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Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression

February 2007
Nordic Journal of Psychiatry 61(5):343-8

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PubMed

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The objective of this study was to assess the efficacy and safety of standardized extract SHR-5 of rhizomes of Rhodiola rosea L. in patients suffering from a current episode of mild/moderate depression. The phase III clinical trial was carried out as a randomized double-blind placebo-controlled study with parallel groups over 6 weeks. Participants, males and females aged 18-70 years, were selected according to DSM-IV diagnostic criteria for depression, the severity of which was determined by scores gained in Beck Depression Inventory and Hamilton Rating Scale for Depression (HAMD) questionnaires. Patients with initial HAMD scores between 21 and 31 were randomized into three groups, one of which (group A: 31 patients) received two tablets daily of SHR-5 (340 mg/day), a second (group B: 29 patients) received two tablets twice per day of SHR-5 (680 mg/day), and a third (group C: 29 patients) received two placebo tablets daily. The efficacy of SHR-5 extract with respect to depressive complaints was assessed on days 0 and 42 of the study period from total and specific subgroup HAMD scores. For individuals in groups A and B, overall depression, together with insomnia, emotional instability and somatization, but not self-esteem, improved significantly following medication, whilst the placebo group did not show such improvements. No serious side-effects were reported in any of the groups A-C. It is concluded that the standardized extract SHR-5 shows anti-depressive potency in patients with mild to moderate depression when administered in dosages of either 340 or 680 mg/day over a 6-week period.

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Clinical trial of Rhodiola rosea L. extract

SHR-5 in the treatment of mild to moderate

depression

V. DARBINYAN, G. ASLANYAN, E. AMROYAN, E. GABRIELYAN, C. MALMSTRO

A. PANOSSIAN

Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmstro

m C, Panossian A. Clinical trial

of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J

Psychiatry 2007;61:343348. Oslo. ISSN 0803-9488.

The objective of this study was to assess the efficacy and safety of standardized extract SHR-5 of

rhizomes of Rhodiola rosea L. in patients suffering from a current episode of mild/moderate

depression. The phase III clinical trial was carried out as a randomized double-blind placebo-

controlled study with parallel groups over 6 weeks. Participants, males and females aged 18

70 years, were selected according to DSM-IV diagnostic criteria for depression, the severity of

which was determined by scores gained in Beck Depression Inventory and Hamilton Rating

Scale for Depression (HAMD) questionnaires. Patients with initial HAMD scores between 21

and 31 were randomized into three groups, one of which (group A: 31 patients) received two

tablets daily of SHR-5 (340 mg/day), a second (group B: 29 patients) received two tablets twice

per day of SHR-5 (680 mg/day), and a third (group C: 29 patients) received two placebo tablets

daily. The efficacy of SHR-5 extract with respect to depressive complaints was assessed on days 0

and 42 of the study period from total and specific subgroup HAMD scores. For individuals in

groups A and B, overall depression, together with insomnia, emotional instability and

somatization, but not self-esteem, improved significantly following medication, whilst the

placebo group did not show such improvements. No serious side-effects were reported in any of

the groups AC. It is concluded that the standardized extract SHR-5 shows anti-depressive

potency in patients with mild to moderate depression when administered in dosages of either 340

or 680 mg/day over a 6-week period.

 Adaptogens, Rhodiola rosea, Depression, Placebo-controlled trial, Double-blind parallel-group

trial.

A. Panossian, Swedish Herbal Institute Research &Development, Spa˚rva

gen 2, SE- 432 96

skloster, Sweden, E-mail: alexander.panossian@shi.se; Accepted 21 July 2006.

epressive symptoms are not only disabling but are

also very common. It is estimated that around 10%

of the adult population suffer from such disorders,

although some studies indicate that the true figure may

be higher. Typically, mild to moderate depression pre-

sents itself in the form of mood disturbance, lack of

mental energy, sleep disturbance, low self-esteem and a

wide variety of somatic complaints. In those cases that

do not present serious melancholy or suicidal risk, it

would be preferable to treat the disorder with anti-

depressive medications that do not exhibit any of the

disturbing side-effects associated with the standard

drugs, such as tricyclic anti-depressants, selective ser-

otonin or noradrenaline reuptake inhibitors (13).

Rhodiola rosea L. is a well-known adaptogen that

induces a state of non-specific resistance to damaging

effects of various stressors (46). Previously, it has been

demonstrated that when an extract of R. rosea is

administered together with tricyclic anti-depressants

there is a marked reduction in the side-effects of the

drugs and a positive effect on psychopathological

symptoms in patients with psychogenic depression

(7, 8). However, we have not been able to find any

publications concerning the clinical trial of the anti-

depressive effect of mono-therapy with R. rosea.

The aim of the present study was to investigate the

direct anti-depressive effect of SHR-5, a standardized

extract of R. rosea rhizome, in patients suffering from

mild to moderate depression. A double-blind, placebo-

controlled, randomized phase III pilot study was carried

out in order to determine the therapeutic efficacy and

safety of SHR-5 extract compared with placebo.

# 2007 Taylor & Francis DOI: 10.1080/08039480701643290

The relationship between different doses of the adapto-

gen (340 and 680 mg/day of extract per day) and their

anti-depressant efficacy compared with placebo were

examined.

Material and Methods

Study protocols were submitted to and approved by the

Ethics Committee of the Armenian Drug and Medical

Technology Agency of the Ministry of Health of the

Republic of Armenia. Studies were performed in com-

pliance with the revised declaration of Helsinki (9) and

written informed consent was obtained from all partici-

pants.

Study drugs

All test medications were manufactured according to

Good Manufacturing Practice (GMP) by the Swedish

Herbal Institute (SHI: Gothenburg, Sweden) and pre-

sented in the form of white tablets coated with sugar.

The verum tablets (400 mg) each contained 170 mg of

Rhodiola extract SHR-5. Placebo tablets (400 mg) were

prepared using the inactive ingredients that were iden-

tical to verum tablets except 170 mg of lactose. Verum

and placebo tablets were identical in appearance and

organoleptic properties. Individual medication packs

were provided to subjects in the form of plastic jars

containing 100 tablets and bearing a code number

(randomly encoded in a drug list) on a label that was

designed in accordance with the valid guidelines for

Good Clinical Practice (GCP). In addition to the main

label, each jar had a small supplementary label with

information on dosage regimen (two or four) were to be

taken daily. Duplicate jars, each containing 100 tablets,

were provided to those patients required to take four

tablets daily.

The code was broken after completion of the study

and after statistical analyses had been performed.

Study design

The investigation was a double-blind, randomized,

parallel-group evaluation of SHR-5 extract vs. placebo.

Male and female subjects, aged between 18 and 70 years

and diagnosed with mild or moderate depression ac-

cording to the Diagnostic and Statistical Manual of

Mental Disorders (DSM-IV) criteria (10), attending the

in- or outpatients sections of the Erebouni Medical

Center, Department of Neurology, Armenian State

Medical University, Yerevan, Armenia, were considered

for inclusion in the study. Since eligible individuals were

required to have clinically significant depression, only

patients with initial scores of ]13 on the Beck Depres-

sion Inventory (BDI: 13-item short form) and of ]21

on the Hamilton Rating Scale for Depression (HAMD;

21-item version) (1113) were selected. The BDI and

HAMD tests were performed by skilled physicians using

Armenian and Russian language versions of the ques-

tionnaires as appropriate in order to avoid possible

misinterpretations.

Subjects were excluded from the study if: 1) there was

evidence of a previously documented or reported

attempt to commit suicide, 2) if they scored ]1on

BDI item H or ]2 on HAMD item 3 (suicidal

tendency), 3) if they presented a total HAMD score

above 31, 4) if they presented progressive organic or

metabolic brain syndrome, or compulsive, schizophrenic

or other delusive disorders, or 5) if they were pregnant or

lactating. Patients suffering from, and/or receiving

medication for serious chronic illnesses (including car-

diovascular diseases and diabetes) were also excluded

because of the possibility of drug interactions.

Prior to the commencement of the study, all included

subjects underwent routine blood tests and a general

medical examination. This was followed by a 2-week

run-in period, during which time no medication was

provided for any patients, including those who were

receiving, or who had recently received, anti-depressant

or psychotropic drugs. After this time, patients were

randomly distributed amongst one of three groups,

group A receiving two tablets once daily of SHR-5

standardized extract (340 mg/day), group B receiving

two tablets twice daily of SHR-5 standardized extract

(680 mg/day), and group C receiving two placebo tablets

once daily. The distribution of subjects within groups

was carried out, according to the principles of total

randomization, whereby each patient was randomly

assigned an integer 190.

The number selected provided the identification code

for the patient and the drug code number (randomly

encoded in a drug list), and both were recorded in a

protocol and in the journal for each patient in order to

permit subsequent identification. Information concern-

ing the content of extracts became available to the

investigators and volunteers only after completion of the

study and final statistical analysis of the results.

A sample size of 30 subjects per group was estimated

to be sufficient for a 15% significance level by assuming

a 30% effect difference between the treatment groups

and the placebo group over the study period, with a 95%

confidence interval. A total of 91 patients, 31 in group A

and 30 each in groups B and C, formed the initial

baseline set.

BDI and HAMD questionnaires were administered to

subjects at the start (day 0) and the end (day 42) of the 6-

week period of treatment. Throughout the study phase,

patients were followed-up by telephone contact or

personally by attending physicians, and any adverse

events were recorded. At the end of the study, patients

underwent further routine blood tests and a general

medical examination. All complaints arising from the use

of the study medications were documented by the

V. D

ARBINYAN ET AL

344 NORD J PSYCHIATRY ×VOL 61 ×NO 5 ×2007

attending principal investigator, physicians and monitors

in order to assess the safety of the materials employed.

Compliance with the regime of medication by individuals

was determined by collecting the used jars and unused

tablets on the last visit, and by questioning of the patients

by the investigator. Deviations from required protocols

were recorded together with the reason and the date.

All data, including signed written consents, personal

information, clinical reports, medical histories, results of

BDI and HAMD assessments, adverse reaction reports

and reasons for study termination, were collected in a

journal for each patient, which was signed by the

principal investigator and the study monitor.

Parameters for measuring efficacy of treatment

The efficacy of medication with respect to depressive

symptoms was assessed from the symptom scores in the

BDI and HAMD questionnaires administered at the

start and at the end of the treatment period. The primary

efficacy variable was represented by the change in total

BDI and HAMD scores over the study period. Second-

ary efficacy variables were classified as the changes, over

the study period, in the HAMD symptom indicator

subgroups I (points 4, 5 and 6: insomnia), II (points 9

and 10: emotional instability), III (points 1216: soma-

tization and hypochondria) and IV (points 17 and 18:

self-esteem), which reflect the different somatic and

physiological aspects of mild and moderate depression.

Statistical methods

The data for each subject, identified only by the entry

number of the patient, were entered into the study

database. Data management and statistical analyses

were performed using PRISM Statistical Software (ver-

sion 2.01, 1996). The statistical analyses were performed

according to Student’s t-test and the Wilcoxon non-

parametric two-tailed rank test. Pearson’s correlation was

used to test for correlation between variables. The study

was planned with adaptive interim analyses (14) following

treatments involving three groups of 30 patients. The

overall type 1 error rate was set at a 0.05, implying a

nominal level of a 0.0299 for the assessment of the

statistical significance in the interim analyses.

It was estimated that a sample size of 30 patients per

group would permit detection of a standardized treat-

ment difference of 0.50 with a power of 80% (two-sample

t-test: a 0.05: one-sided).

Results

A total of 91 patients, with mild to moderate depression,

were initially selected according to the inclusion and

exclusion criteria, and 89 were randomized to one of

three treatment groups, treatment group A and B and a

placebo group C. Two patients dropped out of the study

for non-medical reasons. No patients reported serious

adverse side-effects of the medications and none were

excluded through non-compliance with the prescribed

treatment. The distribution by sex and the mean ages of

the 89 participants who completed the study are

presented in Table 1. No statistically significant differ-

ences in demographic data could be determined between

the groups.

Tables 2 and 3 show the HAMD scores at the start of

the study (day 0) and following treatment (day 42),

which involved the administration of tablets containing

either SHR-5 standardized extract (340 mg/day*group

A; 680 mg/day*group B) or placebo (group C). There

were no statistically significant differences (n.s.) in the

mean HAMD and BDI scores between the three groups

prior to the start of the treatment. However, the scores

obtained by subjects in groups A and B after 42 days of

treatment with SHR-5 indicated the presence of sig-

nificantly (PB0.0001) reduced total levels of symptoms

(Fig. 1). Thus, in groups A and B, the mean total

HAMD scores declined from 24.52 to 15.97 (PB0.0001),

and from 23.79 to 16.72 (PB0.0001), respectively, whilst

the score of the placebo group C showed no such

improvement (mean HAMD score of 24.17 before

treatment vs. 23.41 after treatment (P0.3306). The

mean total HAMD scores for groups A and B at the end

of the study were statistically significantly different (PB

0.001) from that of group C (Tables 2 and 3).

Fig. 2 shows the efficacy of the SHR-5 standardized

extract, as administered to subjects suffering from mild

to moderate depression, with respect to changes in

insomnia, emotional instability and the level of somati-

zation (Fig. 2ac, respectively), whilst the intensity of

these symptoms of depression, as determined from the

scores in the HAMD symptom indicator subgroups,

were similar in the treatment groups A and B and the

placebo group C prior to the start of treatment.

Statistical significant improvements were shown in the

subjects of both treatment groups, but not of the placebo

group.

In contrast, the initially low levels of self-esteem

determined in subjects of all groups at the start of the

study (Fig. 2d), remained unchanged after 42 days of treat-

ment with two tablets daily of SHR-5 (group A) or with

placebo (group C), but improved significantly (2.690

Table 1. Characteristics of selected patients suffering from

mild and moderate depression randomized into treatment

groups within the study.

Group Males Females

Age (years),

mean9s

Group A (verum) (n 31) 10 (32.3%) 21 (67.7%) 44.9911.5

Group B (verum) (n29) 12 (41.4%) 17 (58.6%) 44.60925.49

Group C (placebo) (n29) 14 (48.3%) 15 (51.7%) 42.80912.87

s, standard deviation.

HODIOLA AND THE TREATMENT OF DEPRESSION

NORD J PSYCHIATRY ×VOL 61 ×NO 5×2007 345

before treatment and 1.897 after treatment, P 0.0002)

after medication with four tablets daily of SHR-5 (group B).

Discussion

Previous research concerning the pharmacological ef-

fects of R. rosea extract has focused mainly on its ability

to increase mental performance under stress and to

relieve temporary fatigue. During the last decade or so,

R. rosea has been used extensively as a herbal remedy for

negative stress reactions, and the number of physicians

prescribing the drug, especially in northern

Europe, has increased. Our own clinical experience,

combined with experience from colleagues using

Table 2. Total scores obtained by patients suffering from mild and moderate depression in treatment groups A and B (verum) and

the placebo group C submitted to Hamilton Rating Scale for Depression (HAMD) questionnaires before (day 0) and after (day

42) treatment.

Group A (verum),

two tablets SHR-5/day

Group B (verum),

four tablets SHR-5/day Group C (placebo)

Day of treatment period 0 42 0 42 0 42

Number of patients questioned 31 31 29 29 29 29

Mean HAMD score 24.52 15.97 23.79 16.72 24.17 23.41

s 2.249 4.637 1.698 4.174 1.692 3.803

SE 0.4039 0.8328 0.3154 0.7751 0.3142 0.7063

95% confidence interval

Lower limit 23.69 14.27 23.15 15.14 23.53 21.97

Upper limit 25.34 17.67 24.44 24.44 24.82 24.86

Coefficient of variation 9.17% 29.04% 7.14% 24.96% 7.00% 16.24%

Within group comparison of mean HAMD scores

before (day 0) and after (day 42) treatment

Comparison within group A B C

P-value (paired t-test) B0.0001 B0.0001 0.33

Difference between mean scores Highly significant Highly significant Not significant

Therapeutic effect demonstrated Yes Yes No

Between group comparison of mean HAMD

scores before treatment (day 0)

Comparison between groups A and B A and C B and C

P-value (paired t-test) 0.077 0.51 0.19

Difference between mean scores Not significant Not significant Not significant

Between group comparison of mean HAMD

scores after treatment (day 42)

Comparison between groups A and B A and C B and C

P-value (paired t-test) 0.34 PB0.0001 PB0.0001

Difference between mean scores Not significant Highly significant Highly significant

s, standard deviation.

042

***

Group C (placebo)

Group A (verum) two tablets SHR-5/day

Group B (verum) four tablets SHR-5/day

Groups of patients

erocsDMAH

042

***

Groups of patients

erocsIDB

Fig. 1. The effect of treatment with SHR-5 (groups A and B) vs. placebo (group C) as measured by the primary efﬁcacy variable,

namely, the change in total Hamilton Rating Scale for Depression (HAMD) and Beck Depression Inventory (BDI) scores

between the start (day 0) and the end (day 42) of medication. (For the within-group comparisons of mean scores at days 0 and 42

the signiﬁcance of the differences are shown as: ns, not signiﬁcant, and ***, signiﬁcantly different with PB0.0001).

V. D

ARBINYAN ET AL

346 NORD J PSYCHIATRY ×VOL 61 ×NO 5 ×2007

Table 3. Total scores obtained by patients suffering from mild and moderate depression in treatment groups A and B (verum) and

the placebo group C submitted to the Beck Depression Inventory (BDI) questionnaire prior to (day 0) and after (day 42) treatment.

Group A (verum),

two tablets SHR-5/day

Group B (verum), four

tablets SHR-5/day Group C (placebo)

Day of treatment period 0 42 0 42 0 42

Number of patients questioned 31 31 29 29 29 29

Mean HAMD score 12.23 7.097 10.38 4.750 11.33 9.897

s 5.214 3.636 4.296 2.744 2.440 5.659

SE 0.9364 0.6531 0.7978 0.5185 0.4455 1.051

95% confidence interval

Lower limit 10.31 5.763 8.745 3.686 10.42 7.744

Upper limit 14.14 8.431 12.01 5.814 12.24 12.05

Coefficient of variation 42.64% 51.24% 41.39% 57.76% 21.53% 57.18%

Within group comparison of mean HAMD scores

before (day 0) and after (day 42) treatment

Comparison within group A B C

P-value (paired t-test) PB0.0001 PB0.0001 0.21

Difference between mean scores Highly significant Highly significant Not significant

Therapeutic effect demonstrated Yes Yes No

Between group comparison of mean

HAMD scores before treatment (day 0)

Comparison between groups A and B A and C B and C

P-value (paired t-test) 0.14 0.40 0.72

Difference between mean scores Not significant Not significant Not significant

Between group comparison of mean

HAMD scores after treatment (day 42)

Comparison between groups A and B A and C B and C

P-value (paired t-test) 0.0075 PB0.0001 PB0.0001

Difference between mean scores Significant Highly significant Highly significant

s, standard deviation.

insomnia

day 0 day 42

day 0

day 42

0.0

2.5

5.0

7.5

***

Groups of patients

puorgbus-erocsDMAH

emotional instability

***

Groups of patients

uorgbus-e

sDMA

somatization

***

Groups of patients

HAMD score - subgroup

III

self-esteem

***

Group A (verum) two tablets SHR-5/day

Group C (placebo)

Group B (verum) four tablets SHR-5/day

Groups of patients

rgbus-e

DMAH

Fig. 2. The effect of treatment with SHR-5 (groups A and B) vs. placebo (group C) as measured by the secondary efﬁcacy

variables, namely, the change in the four Hamilton Rating Scale for Depression (HAMD) subgroups: (a) insomnia, (b) emotional

instability, (c) somatization and (d) self-esteem (corresponding to the different somatic and physiological aspects of mild and

moderate depression) between the start (day 0) and the end (day 42) of medication. (For the within-group comparisons of mean

scores at days 0 and 42 the signiﬁcance of the differences are shown as: ns, not signiﬁcant, **, signiﬁcantly different at P B0.001,

and ***, signiﬁcantly different with PB0.0001).

HODIOLA AND THE TREATMENT OF DEPRESSION

NORD J PSYCHIATRY ×VOL 61 ×NO 5×2007 347

R. rosea as a treatment, is that the positive effect of the

drug is mediated by mood stabilization and energy

restoration. This is the first randomized controlled study

that confirms the potential anti-depressive effects of

R. rosea as mono-therapy.

The present clinical study has shown that the stan-

dardized extract SHR-5 from R. rosea possesses a clear

and significant anti-depressive activity in patients suffer-

ing from mild to moderate depression. When adminis-

tered in a dosage of two tablets, each containing 170 mg

of extract, daily over a 6-week period, statistical

significant reduction in the overall symptom level of

depression as well as in specific symptoms of depression,

such as insomnia, emotional instability and somatiza-

tion, could be demonstrated. In higher doses, four

tablets per day over a 6-week period, an additional

positive effect could be shown, the level of self-esteem

increased significantly. No side-effects resulting from

treatment with SHR-5 could be detected in any group of

the groups.

Future studies with follow up period up to 12 weeks as

well larger multicenter studies, could eventually answer

the question of how SHR-5 compares with the classic

anti-depressants in efficacy.

Such studies could also focus on of the pharmacolo-

gical mechanisms for the mode of action for R. rosea in

mild to moderate depression.

Acknowledgements*This study was funded with project grants from

the Swedish Herbal Institute. The funding sponsor, however, had no

role in any practical aspect of the study including collection,

management, analysis and interpretation of the data, or review and

approval of the manuscript. The study was conceived by AP, the

protocol was formulated by VD, and the ethical application was

administered by GA. VD enrolled patients and performed the study

interventions, the assays and, together with EA, the data analysis. CM

drafted the manuscript, and all authors were involved in its critical

appraisal and ﬁnal approval. The authors wish to thank the volunteers

for their invaluable help with the study. (The use of SHR-5 for the

treatment of depression is the subject of pending patent application by

Swedish Herbal Institute.)

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V. Darbinyan, Department of Neurology, Armenian State Medical

University, Yerevan, Armenia.

G. Aslanyan, Scientific Centre of Drug and Medical Technology

Expertise, 15, Moscovyan Street, Yerevan, 375001, Armenia.

E. Amroyan, Scientific Centre of Drug and Medical Technology

Expertise, 15, Moscovyan Street, Yerevan, 375001, Armenia.

E. Gabrielyan, Scientific Centre of Drug and Medical Technology

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m, The PBM Clinic, Institute of Health Competence,

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A. Panossian, Swedish Herbal Institute Research &Development,

Spa˚rva

gen 2, SE- 432 96 A

skloster, Sweden.

V. D

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348 NORD J PSYCHIATRY ×VOL 61 ×NO 5×2007

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Feb 2025

Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine cycle imbalance, glucose metabolism, and ATP energy supply, which are associated with multiple molecular targets and signaling pathways in neuroendocrine-immune and blood circulation systems. Regeneration of damaged brain tissue is a long-lasting multistage process, including spontaneously regulating hypothalamus-pituitary (HPA) axis-controlled anabolic–catabolic homeostasis to recover harmonized sympathoadrenal system (SAS)-mediated function, brain energy supply, and deregulated gene expression in rehabilitation. The driving mechanism of spontaneous recovery and regeneration of brain tissue is a cross-talk of mediators of neuronal, microglia, immunocompetent, and endothelial cells collectively involved in neurogenesis and angiogenesis, which plant adaptogens can target. Adaptogens are small molecules of plant origin that increase the adaptability of cells and organisms to stress by interaction with the HPA axis and SAS of the stress system (neuroendocrine-immune and cardiovascular complex), targeting multiple mediators of adaptive GPCR signaling pathways. Two major groups of adaptogens comprise (i) phenolic phenethyl and phenylpropanoid derivatives and (ii) tetracyclic and pentacyclic glycosides, whose chemical structure can be distinguished as related correspondingly to (i) monoamine neurotransmitters of SAS (epinephrine, norepinephrine, and dopamine) and (ii) steroid hormones (cortisol, testosterone, and estradiol). In this narrative review, we discuss (i) the multitarget mechanism of integrated pharmacological activity of botanical adaptogens in stress overload, ischemic stroke, and long-lasting brain fatigue; (ii) the time-dependent dual response of physiological regulatory systems to adaptogens to support homeostasis in chronic stress and overload; and (iii) the dual dose-dependent reversal (hormetic) effect of botanical adaptogens. This narrative review shows that the adaptogenic concept cannot be reduced and rectified to the various effects of adaptogens on selected molecular targets or specific modes of action without estimating their interactions within the networks of mediators of the neuroendocrine-immune complex that, in turn, regulates other pharmacological systems (cardiovascular, gastrointestinal, reproductive systems) due to numerous intra- and extracellular communications and feedback regulations. These interactions result in polyvalent action and the pleiotropic pharmacological activity of adaptogens, which is essential for characterizing adaptogens as distinct types of botanicals. They trigger the defense adaptive stress response that leads to the extension of the limits of resilience to overload, inducing brain fatigue and mental disorders. For the first time, this review justifies the neurogenesis potential of adaptogens, particularly the botanical hybrid preparation (BHP) of Arctic Root and Ashwagandha, providing a rationale for potential use in individuals experiencing long-lasting brain fatigue. The review provided insight into future research on the network pharmacology of adaptogens in preventing and rehabilitating long-lasting brain fatigue following stroke, trauma, and viral infections.

Adaptogens in Long-Lasting Brain Fatigue: An Insight from Systems Biology and Network Pharmacology

Preprint

Full-text available

Jan 2025

Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine cycle imbalance, glucose metabolism, and ATP energy supply, which are associated with multiple molecular targets and signaling pathways in neuroendocrine-immune and blood circulation systems. Regeneration of damaged brain tissue is a long-lasting multistage process, including spontaneously regulating hypothalamus-pituitary (HPA) axis-controlled anabolic–catabolic homeostasis to recover harmonized sympathoadrenal system (SAS)-mediated function, brain energy supply, and deregulated gene expression in rehabilitation. The driving mechanism of spontaneous recovery and regeneration of brain tissue is a cross-talk of mediators of neuronal, microglia, immunocompetent, and endothelial cells collectively involved in neurogenesis and angiogenesis, which plant adaptogens can target. Adaptogens are small molecules of plant origin that increase the adaptability of cells and organisms to stress by interaction with the HPA-axis and SAS of the stress system (neuroendocrine immune and cardiovascular complex), targeting multiple mediators of adaptive GPCR signaling pathways. Two major groups of adaptogens comprise (i) phenolic phenethyl and phenylpropanoid derivatives and (ii) tetracyclic and pentacyclic glycosides, whose chemical structure can be distinguished as related correspondingly to (i) -monoamine neurotransmitters of SAS (epinephrine, norepinephrine, and dopamine), and (ii) - steroid hormones (cortisol, testosterone, and estradiol). In this narrative review, we discuss (i) the multitarget mechanism of integrated pharmacological activity of botanical adaptogens in stress overload, ischemic stroke, and long-lasting brain fatigue, (ii) - time-dependent dual response of physiological regulatory systems to adaptogens to support homeostasis in chronic stress and overload, and (iii) - dual dose depending reversal (hormetic) effect of botanical adaptogens. This narrative review shows that the adaptogenic concept cannot be reduced and rectified to the various effects of adaptogens on selected molecular targets or specific modes of action without estimating their interactions within the networks of mediators of the neuroendocrine-immune complex that, in turn, regulates other pharmacological systems (cardiovascular, gastrointestinal, reproductive systems) due to numerous intra- and extracellular communications and feedback regulations. These interactions result in polyvalent action and the pleiotropic pharmacological activity of adaptogens, essential for characterizing adaptogens as distinct types of botanicals. They trigger the defense adaptive stress response that leads to the extension of the limits of resilience to overload, inducing brain fatigue and mental disorders. For the first time, this review justifies the neurogenesis potential of adaptogens, particularly botanical hybrid preparation (BHP) of Arctic Root and Ashwagandha, providing a rationale for potential use in individuals experiencing long-lasting brain fatigue. The review provided insight into future research on network pharmacology of adaptogens in preventing and rehabilitating long-lasting brain fatigue following stroke, trauma, and viral infections.

The Potential of Selected Plants and Their Biologically Active Molecules in the Treatment of Depression and Anxiety Disorders

Article

Full-text available

Mar 2025
INT J MOL SCI

The incidence of anxiety and depression disorders is increasing worldwide. There is an increasing incidence of hard-to-treat depression with various aspects of origin. Almost 80% of people prefer to use natural remedies and supplements as their primary healthcare solution. Not surprisingly, around one-third of drugs were inspired by nature. Over the past three decades, the use of such remedies has increased significantly. Synthetic antidepressants may cause various negative side effects, whereas herbal medicines are favored because of their ability to relieve symptoms with minimal to no side effects and lower financial burden. This review provides an overview of herbs and biologically active compounds used to treat depression.

Efficacy of Pharmacological Interventions in Milder Depression: A Systematic Review and Meta‐Analysis

Article

Full-text available

Feb 2025

Background Mild depression lacks a consistent definition across diagnostic criteria and rating scales, posing challenges to standardizing treatment strategies. International guidelines predominantly recommend psychotherapy as the first‐line treatment for mild depression, while the use of antidepressants remains contentious. Supplements such as omega‐3 fatty acids, St. John's Wort, and magnesium have garnered attention as alternative therapeutic options for depression. This systematic review aims to assess the efficacy of pharmacological interventions, including supplements, in the treatment of mild depression. Methods Comprehensive searches were performed in PubMed and Embase through November 2024 to identify randomized controlled trials (RCTs) investigating pharmacotherapy or supplements for mild depression diagnosed using standardized criteria. Eligible studies underwent screening and risk of bias assessment utilizing the ROB2 tool. Data on remission rates, symptom improvement, dropout rates, and adverse events were extracted, with meta‐analyses conducted where applicable. Results Eight RCTs comprising 1049 participants met inclusion criteria. Among the agents studied, St. John's Wort was analyzed in two trials, both comparing it to fluoxetine. A meta‐analysis found no significant difference in response rates between the two treatments (risk ratio [RR] = 0.96, 95% CI: 0.78–1.18) or dropout rates (RR = 1.08, 95% CI: 0.62–1.88). For other agents, single studies evaluated their effects. Eicosapentaenoic acid and Rhodiola rosea demonstrated significant improvements in depressive symptoms compared to placebo. In non‐blinded trials, magnesium chloride showed efficacy in alleviating depressive symptoms. Other interventions, such as lavender, lemon balm, and transcranial electroacupuncture stimulation, were as effective as antidepressants. Conversely, S‐adenosylmethionine did not produce significant improvements relative to placebo. Conclusion This review demonstrates that certain supplements, such as eicosapentaenoic acids and Rhodiola rosea, are therapeutic options for mild depression. However, no RCTs compared antidepressants directly to placebo for mild depression. The paucity of high‐quality RCTs exclusively targeting mild depression limits definitive conclusions, warranting further rigorous research.

Herbal Medicines: From History to Current Research—A Comprehensive Survey

Chapter

Dec 2024

The use of natural resources, particularly plants, for prophylactic and curative purposes dates back to ancient times and has been employed by various indigenous peoples. To survive, plants produce a variety of substances known as secondary metabolites, which are known for their distinct biological properties useful in treating diverse pathologies. Integrating empirical, traditional, and scientific knowledge has led to an increased use of natural resources as therapeutic solutions. Consequently, regulating the production processes of herbal medicines is vital to ensure their safety and efficacy. With this context, the primary aim of this chapter is to explore herbal medicines and related aspects, offering a historical perspective alongside the advances and processes involved in their extraction and production.

Rhodiola rosea and its neuropsychotropic effects

Article

Mar 2016

Recent advancements in digital and traditional treatment strategies for major depressive disorder using medicinal herbs

Article

Dec 2024

Exploring the Therapeutic Potential of Bioactive Compounds from Plant Sources

Chapter

Feb 2025

This chapter delves into the therapeutic possibilities of bioactive compounds derived from plants. This chapter explores the therapeutic potential of bioactive compounds sourced from plants. These compounds have attracted significant interest in the medical, pharmaceutical, and nutritional fields because of their diverse biological effects and possible health benefits. The chapter offers a comprehensive examination of the various classes of bioactive mixtures present in plants, such as polyphenols, alkaloids, terpenoids, and flavonoids, elucidating their bioavailability, pharmacological properties, and mechanisms of action, all of which underscore their potential efficacy in preventing and treating diverse illnesses. Moreover, it investigates how bioactive compounds can enhance human health and well-being under their antioxidant, anti-inflammatory, antimicrobial, and anticancer properties. The chapter underscores the significance of sustainable sourcing and extraction techniques for procuring plant bioactive compounds, aligning with the escalating global demand for natural, plant-based remedies. It also addresses forthcoming research prospects and challenges in exploring and leveraging bioactive compounds from plants, underscoring the necessity for interdisciplinary partnerships and innovative strategies to tap into the therapeutic potential of these natural compounds fully. In essence, this chapter presents a valuable reservoir of knowledge for researchers, academics, and professionals in the fields of pharmacology, natural products chemistry, and phytotherapy, offering profound insights into the promising applications of bioactive mixtures derived from plants in enhancing human health and propelling medical advancements.

Natural Health Sciences: A Comprehensive Guide

Book

Jan 2025

Raşit Dinç

Rosavin derived from Rhodiola alleviates colitis in mice through modulation of Th17 differentiation

Article

Dec 2024
PHYTOMEDICINE

The use of herbal adaptogens together with tricyclic antidepressants in patients with psychogenic depressions

Article

Jan 1986

World medical association declaration of Helsinki: Ethical principles for medical research involving human subjects

Article

Jan 2014
J Am Coll Dent

General Assembly of the World Medical Association

Anxiety and Depression in a Primary Care Clinic

Article

Feb 1987
ARCH GEN PSYCHIAT

Michael Von Korff

• Over one half of all persons seen in a primary care clinic were identified as having anxiety or depressive disorder by the primary care provider, the General Health Questionnaire (GHQ), or the Diagnostic Interview Schedule (DIS). In only about 5% of all patients were findings positive on all three assessments concurrently. Both the GHQ and the practitioners identified over 30% of all patients as having a disorder, while about 8% had one or more of five DIS anxiety or depressive disorders (major depression, dysthymia, panic disorder, generalized anxiety disorder, or obsessive-compulsive disorder). Of the patients with DIS disorders 83% had positive GHQ scores, and 73% were identified by the practitioner as having a mental disorder.

Psychiatric Disorder in a Sample of the General Population with and without Chronic Medical Conditions

Article

Sep 1988

The authors studied data on psychiatric disorders and eight chronic medical conditions in a community sample of 2,554 persons. The sex- and age-adjusted prevalence of any psychiatric disorder in the preceding 6 months was 24.7% and of lifetime psychiatric disorder was 42.2% among persons with one or more medical conditions, compared to 17.5% and 33.0%, respectively, for persons with no medical condition. Persons with chronic medical conditions were more likely to have lifetime substance use disorders and recent affective and anxiety disorders. Arthritis, cancer, lung disease, neurological disorder, heart disease, and physical handicap were strongly associated with psychiatric disorders, but hypertension and diabetes were not.

Anxiety and depression in a primary care clinic: Comparison of Diagnostic Interview Schedule, General Health Questionnaire, and practitioner assessments

Article

Mar 1987
ARCH GEN PSYCHIAT

Over one half of all persons seen in a primary care clinic were identified as having anxiety or depressive disorder by the primary care provider, the General Health Questionnaire (GHQ), or the Diagnostic Interview Schedule (DIS). In only about 5% of all patients were findings positive on all three assessments concurrently. Both the GHQ and the practitioners identified over 30% of all patients as having a disorder, while about 8% had one or more of five DIS anxiety or depressive disorders (major depression, dysthymia, panic disorder, generalized anxiety disorder, or obsessive-compulsive disorder). Of the patients with DIS disorders 83% had positive GHQ scores, and 73% were identified by the practitioner as having a mental disorder.

The Beck Depression Inventory with medical patients

Article

Feb 1967

Hamilton Rating Scale for Depression with Medical In-Patients

Article

Feb 1967

The HRS was used as part of a comprehensive evaluation of depression in 153 medical inpatients. All the patients had some of the symptoms characteristic of depression as measured by the HRS. Although the scores did not agree with physicians' provisional diagnoses, they correlated well with scores obtained on the Beck Depression Inventory and with other depressive criteria. Further, patients with psychiatric diagnoses other than depression had low scores on the HRS. Negroes, younger patients, and those with lower income tended to have high scores. The HRS provides information about depression in medical in-patients.

Evaluation of Experiments With Adaptive Interim Analyses

Article

Jan 1995

A general method for statistical testing in experiments with an adaptive interim analysis is proposed. The method is based on the observed error probabilities from the disjoint subsamples before and after the interim analysis. Formally, an intersection of individual null hypotheses is tested by combining the two p-values into a global test statistic. Stopping rules for Fisher's product criterion in terms of critical limits for the p-value in the first subsample are introduced, including early stopping in the case of missing effects. The control of qualitative treatment-stage interactions is considered. A generalization to three stages is outlined. The loss of power when using the product criterion instead of the optimal classical test on the whole sample is calculated for the test of the mean of a normal distribution, depending on increasing proportions of the first subsample in relation to the total sample size. An upper bound on the loss of power due to early stopping is derived. A general example is presented and rules for assessing the sample size in the second stage of the trial are given. The problems of interpretation and precautions to be taken for applications are discussed. Finally, the sources of bias for estimation in such designs are described.

Anxiety Disorders in Primary Care

Article

Feb 1995
B MENNINGER CLIN

Studies indicate that persons with anxiety disorders seek treatment from general medical facilities as often as they do from mental health care settings. Yet primary care providers often do not recognize and treat these individuals effectively, perhaps because anxiety disorders present differently in the general health setting. In light of this situation, the authors note the need to disseminate efficacious treatment approaches to primary care settings. With this goal in mind, they review the prevalence of anxiety in the community and in primary care patients, the presentation of anxiety disorders in primary care, how to improve recognition of anxiety and depression in primary care, and treatment strategies for primary care providers.

A Rating Scale for Depression

Article