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- Rhodiola (Rhodiola rosea, Crassulaceae)
- Depression
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Date:
12-15-2016 | HC# 061662-558
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Re: Review of Rhodiola in the Treatment of Depression
Amsterdam
JD, Panossian AG. Rhodiola rosea L.
as a putative botanical antidepressant. Phytomedicine.
June 15, 2016;23(7):770-783.
In addition to enhancing energy and performance,
the botanical adaptogen rhodiola (Rhodiola
rosea, Crassulaceae) root and rhizome is used to counter the effects of
stress and fatigue. Stress and fatigue are common symptoms in patients with
depression. In this article, the authors review the scientific evidence
supporting the potential efficacy of rhodiola in the treatment of depression.
STN Easy service was used to search all
comprehensive databases including BIOSIS, CAplus, EMBASE, NAPRALERT, PubMed, TOXCENTER,
etc. The Russian State Library (Moscow, Russia) and the library of the Swedish
Herbal Institute (Vallberga, Halland, Sweden) also were searched. The latter facility
contains a complete collection of full-text Russian articles on this topic and
their English translations dating back to 1943. Search terms were not specified.
Experimental evidence
Early studies conducted in the former Soviet Union
between 1965 and 1986 found that rhodiola extract increased bioelectrical activity
in the brain, enhanced conditioned avoidance behavior and facilitated learning
in rats, and a single dose of extract improved learning and attention in rats
24 hours and ten days after administration.
Studies conducted between 2002 and 2015 have reported
more detailed results. Administration of rhodiola extract for three weeks
ameliorated behavioral and metabolic responses to chronic stress in rats,
comparable to the antidepressant fluoxetine. Rhodiola root and rhizome extract
had antidepressant activity in the despair forced swimming test, comparable to
that of the antidepressants imipramine and amitriptyline. This effect was
evident after a single oral dose. In the same animal model, the effects of
rhodiola extract and rhodiola constituents were compared to imipramine and St.
John's wort (Hypericum perforatum,
Hypericaceae) flowering tops. The rhodiola extract exerted greater
antidepressant effects than comparable doses of imipramine and St. John's wort;
the constituents rhodioloside (salidroside) and tyrosol were active, while
rosavin, rosarin, rosin, cinnamic alcohol, cinnamaldehyde, and cinnamic acid
were inactive. However, in another study, a fixed combination of rhodioloside, rosavin,
rosarin, and rosin was more effective than any of the individual compounds
alone, suggesting a synergistic effect.
Several studies using animal models of depression
have provided evidence that rhodiola extract modulates neurotransmitter levels
in the hippocampus, brainstem, cerebral cortex, and hypothalamus. It has also
been reported to promote proliferation and differentiation of neural stem
cells, and to increase the permeability of the blood-brain barrier to
precursors of dopamine and serotonin. In rabbits exposed to stress, seven days
of treatment with rhodiola extract and rhodioloside significantly inhibited the
stress response mediator phosphorylated kinase (JNK). In a rat model of
depression, two weeks of treatment with rhodioloside decreased tumor necrosis
factor-α and interleukin-1β levels, increased the expression of glucocorticoid
receptor and brain-derived neurotrophic factor, and decreased levels of
corticotropin-releasing hormone.
Mechanisms of action
The mechanisms of action of rhodiola extract and
its constituents have been studied in cell cultures, nematodes, rodents, and
humans. These studies have provided evidence that the antidepressant effect of
rhodiola may be associated with the following mechanisms: modulation of stress
response mediators, modulation of the hypothalamic-pituitary-adrenal axis
homeostasis, modulation of G-protein coupled receptor signaling pathways, and stimulation
of expression and release of neuropeptide Y (NPY). In addition, rhodiola
extract has been shown to modulate the expression of over 50 genes which are
thought to be involved in the pathogenesis of depression. Although the
constituent rosiridin has been found to be an active inhibitor of monoamine
oxidase A, the authors point out that the amount of this compound found in
rhodiola extract is so minute that it precludes monoamine oxidase inhibition as
the antidepressant mechanism.
Early clinical studies (1966-1986)
The authors point out that the early clinical
trials conducted in the former Soviet Union (n=7) are of poor quality and
difficult to interpret because of the following: studies were not randomized,
most studies were not controlled or blinded, standardized psychological
measures were not used, and some of the trials enrolled both healthy and
depressed subjects. Moreover, the diagnostic criteria for depression used were
different from those employed in other countries and as a result, patients with
varying psychological conditions were enrolled (depression, asthenic-depressive
syndrome, neurosis, and anxiety).
The results of these early studies may be briefly
summarized as follows: treatment with rhodiola extract for two to three weeks
had antidepressant effects in healthy subjects and in subjects with pronounced
fatigue; patients with insomnia, irritability, and somatic complaints treated
for ten days had improved motor and cognitive function, as well as lower
irritability and lower anxiety levels; and three studies reported that rhodiola
as an adjunct to psychotropic drugs not only had an additive effect but also
reduced the adverse effects of the drugs.
Recent clinical trials (2007-2015)
In a 2008 open-label study of ten patients with
generalized anxiety disorder, 340 mg of RhodaX™ (Bodyonics Ltd.; Hicksville,
New York) daily for ten weeks resulted in a significant lessening of Hamilton
Anxiety Rating Scale (HAM-A) scores (P=0.01) and Hamilton Depression Rating
Scale (HAM-D) scores (P=0.001).
A 2007 randomized, double-blind, placebo-controlled
trial investigating the effect of the rhodiola extract SHR-5 (Swedish Herbal
Institute) in 89 patients with mild to moderate depression compared six weeks of
treatment with daily dosages of 340 mg and 680 mg to placebo. HAM-D scores
significantly improved in both dosage groups (P<0.0001 for both) compared to
baseline, while no significant change was observed in the placebo group;
compared to placebo, the improvement in both dosage groups was significant
(P<0.001). However, the results of this trial have been questioned. First,
there is invariably a significant placebo response in all placebo-controlled antidepressant
trials and this trial reported no significant change from baseline in the mean
score for the placebo group. Second, the "magnitude [of the treatment
effect] is unlikely in an under-powered pilot trial of this design."
A 2015 randomized, double-blind,
placebo-controlled study of patients with major depressive disorder compared 340
mg/day SHR-5 versus 50 mg/day sertraline versus placebo for 12 weeks. The SHR-5
capsules contained powdered extract standardized to a content of 3.07% rosavin
and 1.95% rhodioloside (Investigational New Drug #105,063). The primary outcome
was change in HAM-D score; secondary outcomes were changes in Clinical Global
Impression (CGI) and Beck Depression Inventory (BDI) scores. There was no
significant change in HAM-D, CGI, or BDI scores among treatment groups.
However, there were clinically meaningful odds ratios of global improvement for
rhodiola and sertraline versus placebo; compared to placebo, the odds of
improvement were 1.4 for rhodiola and 1.9 for sertraline. More study-related
adverse effects were reported in the sertraline group (63.2%) compared to the
rhodiola (30.0%) and placebo (16.7%) groups.
The authors conclude that rhodiola "demonstrates
multi-target effects on various levels of the regulation of cell response to
stress, affecting various components of the neuroendocrine, neurotransmitter
receptor and molecular networks associated with possible beneficial effects on mood."
Rhodiola was well tolerated in the short-term clinical studies with a good
safety profile. Despite the shortcomings of the human trials, the clinical
evidence suggests that rhodiola "may represent a potential alternative
treatment for individuals who are intolerant to conventional antidepressants or
seek to avoid them." Larger, well-designed, and sufficiently powered
clinical studies are needed to confirm the potential efficacy of rhodiola in
the treatment of depression.
One of the authors (AG Panossian) is an employee of Swedish Herbal
Institute.
—Amy C. Keller, PhD
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