ST.JOHN'S WORT EXTRACT,GINGKO BILOBA & ANTIDEPRESSANTS

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ST.JOHN'S WORT EXTRACT,GINGKO BILOBA & ANTIDEPRESSANTS

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ST. JOHN'S WORT EXTRACT

by Michael T. Murray, N.D.

 

http://www.doctormurray.com/articles/worteditorial.htm

 

The fastest rising star in herbal medicine in Germany and now the

United States is the St. John's wort extract standardized to contain

0.3% of hypericin.

 

A total of 66 million daily doses of St. John's wort extracts were

prescribed by German physicians in 1994 are expected to be

dramatically higher when tallied for 1995, 1996, and beyond. In

fact, these German doctor's now prescribe St. John's wort extract 8

times more often than Prozac.

 

These doctors are knowledgeable about both medicines, but clearly

favor St. John's wort extract. Why? The simple answer is that St.

John's wort produces equal or better results in relieving

depression, but has far fewer side effect. Over 25 double-blind

randomized trials involving a total of 1,757 outpatients with mild

to moderately severe depression

have shown St. John's wort extracts standardized for hypericin to

yield excellent results in the treatment in depression with

virtually no side effects.

 

What is St. John's wort?

 

St. John's Wort (Hypericum perforatum) is a shrubby perennial plant

with numerous bright yellow flowers. The term wort is an old English

term for plant

 

.. Its naming after St. John was based on the claim that red spots,

symbolic of the blood of St. John, appeared on the leaves of the

plant on the anniversary of the saint's beheading.

 

St. John's wort is cultivated worldwide, but grows quite well in

Northern California and Southern Oregon.

 

How can I be assured I will benefit from St. John's wort extract?

 

If you want to see the same sort of results noted in the clinical

trials in Europe, it is absolutely essential that you use the same

extract used in the studies.

 

This extract is a specially-prepared extract produced

via an extraction with 80% methanol (subsequently the methanol is

removed). The extract is standardized to contain 0.3% hypericin.

 

Although hypericin is a key component, this extract is composed of a

wide range of compounds constituting the remaining 99.7% of the

extract.

 

 

Distributors of this standardized extract employ HPLC techniques to

identify not only the hypericin and pseudohypericin, but also

related compounds, flavonoid components, xanthones, cinnamic acid,

and several other key components.

 

The point is that although the dosage is based

upon hypericin levels (2.7 mg per day), assuring appropriate levels

of these other constituents is also vitally important.

 

How does St. John's extract work?

 

Originally it was thought that the action of St. John's wort extract

as an antidepressant was due to hypericin acting as an inhibitor of

the enzyme monoamine oxidase (MAO) - thereby resulting in the

increase of CNS monoamines such as serotonin and dopamine.

 

However, newer information indicates that St. John's wort possesses

no in vivo inhibition of MAO.

 

At least two other mechanisms have been proposed: modulation of

interleukin-6 activity and inhibition of the re-uptake of serotonin.

 

The modulating effects of St. John's wort extract on interleukin-6

(IL-6) is the most interesting as it proposes a mechanism by which

St. John's wort

interacts with the link between the immune system and mood.

 

The immune system and the nervous system share many common

biochemical features and regulatory interactions.

 

In regards to IL-6, this cytokine is heavily involved in the

communication between cells within and outside the immune system.

 

In relationship to the nervous system, IL-6 is known to modulate

hypothalamic-pituitary-end organ axes, especially the

hypothalamic-pituitary-adrenal (HPA) axis.

 

The hypothesis is that an elevation in IL-6 results in activation of

the HPA axis leading to elevations in CRH and other adrenal

regulatory hormones - hallmark features in depression.

 

St. John's wort extract has shown an ability to reduce IL-6 levels,

hence this action may explain

the clinical effectiveness of St. John's wort extract.5

 

St. John's wort extract has also been shown to inhibit the re-uptake

of serotonin similar in fashion to drugs like fluoxetine (Prozac),

paroxetine (Paxil), and sertraline (Zoloft).

 

The study demonstrating a 50% serotonin re-uptake inhibition

utilized the 0.3% hypericin content standardized extract at a

concentration of 6.2 mcg/ml and did not attempt to identify the

active inhibitors.

 

Even though the authors of the study concluded " that the

antidepressant activity of Hypericum extract is due to inhibition of

serotonin uptake

by postsynaptic receptors. "

 

An important point must be made - until pharmacokinetic studies

demonstrate that St. John's wort components pass across the blood-

brain barrier a primary site of action outside the central nervous

system cannot be ruled out.

 

How effective is St. John's wort?

 

Very. As stated above, there have been over 25 double-blind studies

with St. John's wort extract in the treatment of depression. The

methodological quality of this research, particularly the studies

since

1989, has been judged as being acceptable by strict criteria.

 

The overall results have also been judged as providing good

documentation of antidepressant activity. Those studies with the

highest

methodological quality rating are listed in Table 1.

 

Table 1 - Summary of Clinical Trials with St. John's wort Extract in

Depression

 

Trials comparing St. John's wort to placebo

Trial # of patients HDS at baseline Total hypericin per day(mg)

Duration (weeks) Responder rate St. John's wort Responder rate

Placebo

 

---

 

 

 

Halama7 50 18.0 1.08 4 10/25 0/25

Hansgren8 72 20.4 2.7 4 27/34 9/38

Harrer9 120 20.9 0.75 6 22/58 9/58

Hubner10 40

12.4 2.7 4 14/20 9/20

Quandt11 88 17.3 0.75 4 29/44 3/44

Reh12 50 20.0 1.0 8 20/25 11/25

Schmidt (1993)13 65 16.4 1.08 6 20/32 6/33

Schmidt (1989)14 40 29.5 0.75 4 15/25 3/24

Sommer14 105 15.8 2.7 4 28/50 13/55

Totals 630 185/313

(59%) 63/322

(20%)

 

 

Trials comparing St. John's wort extract to an antidepressant drug

Trial # of patients HDS at baseline Total hypericin per day(mg)

Duration (weeks) Responder rate St. John's wort Responder rate Drug

Bergman16 (amitryptiline) 80 15.4 0.75 6 32/40 28/40

Harrer17 (maprotiline) 102 19.4 2.7 4 27/51 28/51

Vorbach18 (imipramine) 135 19.4 2.7 4 42/67 37/68

Totals 317 101/158

(64%) 93/159 (58%)

 

* Responder rate - a decrease in the HAMD of greater than 50% or

achieving a value less than 10

 

In the study with the highest methodological rating, 135 depressed

patients were treated in 20 centers.18 Patients were given either

St. John's wort extract (0.3% hypericin content, 300 mg t.i.d.) or

imipramine (25 mg t.i.d.) for a period of six weeks.

 

Inclusion diagnoses were typical depressions with single episode,

several episodes, depressive neurosis, and adjustment disorder with

depressed mood in accordance with DSM-III-R. Main assessment

criteria

were the Hamilton Depression Scale (HAMD), the Depression Scale

according to von Zerssen (D-S) and the Clinical Global Impressions

(CGI).

 

In both treatment groups, there were significant decreases in the

HAMD from 20.2 to 8.8 in the St. John's wort group and from 19.4 to

10.7 in the imipramine group. The D-S point value also dropped from

39.6 to 27.2 in the St.John's wort group and 39.0 to 29.2 in the

imipramine group.

 

The analysis of CGI revealed comparable results in both treatment

groups.

 

The main advantage, however, was not so much a difference in

therapeutic outcome, but rather a significant advantage in terms of

lack of side effects and excellent patient tolerance in the St.

John's wort group.

 

St. Johns Wort Imipramine

Hamilton Depression Scale

Initial measurement 20.2 19.4

 

Week 6 8.8 10.7

Depression Scale (von Zerssen)

Initial measurement 39.6 39

Week 6 27.2 29.2

 

 

Is there anyone who should not use St. John's wort extract?

 

At this time, St. John's wort is most appropriate for the treatment

of

mild to moderately-severe depression.

 

Can St. John's wort extract be used with other antidepressant drugs?

 

Yes, I have used St. John's wort successfully without incident in

patients taking SSRIs, Effexor, and various tricyclics.

 

I have not used it in conjunction with MAO inhibitors.

 

I have also used St. John's wort extract with 5-hydroxytryptophan

(5-HTP). The real concern when mixing antidepressant drugs is

producing

what is referred to as the " serotonin syndrome. " It is characterized

by

confusion, fever, shivering, sweating, diarrhea, and muscle spasms.

 

Although this syndrome has never been produced when St. John's wort

extract has been given alone, it is theoretically possible that

combining St. John's wort with standard antidepressant drugs could

produce this syndrome.

 

My recommendation is that when using St. John's wort in combination

with

standard antidepressant drugs that patients be monitored closely for

any

symptoms suggestive of the serotonin syndrome. If these symptoms

appear,

elimination of one of the therapies is indicated.

 

What is your recommendation for tapering off the antidepressant

drug?

 

It really depends on the patient and the severity of the pre-

treatment

depression. First of all, I should state that I always try to work

in

conjunction with the prescribing physician to accomplish the

patient's

goal of getting off the drug.

 

In mild cases, I will have the patients start the St. John's wort

extract while reducing the drug to ½ the daily dosage for two weeks.

After which, they will totally eliminate the drug. For more severe

cases, they keep the dosage of their antidepressant as it is and add

the

St. John's wort extract. We then evaluate at the end of one month

and

begin tapering off the drug is sufficient mood-elevating effects

have

been noted.

 

How long should a patient stay on St. John's wort extract?

 

Again, it really depends upon the patient. In general, I view St.

John's

wort as a " crutch " until dietary, lifestyle, and attitude changes

have

had a chance to really take hold.

 

My experience is that only about 25% of people really require

prolonged

therapy beyond six months. This patients typically have dysthymic

personality traits and possibly a genetic predisposition to

depression.

 

Given St. John's wort excellent safety profile and the concern over

the

long-term safety of antidepressant drugs, I would much rather see

patients using St. John's wort extract for an indefinite period than

drugs like Prozac, Paxil, Zoloft, and others.

 

Does St. John's wort extract negatively affect sleep like other

antidepressant agents?

 

No. While antidepressant drugs, particularly tricyclic

antidepressants

and MAO inhibitors, interfere with REM (rapid eye movement) sleep

and

reduce sleep quality,

St. John's wort has been shown to not interfere with REM sleep and

to

actually improve sleep quality and well-being.

 

The ability to improve sleep quality may turn out to be a key

mechanism

of action for St. John's wort extract. It does not act as a sedative

(i.e., it does not reduce sleep onset) nor does it change total

sleep

duration. It simply improves sleep quality. St. John's wort

accomplishes

this when given in divided dosages throughout the day (e.g., 300 mg

three times daily).

 

How long does it take before its antidepressant effects are noted?

 

Most patients begin reporting effects within the first two weeks.

Like

most antidepressant agents, maximum benefits are typically seen

after

six to eight weeks of continued use.

 

What should be done if someone does not respond to St. John's wort

extract?

 

Depression requires a comprehensive treatment plan.

 

St. John's wort extract will not be effective if there is an

underlying

nutrient deficiency or hormonal imbalance.

 

For example, if some is deficient in folic acid or suffering from

hypothyroidism it is unrealistic to expect St. John's wort extract

to

produce a dramatic improvement.

 

In cases of depression that have not responded to St. John's wort

extract alone where no other identifiable cause of depression could

be

found,

I have used supportive therapy.

 

If the patient is over the age of 50, supportive therapy consists of

Ginkgo Phytosome (80 mg three times per day).

 

Researchers began studying the antidepressive effects of Ginkgo

biloba

extract as a result of the improvement in mood noted by patients

suffering from decreased blood flow to the brain (cerebrovascular

insufficiency).

 

Several studies were conducted to determine if Ginkgo biloba extract

was, in fact, an antidepressant.

 

In one of the more recent double-blind studies, 40 patients (ages

ranged

from 51 to 78 years) with depression who had not benefited fully

from

standard antidepressant drugs were given

either 80 mg of Ginkgo biloba extract three times daily or a placebo.

 

By the end of the 8th week study, the total score of the Hamilton

Rating Scale for Depression in the Ginkgo biloba extract group had

dropped from 14 to 4.5.

In comparison, the placebo group dropped from 14 to only 13.

 

This study indicated two things:

 

(1) Ginkgo biloba extract can be used with standard antidepressants

and/or St. John's wort extract and

 

(2) it may enhance their effectiveness, particularly in patients

over 50

years of age.

 

I prefer the Ginkgo biloba extract bound to phosphatidylcholine

(Ginkgo

Phytosome) to un-bound ginkgo.

 

In patients, under the age of fifty, I tend to favor 5-

hydroxytryptophan

(5-HTP) - the direct precursor to serotonin.

 

5-HTP has shown impressive results as an antidepressant agent in

numerous double-blind studies including head-to-head comparison

studies

with standard antidepressant drugs.

 

Currently, 5-HTP is only available through compounding pharmacists.

To

find a compounding pharmacist in your area, call the International

Academy of Compounding Pharmacists 1-800-927-4227.

 

Is St. John's wort extract effective in seasonal affective disorder?

 

Yes, but best results are achieved when it is combined with light

therapy. Seasonal affective disorder (SAD) represents a subgroup of

major depression with a regular occurrence of symptoms in

autumn/winter

and full remission in spring/summer.

 

Light therapy has become the standard treatment of this type of

depression. Apart from this, St. John's wort extract also seems to

provide an improvement of SAD symptoms.

 

The aim of a controlled, single-blind study was to evaluate if St.

John's wort could be beneficial in treating SAD patients and whether

the

combination with light therapy would be additionally advantageous.

 

Patients who fulfilled DSM-III-R criteria for major depression with

seasonal pattern were randomized in a 4-week treatment study with

900 mg

of St. John's wort extract (0.3% hypericin content) per day combined

with either bright (3000 lux, n = 10) or dim light (<300 lux

therapy).

 

The fact that there was a significant reduction in the Hamilton

Depression scale in both groups (72% and 60%, respectively)

indicates

that St. John's wort extract may offer support to patients with SAD

as a

sole therapeutic agent as well as in combination with light therapy.

Obviously, the best results were obtained in combination with bright

light.

 

Are there any other indications for St. John's wort extract?

 

One of the key indications for St. John's wort extract in my

clinical

practice is in the treatment of fibromyalgia. Fibromyalgia is a

recently

recognized disorder regarded as a common cause of chronic

musculoskeletal pain and fatigue.

 

Although fibromyalgia may be the " pop " diagnosis of the 1990s, it is

a

real clinical entity estimated to affect about 4% of the general

population. Although fibromyalgia is a disorder that has many

facets,

the central cause of the pain of fibromyalgia are low levels of

serotonin. As a result of a chronic low level of serotonin, the

sensation of pain is great exaggerated.

 

Table - Diagnostic Criteria for Fibromyalgia

 

Diagnosis requires fulfillment of all three major criteria and four

or

more minor criteria.

 

Major criteria

 

Generalized aches or stiffness of at least three anatomic sites for

at

least three months.

Six or more typical, reproducible tender points.

Exclusion of other disorders which can cause similar symptoms.

Minor criteria

Generalized fatigue

Chronic headache

Sleep disturbance

Neurological and psychological complaints

Joint swelling

Numbing or tingling sensations

Irritable bowel syndrome

Variation of symptoms in relation to activity, stress, and weather

changes

 

Although St. John's wort extract can certainly be effective on its

own,

in my clinical experience I have found that the combination of St.

John's extract (300 mg, 0.3% hypericin content),

magnesium (200 to 250 mg),

and 5-HTP (100 mg) three times daily seems to work better than using

any

of these three supplements alone.

 

Low magnesium levels are a common finding in patients with

fibromyalgia

as well as in chronic fatigue syndrome.

 

Magnesium supplementation has produced very good results in both

conditions part of which may be due to its importance to serotonin

function.

 

One of the primary benefits with St. John's wort as well as 5-HTP

relates to their ability to improve sleep quality. One of the key

findings in patients with fibromyalgia is a reduced REM sleep and an

increased non-REM sleep.

 

In addition, the deeper levels (stage III and IV) are not achieved

for

long enough periods. As a result people with fibromyalgia wake up

feeling tired, wornout, and in pain. The severity of the pain of

fibromyalgia correlates with the rating of sleep quality. What I

mean by

this statement is that when patients with fibromyalgia get a good

night's sleep they have less pain. Conversely, when they sleep

poorly,

they feel terrible.

 

The analogy I give my patients suffering from fibromyalgia is that

sleep

is like a battery re-charger. If the body, especially our muscles,

is

not being re-charged, it hurts. With a good, restful sleep the

battery

become fully charged and functions more optimally. The outcome is

the

body doesn't hurt anymore.

 

What is the best dosage schedule for St. John's wort?

 

The dosage of St. John's wort preparations are based upon the

hypericin

content. The overwhelming majority of the studies in depression have

used the St. John's wort extract standardized to contain 0.3%

hypericin

at a dosage of 300 mg three times daily.

 

Is St. John's wort extract safe?

 

No significant side effects have been reported in the numerous

double-blind studies, but perhaps the best demonstration of the

excellent safety record of St. John's wort extract is a large scale

study involving 3,250 patients conducted in Germany.

 

Results were analyzed by means of a patient questionnaire. Pooled

data

indicated that symptoms of depression were reduced in frequency and

intensity by approximately 50%. The frequency of undesired side

effects

were reported in 79 patients (2.43%) and 48 (1.45%) discontinued

therapy. The most frequently noted side effects were

gastrointestinal

irritation (0.55%), allergic reactions (0.52%), fatigue (0.4%), and

restlessness (0.26%).

 

The frequency and severity of side effects with St. John's wort

extract

are clinically insignificant, especially when compared to the well-

known

side effects of tricyclics and other antidepressants. There have

been no

deaths due to St. John's wort toxicity, a stark contrast to the 31

deaths per one million prescriptions produced by synthetic

antidepressants.31

 

What about phototoxicity?

 

There is considerable evidence that St. John's Wort can cause severe

photosensitivity in animals grazing extensively on the plant.

 

Because of the possibility of photosensitivity, it is often

recommend that individuals, especially those with fair skin, avoid exposure to

strong sunlight and other sources of ultraviolet light when using

St. John's Wort.

However, while this recommendation may be appropriate it must be

pointed out that the therapeutic dosage

of 2.7 mg hypericin per day is about 30 to 50 times below

the level

required to produce phototoxicity.

 

Reports of photosensitivity in humans have been rare and have been

limited to those taking excessive quantities for HIV infection.

 

St. John's Wort is unlikely to be toxic to humans when used at

recommended medicinal doses. However, individuals with AIDS taking

larger amounts of St. John's wort extracts (or hypericin) have

developed photosensitivity.

 

Should tyramine-containing foods be avoided?

 

Initially it was also recommended that those taking St. John's wort

should also avoid foods and medications that are known to negatively

interact with MAO-inhibiting drugs such as tyramine-containing foods

(cheeses, beer, wine, pickled herring, yeast, etc.) and drugs such

as L-dopa and 5-HTP should be avoided.

 

However, given recent information

on the lack of any in vivo MAO

inhibition, this recommendation is not justified.

 

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