic pyramidal cells.
Compared to placebo-treated
rats, Damiana treatment
attenuated this response,
visible through significantly
lower amplitude of
population spikes (lower
excitability, Fig. 2).
We found important CNS effects of the traditional Damiana extract that is used in
commercial products. AMPA-antagonism has been linked to anxiolytic response [7] and
reuptake-inhibition of monoamine neurotransmitter, as well as NMDA modulation, are
associated with mood-enhancing / antidepressant properties [8]. This might contribute to
the aphrodisiac activity of Damiana. Furthermore, it is known that sexual desire is not only
regulated by sex hormones; high levels of DA and NA also play their role. The mode of
action of flibanserin (for hypoactive sexual desire disorder) is based on this effect [9].
[1] Estrada-Reyes, R. et al.; Turnera diffusa Wild (Turneraceae) recovers sexual behavior in sexually exhausted males.
J Ethnopharm 123: 423-429, 2009
[2] Feistel, B., Walbroel, B.; Traditional aphrodisiaca Turnera diffusa WILLD. new human aspects. Poster at 15th Internat.
Congress PHYTOPHARM, July 25-27 2011, Nuremberg, Germany, 2011
[3] Zhao, J. et al.; Anti-aromatase activity of the constituents of Damiana (Turnera diff.). J Ethnopharm 120: 387- 393, 2008
[4] Feistel, B., Appel, K., Pischel, I.; Traditional aphrodisiac Turnera diffusa WILLD. new pharmacological aspects about
Damiana. PHYTO Therapie Austria 3-18: PA7, 2018
[5] Estrada-Reyes, R., Carro-Juárez, M., Martínez-Mota, L.; Pro-sexual effects of Turnera diffusa Wild (Turneraceae) in male
rats involves the nitric oxide pathway. J Ethnopharm 146: 164-172, 2013
[6] Kumar, S. et al.; Pharmacological evaluation of bioactive principle of Turnera aphrodisiaca. Indian J Pharm Sci 70: 740 -
744, 2008
[7] Andreasen, J.T. et al.; Differential role of AMPA receptors in mouse tests of antidepressive and anxiolytic action.
Brain Res 1601: 117-126, 2015
[8] Pochwat, B. et al.; NMDA antagonists under investigation for the treatment of major depressive disorder. Expert Opin
Investig Drugs 23: 1181-1192, 2014
[9] Stahl, S.M.; Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in
hypoactive sexual desire disorder. CNS spectrums 20: 1-6, 2015
Acknowledgement: We would like to thank Prof. Dr. Wilfried Dimpfel, NeuroCode AG, for his technical guidance.
In order to test the interference with specific glutamate receptors, glutamatergic
neurotransmission was tested in the presence of potent and selective agonists. There was
no difference between responses of Damiana-pretreatment only and Damiana + AMPAR
agonist (S)-(-)-5-Fluorowilardine (Fig. 3). The agonist was not able to exert its usual action
due to modulated AMPAR-mediated neurotransmission by the Damiana extract: direct
antagonism may be possible. Also, NMDAR-mediated transmission was slightly, but
significantly, influenced by the extract, implying a modulation of this particular glutamate
receptor, too.
Fig. 1: Inhibition of neurotransmitter reuptake.
n=4; deviation expressed as SEM
Fig. 2: Damiana reduced glutamatergic neurotransmission provoked by
electrical stimulation
Fig. 3: Damiana antagonized actions of AMPAR agonist Fluorowilardine
Fig. 4: A multitude of mechanisms may contribute to sexual arousal and potency of both genders
Inhibition of PDE5
improved
blood circulation
Inhibition of
aromatase
stabilization of
testosterone level
Higher activity
of DA/NA
increased sexual desire
AMPA modulation
anxiolytic effect
Reuptake-inhibition
of monoamines;
NMDA modulation
mood
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Full-text available
Poster
The leaves of Turnera diffusa var. aphrodisiaca (Damiana), a shrub native to Central America and the Caribbean, have been used as a traditional aphrodisiac to boost sexual potency by the native peoples of Mexico, including the Mayan Indians. In 1874 the Damiana herb was added as a tonic and aphrodisiac to the US American pharmacopoeia [1]. The herb was used in Mexico as a “love potion” by both genders. In the Western world, Damiana preparations have been well established in different pharmacopeias (firstly BPC in 1934, followed by USP and DAB). It`s most cited indication is aphrodisiac in traditional forms of teas, hydro-ethanolic tinctures/extracts or dried preparations hereof. Since 2016/2017 some commercial finished products in form of tablets, containing an EtOH 90% v/v Damiana dry extract (DER native 5-7:1), are marketed as traditional herbal medicinal product as aphrodisiacs. However, proven scientific data are scarce. Hydro-ethanolic Damiana extracts were shown to stimulate sexual behaviour in rats [1] as well as an EtOH 60% w/w extract was tested in men over 8 weeks to demonstrate a time-dependent efficacy on mild erectile dysfunction [2]. Aim of our investigations was to analyze the effects of Damiana leaf extract (EtOH 90% v/v) in “aphrodisiac relevant” in vitro models. Phosphodiesterase-5 enzyme activity was dose dependently inhibited (IC50-value ~ 30 µg/mL]. Furthermore an Aromatase enzyme activity was inhibited by the Damiana extract (IC50 ~ 100 µg/mL) as well as by single plant constituents herein (e.g. IC50 Acacetin 1.5 µg/mL; Apigenin 15 µg/mL). However Damiana leaf extract (EtOH 90% v/v) had no effect on melanocortin-4 receptor and on estrogen receptor binding, which might be an advantage with respect to unwanted side effects. In summary our results agree with previous reports on PDE-5 and Aromatase inhibition, showing similar effects of other Damiana preparations. This results help to elucidate the mode of action for this traditional aphrodisiac. [1] Bauer, R.; Zeitschrift für Phytotherapie 2017; 38: 275-280 [2] Feistel, B., Walbroel, B.; Traditional aphrodisiaca Turnera diffusa WILLD. – new human aspects. Poster at 15th International Congress PHYTOPHARM 2011, July 25-27, 2011, Nuremberg, Germany
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Flibanserin is a novel multifunctional serotonin agonist and antagonist (MSAA) that improves sexual functioning in premenopausal women who suffer from reduced sexual interest and desire.
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In the present investigation, pharmacological evaluation of apigenin, a bioactive principle of Turnera aphrodisiaca Ward (Turneraceae) was carried out. Apigenin was evaluated for antianxiety activity at a dose of 2 mg/kg using well established models of anxiety, the hole board test, light/dark test and mirrored chamber test. Apigenin significantly increased head dipping in hole board test. Further, apigenin increased latency to leave light zone and the time spent in light compartment of light/dark model of anxiety. Apigenin also decreased the latency time to enter the mirrored chamber, and increased the total time spent/number of entries in the mirrored chamber with respect to control. All these observations confirmed the anxiolytic activity of apigenin. At a higher dose (about 12 fold the anxiolytic dose), apigenin showed mild sedative activity in actophotometer as it decreased activity scores. It (2, 5 or 10 mg/kg) was found to be devoid of anticonvulsant, antidepressant and antistress activity in MES-induced convulsion test, despair swim test and cold swimming endurance test, respectively. In tail immersion test for six hours, apigenin exhibited excellent dose dependent analgesic activity, which was comparable to that of morphine sulphate (5 mg/kg). Maximum activity was observed 30 min after the administration of 10 mg/kg dose of apigenin.
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In folk medicine, Turnera diffusa Wild (Turnera diffusa, Turneraceae) is considered as an aphrodisiac, but its ability to restore copulation in sexually inhibited subjects has not been reported. To determine whether Turnera diffusa recovers sexual behavior in sexually exhausted (SExh) male rats and to identify the main components in an aqueous extract. SExh males were treated with Turnera diffusa, 20-80 mg/kg, yohimbine, 2 mg/kg, or vehicle. Yohimbine and Turnera diffusa (80 mg/kg) significantly increased the percentage of males achieving one ejaculatory series and resuming a second one. In addition, Turnera diffusa significantly reduced the post-ejaculatory interval. These effects were not associated to an increase in locomotor activity or anxiety-like behaviors. The HPLC-ESI-MS analysis showed the presence of caffeine, arbutine, and flavonoids as the main compounds in the active extract. The results support the use of Turnera diffusa as an aphrodisiac in traditional medicine and suggest possible therapeutic properties of Turnera diffusa on sexual dysfunction. The flavonoids present in active extract may participate in its pro-sexual effect, which is analogous to those produced by yohimbine, suggesting a shared mechanism of action.
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Damiana (Turnera diffusa Willd. Ex Schult) has traditionally been used as an herbal aphrodisiac. The study was aimed to investigate the anti-aromatse activity and the estrogenic activity of the constituents isolated from Turnera diffusa. The methanolic extract and 24 compounds isolated from the leaves of Turnera diffusa were evaluated for aromatase activity by using a tritiated-water release assay and for estrogenic activity by using yeast estrogen screen (YES) assay. The methanolic extract demonstrated a dose-dependent inhibitory activity of the aromatase enzyme with the IC(50) value of 63.1 microg/ml. Among the 24 tested compounds, pinocembrin and acacetin showed the most potent inhibition with IC(50) values of 10.8 and 18.7 microM, respectively. Estrogenic activity was also observed in the extract and three compounds including apigenin 7-glucoside, Z-echinacin and pinocembrin with EC(50) values of 10, 20 and 67 microuM, respectively. The extract of Turnera diffusa and two isolated compounds pinocembrin and acacetin could significantly suppress aromatase activity. Moreover, apigenin 7-glucoside, Z-echinacin and pinocembrin showed estrogenic activity.
Traditional aphrodisiaca Turnera diffusa WILLD. -new human aspects
  • B Feistel
  • B Walbroel
Feistel, B., Walbroel, B.; Traditional aphrodisiaca Turnera diffusa WILLD. -new human aspects. Poster at 15th Internat. Congress PHYTOPHARM, July 25-27 2011, Nuremberg, Germany, 2011
Traditional aphrodisiac Turnera diffusa WILLD.-new pharmacological aspects about Damiana
  • B Feistel
  • K Appel
  • I Pischel
Feistel, B., Appel, K., Pischel, I.; Traditional aphrodisiac Turnera diffusa WILLD.-new pharmacological aspects about Damiana. PHYTO Therapie Austria 3-18: PA7, 2018