Extracts of Sideritis scardica as inhibitors of monoamine transporters:
A pharmacological mechanism for efficacy in mood disorders and attention-deficit
hyperactivity disorder (ADHD)
Rainer Knörle

Aim of the study: Sideritis species are traditionally used within the mediterranean area for the cure of cold coughand for the treatment of gastrointestinal disorders. The aim of this study was to investigate the effects of Sideritis
scardica extracts on the monoamine transporters and to derive possible medicinal applications from thepharmacological profile of the extracts.
Methods: We have studied the effect of various Sideritis scardica extracts on serotonin, noradrenaline anddopamine uptake into rat brain synaptosomes and serotonin uptake into human JAR cells.
Results: All extracts inhibited the uptake of all three monoamines into rat brain synaptosomes by their respective
transporters, the alcoholic extracts being more effective than the water extract. EC50 values were in the range of
30-40 µg/ml. Inhibition of the human serotonin transporter by the methanol extract was even more effective(EC50: 1,4 µg/ml). Combining Sideritis ethanol extract and fluvoxamine resulted in a leftward shift of the
fluvoxamine concentration-response curve.
Conclusions: The pharmacological profile of Sideritis scardica extracts suggests their use in the phytochemical
therapy of mental disorders associated with a malfunctioning monoaminergic neurotransmission, like major
depression or the attention-deficit hyperactivity disorder.

1. Introduction
The genus Sideritis (Lamiaceae) comprises about
150 species distributed mainly in the mediterraneanarea and in the moderate zones of Asia. The taxa
are attributed to three sections: sect. Sideritis, sect.
Empedoclia (Rafin.) Bentham. and sect. Hesiodora
Bentham. They are growing in low-fertility hilly
and mountainous areas at over 800-1000 m altitude(1,2).
Plants of the genus Sideritis are widely used in folk
medicine in the eastern mediterranean area for thecure of cold cough and for the treatment ofgastrointestinal disorders. This is due to their antiinflammatory (3,4), antibacterial and antifungal(5,6) activities. Studies on the pharmacologicalaction of Sideritis revealed diuretic (7), antioxidant(8) and analgesic effects (9).
Sideritis has become very fashionable in Germany
recently and is found in a variety of shops marketed
as “Bergtee” or “Griechischer Bergtee”. The herb issold cut or sometimes even whole, the latter making
identification much easier. The majority of species
sold in Germany consists of Sideritis syriaca,
Sideritis dichotoma and Sideritis scardica. The
important role of the leaves and flowering tops ofSideritis as traditional tea in the eastern
mediterranean area and Spain (mountain tea,malotira, dag cay, té de puerto) has imposed theneed of cultivation of Sideritis since the production
from wild-collected plants was insufficient to cover
the demand of market.

The chemical constituents of Sideritis have been
investigated for a long time. The essential oil of all
Sideritis species mainly consists of α-pinene, βpinene, β-caryophyllene, caryophyllene oxide,limonene,
1,8-cineole,carvacrol,
myrcene,germacrene D, spathulenol, α-bisabolol, fenchone
and sabinene (10,11). The main components vary
between the species. In addition, 8-hydroxyflavone
allosylglucosides and p-coumaroylglucosides arefound in several Sideritis species (12). For somespecies the presence of phenylpropanoid glycosides(3) or kaurane diterpenoids (13,14) is reported.
Andalusol(ent-6α-8α-18-trihydroxy-13(16),14labdadiene), a diterpene found in Sideritis foetens,
has been shown to inhibit iNOS expression in
macrophages. It is supposed that this effect iscaused by a transcriptional mechanism. This
inhibition of iNOS by andalusol and related
substances might be responsible for the antiinflammatory effect of Sideritis species, since iNOS
is the enzyme responsible for the high-output NO
synthesis (15).
An imbalance in monoaminergic neurotransmission
is considered to be responsible for a multitude ofmood disorders. Mood disorders and conditions of
impaired or diminished cognition and attention
affect more than one in every four persons in thedeveloped world. Representative examples include
depressive disorders, generalised anxiety disorders
or the attention-deficit hyperactivity disorder. In thecentral nervous system, dopamine is involved incontrolling locomotion, cognition, affect and mood,noradrenaline is involved in modulating attention,

2
working memory, behavioural inhibition, planning,alertness, arousal, mood and vigilance. Serotoninplays a role in mood, aggression, anxiety, appetite,
sleep, cognition, learning and locomotion.
Most antidepressants increase synaptic levels of themonoamine neurotransmitter serotonin. They may
also enhance the levels of two otherneurotransmitters, noradrenaline and dopamine.
This observation gave rise to the monoamine
hypothesis of depression. In its contemporary
formulation, the monoamine hypothesis postulates
that the deficit of certain neurotransmitters is
responsible for the corresponding features ofdepression. There are several different monoaminetransporters: the dopamine transporter DAT, thenoradrenaline transporter NET and the serotonintransporter SERT. Modern antidepressants typicallywork by binding to the corresponding transporterand thereby inhibiting serotonin, noradrenaline or
dopamine reuptake and raising active levels in thesynapse (16).
Attention-deficit hyperactivity disorder (ADHD) isa heterogeneous behavioural disorder characterised
by inattention or lack of focus, hyperactivity andimpulsivity. Recent genetic and neuroimaging
studies provide evidence for contributions of a
monoaminergic dysfunction in ADHD. The
efficacy of medications that stimulate thedopaminergic and noradrenergic systems suggeststhat normalizing their activities in relevant brain
areas is necessary for the treatment of ADHD (17).
Especially in the case of central nervous systemdisorders, a large majority of the patients would
prefer nature medicine (18). Example of plants withcentral nervous action are Valeriana officinalis(valerian) and Humulus lupulus (hops), both used
for sleep disturbances, or Passiflora incarnata(passion fruit) and Hypericum perforatum (St.
John’s wort) used for the treatment of affective
disorders.
Although Hypericum extracts are well establishedin the phytotherapy of depression, it would bedesirable to have other phytopharmaceutical entities
with a proof of action for the therapy of central
nervous disorders caused by an imbalance inmonoamine neurotransmission. The aim of thisstudy was to investigate the effects of Sideritis
scardica extracts on the monoamine transporters
and to derive possible medicinal applications fromthe pharmacological profile of the extracts.

2. Materials and methods
2.1
Plant extracts
Farm-cultivated aerial parts of Sideritis scardica
were
obtainedfrom
Tee
Gschwendner,
Meckenheim, Germany (Product No.: 1127, Lot:

PSA07080901). The raw plant material was
analysed and characterised at the trader’slaboratory. Voucher specimens of the crude
botanicals are deposited at the trader’s facilities.
The dry herb was ground and extracts wereprepared by boiling the plant material for 1 h under
reflux with the respective solvent (water, methanol,
70% ethanol). The extracts were filtered and driedby rotary evaporation. Yields of the extract was
320-340 mg (water extract), 100-120 mg per g plantmaterial (methanol extract) and 200-240 mg extract
per g plant material (70% ethanol extract).

2.2
2.2.1

Monoamine uptake experiments
Rat brain synaptosome experiments

Male Wistar rats (250-300 g) were decapitatedunder CO2 anaesthesia and the brain was quickly
removed. Cortex was prepared on ice. The corticaltissue was homogenised in 10 volumes ice cold
0.32 M sucrose/10 mM HEPES pH 7,4. The
homogenate was centrifuged for 10 min at 4° C and900*g. The supernatant was centrifuged again for
10 min at 4° C and 11000*g. The supernatant was
discarded and the pellet was kept on ice. At the
beginning of the experiment, the pellet was
resuspended in buffer to yield a suspension with a
total protein content of 20-30 µg/ml.
The uptake experiments were performed in 96 wellfilter plates (GF-C glass fiber filter Multiscreen FB,
Millipore, Schwalbach, Germany). Each well waswashed with 250 µl of buffer containing 121 mM
NaCl, 1.8 mM KCl, 1.3 mM CaCl2, 1.2 mM
MgSO4, 25 mM NaHCO3, 1.2 mM KH2PO4, 11mM glucose, 0.57 mM ascorbic acid, saturated with
95% O2/5% CO2, final pH 7.4. 50 µM pargyline
were added for the inhibition of MAO. 50 µl
synaptosome preparation in buffer was added toeach well and incubated with various
concentrations of extracts dissolved in DMSO (final
concentration of DMSO 10 µl/well, 8 wells per
extract concentration) in a total volume of 240 µl
for 10 min. After addition of 10 µl of a 100 nM
serotonin solution in buffer containing 0.1 µCi of[³H]-serotonin the plates were incubated for 10 min
at room temperature, the uptake buffer was thenrapidly filtered off, and the filter was washed threetimes with 250 µl buffer. The filters were punchedout and transferred into scintillation vials for liquid
scintillation counting. Nonspecific uptake wasdefined as uptake in the presence of 10 µM
fluvoxamine.
Noradrenaline and dopamine uptake experiments
were performed as described above. The final
concentrations of radiolabelled transmitter were 20nM ([³H]-noradrenaline) or 10 nM ([³H]dopamine). The plates were incubated for 15 min at
37° C. Unspecific binding was determined in thepresence of 10 µM nomifensine.

3
2.2.2

Uptake experiments using JAR cells

In addition, serotonin uptake experiments were
performed with human placental choriocarcinoma
cells (JAR) which constitutively express the human
serotonin transporter hSERT.
JAR cells (DSMZ, Braunschweig, Germany) weregrown in RPMI-1640 medium containing Lglutamine, 10% foetal calf serum, 100 U/ml
penicillin, and 100 mg/ml streptomycin at 37° C in
an atmosphere of 5% CO2, 95% air. The uptake
experiments were performed in poly-(D-lysine)coated 24-well plates (1 day after plating; 50000 200000 cells/well). Each well was washed twicewith 1 ml of buffer containing 10 mM HEPES, 120
mM NaCl, 3 mM KCl, 2 mM CaCl2, 2 mM MgCl2,
5 mM glucose and 0.57 mM ascorbic acid final pH
7.3 and incubated with various concentrations of
extracts dissolved in DMSO (final concentration of
DMSO 10 µl/well, 4 wells per concentration) in a
total volume of 1 ml. After addition of 10 µl of a
100 nM serotonin solution in buffer containing 0.1µCi of [³H]-serotonin the plates were incubated for
10 min at room temperature, the uptake buffer wasthen rapidly aspirated, and the cells were washedthree times with 1 ml buffer. Cells were lysed with
0.5 ml of 0.5 M NaOH and transferred into
scintillation vials for liquid scintillation counting.
Nonspecific uptake was defined as uptake in thepresence of 10 µM fluvoxamine.

2.3
Effect of Sideritis scardica extracts oncell viability
The effect of Sideritis scardica extracts on cell
viability was investigated by measuring lactate
dehydrogenase (LDH), an enzyme locatedintracellularily which is released into theextracellular space when the cells are damaged.
Sideritis
extracts
wereinvestigatedinconcentrations of 50 µg/ml and 500 µg/ml. The
JAR cells were incubated at 20° C with the extracts
in uptake buffer for 3 h. Assay conditions wereadopted from Bergmeyer and Bernt (19). Briefly,
100 µl 69 mM sodium pyruvate in 100 mM sodium
phosphate buffer pH 7.5 were added to 2.8 ml 0,13mM β-NADH solution in sodium phosphate buffer.
100 µl of JAR cell supernatant (or 100 µl buffer forthe control experiments) was added and the change
in absorption at 340 nm was recorded at fixed timesof 15 min, 30 min and 45 min.

2.4

Statistics

Radioactivity accumulated in the filters was
normalised as “percent of specific uptake” always
referring to the specific uptake obtained from total
minus non-specific uptake. EC50 values were
calculated from the normalised data using iterative

curve fitting routines (SigmaPlot® 8.0, SPSS
Science, Chicago, Illinois, USA). The errors givenin this paper represent standard error of mean
(S.E.M.).

3. Results
3.1
Rat brain synaptosomes
Concentration-response curves were recorded forthe inhibition of the monoamine transporters. The
methanol extract of Sideritis scardica inhibited theuptake of [³H]-serotonin, [³H]-noradrenaline and[³H]-dopamine into rat brain synaptosomes with
EC50 values of 31.0 µg/ml [16.4; 58.6] for serotonin
uptake, 42.3 µg/ml [31.8; 56.4] for noradrenaline
uptake and 37.0 µg/ml [27.5; 49.8] for dopamine
uptake (Figure 1). Maximum inhibition was 108%
± 6% for serotonin, 90% ± 6% for noradrenaline
and 89% ± 6% for dopamine uptake.
The water extract of Sideritis scardica also
inhibited the uptake of the monoamines withsimilar EC50 values but mostly lower maximum
effects. EC50 values were 38.5 µg/ml [20.4; 72.8]
for serotonin uptake, 30.6 [25.1; 37.5] fornoradrenaline uptake and 45.5 [31.4; 66.0] for
dopamine uptake. Maximum inhibition was 70% ±8% for serotonin, 122 % ± 13% for noradrenaline
and 57% ± 6% for dopamine uptake.

3.2
JAR cells (human serotonin transporterhSERT)
3.2.1
Inhibition of hSERT by Sideritis scardica
extract
The concentration-response curve for the uptake ofserotonin by the human serotonin transporterhSERT was recorded in this set of experiments.
Sideritis scardica methanol extract inhibited theuptake of [³H]-serotonin into the human JAR cellline with a EC50 of 1.4 µg/ml [0.6; 3.5] and amaximum inhibition of 70% ± 9%. The 70%
ethanol extract showed in this system an EC50 valueof 55.9 µg/ml [31.6; 99.3] and a maximum
inhibition of 96% ± 12%.

3.2.2. Shift of the fluvoxamine dose-response
curve by Sideritis scardica 70% ethanol extract
We investigated the effect of various concentrationsof Sideritis on the inhibition of serotonin uptake by
fluvoxamine. The concentration-response curve of
fluvoxamine (EC50: 3.8 nM [2.2; 6.4]) was shiftedto the left by adding Sideritis ethanol extract.
Addition of 10 µg/ml Sideritis extract resulted in a
EC50 for the combination of Sideritis andfluvoxamine of 1.5 nM [1.2; 1.8], addition of 50

4with 50 µg/ml and 97% ± 16% with 500 µg/ml
Sideritis scardica extract.

µg/ml Sideritis extract yielded an EC50 of 0.5 nM[0.3; 0.7] (Figure 2).

Shift of the fluvoxamine concentration-response curvefor the uptake of serotonin into human JAR cells
in presence of Sideritis scardica ethanol extract.

1,4

A

1,2

fluvoxamine+10 µg/ml+50 µg/ml

1,4

0,8

1,2

specific serotonin uptake

specific serotonin uptake

1,6

1,0

0,6
0,4
0,2
0,0

1,0
0,8
0,6
0,4
0,2
0,0

-0,2
-7

-6

-5

-4

-3

log [µg/ml]

-0,2
-0,4
-12

-10

B

1,2

specific noradrenaline uptake

-8

-6

-4

log [fluvoxamine]

1,4

Values are expressed as mean ± S.E.M. (n=4).

1,0Figure 2: Shift of the fluvoxamine concentration-response curvefor the uptake of serotonin into human JAR cells in presence of
10 µg/ml and 50 µg/ml Sideritis scardica ethanol extract. Values
are expressed as mean ± S.E.M. (n=4).

0,8
0,6
0,4
0,2

4. Discussion

0,0
-0,2
-7

-6

-5

-4

-3

log [µg/ml]

1,4

specific dopamine uptake

1,2

C

1,0
0,8
0,6
0,4
0,2
0,0
-0,2
-7

-6

-5

-4

-3

Previous
pharmacologicalstudieshavedemonstrated that plants of the genus Sideritis haveanti-inflammatory (3,4), diuretic (7), antioxidant(8), analgesic (9) and antibacterial and antifungal(5,6) effects. The herbs are traditionally usedthroughout the mediterranean regions for colds andrespiratory problems. They also are used as an antiinflammatory remedy and to reduce fever. Tea fromSideritis species has become very fashionable inGermany recently, and is to be found in a wide
variety of shops. In this study, we have focussed on
the commercially available and farm-cultivatedspecies Sideritis scardica, one main constituent of“Bergtee” in Germany and have determined its
pharmacological profile with drug-screening
models for the investigation of monoaminetransporter targeting established in our laboratory.

log [µg/ml]

Figure 1: Concentration-response curves of Sideritis scardica
methanol extract for the uptake of serotonin (A), noradrenaline(B) and dopamine (C) into rat brain synaptosomes. Values are
expressed as mean ± S.E.M (n=8).

3.3.
Effect of Sideritis scardica extracts oncell viability
The LDH assay did not show differences between
controls and cells treated with methanolic Sideritis
scardica extract. Relative LDH activities in the
supernatant of the JAR cells were 107% ± 14%

The results of the present study illustrate thatSideritis scardica is a potent inhibitor of themonoamine transporters. The water and alcoholic
extracts of Sideritis scardica inhibited the uptake ofserotonin, noradrenaline and dopamine by theirrespective transporters in a concentration-dependent
manner. The inhibition of the human serotonintransporter hSERT (expressed in human JAR cells)by Sideritis scardica methanol extract was evenmore pronounced than the inhibition of the rat brain
serotonin transporter.
Combining Sideritis scardica 70% ethanol extract
with fluvoxamine leads to a leftward shift of the

5
fluvoxamine concentration-response curve withoutchangingthemaximum
inhibition.
Less
fluvoxamine is needed in the presence of Sideritis
scardica extract to elicit the same level ofbiological response. This increase of drug
sensitivity is to be found even at concentrations ofSideritis, which are per se not active at theserotonin transporter. Sideritis extract increases theapparent potency of fluvoxamine in aconcentration-dependent manner more than 8-fold,which may be explained by a concerted interactionof the two serotonin uptake blockers with theserotonin transporter. Other effects than only
inhibiting serotonin transport like allostericmodulation of the transporter or alteration of thetransporter activity by Sideritis scardica extracts
might also be considered.
The lactate dehydrogenase assay showed thattreatment of the JAR cells with Sideritis scardica
methanol extract at concentrations up to 500 µg/ml
did not affect cell viability. This demonstrates thatthe inhibitory action of the extract on themonoamine transporters does not appear to be due
to variation of cell viability.
In order to exert their mode of action in vivo, thecomponents of the Sideritis scardica extracts must
be able to cross the blood brain barrier to reach
their target site. Most drugs cross the blood brain
barrier by transmembrane diffusion. This is a nonsaturable mechanism that depends on the meldingof the drug into the cell membrane. A high degreeof lipid solubility and low molecular weight favour
crossing by this mechanism. Reviews often quote a
cut-off of 400 to 600 g/mol. Other factors
influencing the ability of a drug to partition fromblood into the blood brain barrier include charge,
tertiary structure and degree of protein binding.
Mechanisms for the crossing of the blood brain
barrier also include saturable transporters,
adsorptive endocytosis and the extracellularpathways (20). Substances which come into
consideration as active elements in the Sideritis
scardica extracts comprise, among others, terpenes,
flavonoids and phenols. These substances typicallyshow molecular weights in the range of 200 – 400
g/mol. They are soluble in alcohol or aqueous
alcohol and therefore are of a lipophilic character.
The Sideritis scardica extracts investigated in thisstudy are therefore likely to cross the blood brain
barrier by transmembrane diffusion.
Depressive disorders are characterised by animbalance in monoaminergic neurotransmission.
Based on findings from studies of antidepressants
treatment, it may be possible to assign specificsymptoms of depression to specific neurochemicalmechanisms. Serotonin may be related to anxiety,obsessions and compulsions; noradrenaline toalertness and energy as well as anxiety, attention
and interest in life; and dopamine to attention,

motivation, pleasure and reward as well as interestin life (21). Increasing any of these threeneurotransmitters will elevate mood, but the otherelements of depression may be particularly
responsivetoelevationofacertainneurotransmitter. It is therefore desirable to have a
remedy which acts on as many monoaminergic
systems as possible.
Extracts of Hypericum perforatum have been usedsince antiquity for the treatment of depressive
symptoms. The exact mechanisms of action are still
unclear, nevertheless randomised clinical trials haveshown that Hypericum extracts are more effective
than placebo and similarly effective as standard
antidepressants while having better tolerability inthe acute treatment of major depressive episodes. St
John's wort may rarely cause photosensitivity. Thiscan lead to visual sensitivity to light and to
sunburns in situations that would not normallycause them. The most important risk associatedwith Hypericum extracts are interactions with otherdrugs. St John's wort has also been shown to cause
multiple drug interactions through induction of thecytochrome P450 enzyme CYP3A4, but also
CYP2C9. This results in the increased metabolismof those drugs, resulting in decreased concentrationand clinical effect. Examples of drugs causing
clinically-significant interactions with St John'swort are antiretrovirals, hormonal contraceptives
and immunosuppressants (22).
A recent study on the Hypericum perforatum
extract Ze 117 showed that it interferes in three
ways with the individual uptakes of the monoamine
neurotransmitters. EC50 values for this extract were
54 µg/ml for noradrenaline uptake, 350 µg/ml for
dopamine uptake and 1600 µg/ml for serotonin
uptake (23). Therefore, the potency of thenoradrenaline uptake inhibition was around 30
times higher than that for serotonin, and seventimes higher than that of the dopamine uptake
inhibition. Combination of Hypericum perforatumwith other plant extracts like passion flower ofvalerian improve the pharmacological profile of thephytodrug by synergistic effects, the EC50 of an
ethanolic Hypericum extract for serotonin uptake
into rat brain slices was lowered from 177.5 µg/ml
for St. John’s wort extract alone to 37.2 µg/ml in
the presence of 200 µg/ml of Passiflora extract(24).
In contrast to St. John’s wort, Sideritis scardica
extract has EC50 values for all three types of
monoamine transporters in the range of 30-40µg/ml. With this background, the pharmacological
profile of Sideritis scardica extract might bebeneficial for the therapy of depressive disorders. It
elevates the extracellular concentration of all threemonoamine neurotransmitters by inhibiting theirtransporters with similar potency and therefore
might ameliorate the symptoms of depression better6and more powerful than monospecific drugs. In
allopathic pharmacology the debate about theadvantage of dual action antidepressants likevenlafaxine and duloxetine is still going on (25,26).
Another possible application of Sideritis scardica
extracts as inhibitors of the monoamine transporters
consists in the therapy of attention-deficit
hyperactivity disorder (ADHD). This behaviouraldisorder is characterised by inattention or lack offocus, hyperactivity and impulsivity. These
symptoms have a childhood onset and often persist
into adolescence and adulthood. Estimates indicatethat 6- 9% of children and adolescents meet
diagnostic criteria for ADHD and that theprevalence of ADHD in adults is around 3-5% (27).
Genetic data and collective evidence fromneurobiologic and neuropsychologic studies pointtoapredominant
involvementofthecatecholaminergic system in ADHD (17). Adequate
catecholaminergic modulation of the prefrontal
cortex, the brain region that plays an important rolein the physiology of cognition and emotion, isessential for attention and vigilance. The
dysfunction of the prefrontal cortex in ADHD has
been attributed to a decreased catecholaminefunction affecting cognition and motor inhibition.

used to try to help regulate mood and behaviour
problems associated with ADHD (33). But no oneof these herbal remedies has a proven mechanismof action which would suggest the use of theseplant extracts for the treatment of ADHD or even a
proven efficacy for the treatment of ADHD until
today.
Sideritis scardica extracts inhibit all monoaminetransporters with approximately the same potency.
With this mode of action, they are the first
phytomedical entity with this proven mode ofaction. All other remedies used in ADHD treatment
show selectivity towards only one of the threetransporters. Methylphenidate has higher affinity to
dopamine transporters than to noradrenalinetransporters and very low affinity for serotonintransporters. Atomoxetine on the other handselectively inhibits noradrenaline transport, itsaction at the serotonin transporter is weaker and it
shows a low affinity towards dopamine transporters(28). Sideritis scardica extracts with their ability toinhibit dopamine, noradrenaline and serotonin
uptake to the same extent may turn out to bebeneficial for a phytochemical therapy of ADHD.

5. Conclusions
Since monoamine transporters are (at least in part)
responsibleforregulating
extracellularconcentrations of the catecholamines noradrenalineand dopamine, the common treatment of ADHD
includes stimulant medications with drugs likemethylphenidate. These stimulants block the
reuptake of noradrenaline and dopamine thus rising
their extracellular levels. Currently, the only
nonstimulant medication approved for the treatment
ADHD is atomoxetine, which selectively enhances
extracellular noradrenaline and dopamine levels
within the prefrontal cortex (28). Althoughnoradrenaline and dopamine are in the main focusof pharmacological therapy of ADHD, an
additional contribution of the serotonergic system
can not be excluded. Recent genetic andneuroimaging studies provide evidence for separate
contributions of altered dopamine and serotoninfunction in this disorder (29). Most tricyclic
antidepressants
actingonserotoninandnoradrenaline transporters are good remedies for
managing behavioural and, to some extent,
cognitive symptoms (30).
Some parents refuse a therapy of their children withstimulants or chemical drugs due to the possible
side effects of these drugs. Therefore, a large
number of alternative medications of ADHD havebeen praised. These remedies are often of aquestionable efficacy. Herbal medicines and natural
substances which are used for the treatment of
ADHD include Ginkgo biloba because of thereputed beneficial effects of this plant upon thebrain (31,32). St. John's wort is also sometimes

Aqueous and alcoholic extracts of Sideritis scardica
are able to inhibit serotonin, noradrenaline anddopamine transporters with similar EC50 values. By
inhibiting neurotransmitter reuptake the active
levels of the monoamines are elevated within thesynapse. This is a biochemical and pharmacologicalmode of action which suggests to use Sideritis
scardica extracts for the treatment of disorders
associated with an altered or malfunctioning
monoaminergic
neurotransmission.
Sideritis
scardica extracts may be superior to other plant
extracts in the therapy of depressive disorders, since
the long-term traditional use in the mediterraneanarea did not reveal side effects of the drug until
now. Sideritis scardica extracts also may have agood potential to get a proof of action as the firstplant extract for the treatment of attention-deficit
hyperactivity disorder (ADHD).

Acknowledgements
This study was supported by a grant from the
Bundesministerium für Wirtschaft und Technologie(ProInno II; KU 0004501 AJ4).

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