St. John's Wort Extract

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St. John's Wort Extract

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.3,4

 

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.6 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.1,2 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) Reponder 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) Reponder 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. For the severely depressed

patient, due to the lack of studies in this subcategory with St.

John's wort at this time the best recommendation is conventional

pharamacotherapy.

 

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.19 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.20 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.21-23 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.24 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.25,26 Magnesium

supplementation has produced very good results in both conditions

part of which may be due to its importance to serotonin

function.27,28

 

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.29 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.30 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. In

fact, the term " hypericism " has been used to describe a skin disease

found in animals who graze on large quantities of St. John's Wort.32

 

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.33 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.34

 

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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