The Problem With St. John's Wort

Is this herbal medicine an alternative to treating depression with drugs, or just a drug in another form?

Saint John’s Wort has a large body of literature supporting its use for depression, but it is relegated to a position of last resort in the Depression Protocol because it is really an herbal version of an SSRI rather than an alternative.

A meta-analysis of 27 trials including 3,808 patients supports St. John’s Wort as a monotherapy having nearly identical efficacy to SSRIs when used for four to twelve weeks, but with a 41% lower rate of dropping out due to side effects.

A meta-analysis focused on clinical recommendations concluded that “St John’s wort flowers at doses of 600mg to 1800mg (3:1–7:1 extract depending on product) per day standardised to a dose of approximately 0.2–0.3% hypericin and/or 5–6% hyperforin (once to three times per day depending on extract) is recommended for monotherapy in mild to moderate depression.”

However, St. John’s Wort makes little sense as a substitute for SSRIs when it essentially is an example of the closely related drug class of SNRIs. Pharmacological investigations suggest that it is a modest inhibitor of monoamine oxidase and a powerful inhibitor of the reuptake of serotonin, norepinephrine, and dopamine. It may also activate the sigma-1 receptor, a powerful mitochondrial effect exhibited to varying degrees by the different SSRIs. By blocking the cellular uptake of serotonin, we would expect it to have all the same effects on mitochondrial function as SSRIs broadly have.

Indeed, this herb might have a similar withdrawal syndrome as SSRIs do. One case was reported where a 58-year-old postmenopausal woman used 1800 milligrams three times a day for 32 days. She started developing photosensitivity, so stopped using it. Within 24 hours, she developed nausea, anorexia, dry retching, dizziness, dry mouth, thirst, cold chills, and extreme fatigue. These problems peaked on day 3, started getting better on day eight, and led to nine pounds of weight loss.

In a telephone survey of 43 individuals who used St. John’s Wort, thirteen developed withdrawal symptoms when they tried stopping. Nine had to restart it to make them go away, one had them resolve in a week, two in two to three weeks, and one was still suffering from them at the time of the survey.

Twenty of them reported side effects, four reporting photosensitivity, eight gastrointestinal upset, ten sleeping difficulties, two fatigue, seven anxiety and restlessness, and one reported sexual dysfunction. Among five who were using it in conjunction with other serotonin-modulating medications, two developed serotonin syndrome.

39 of them used the herb alongside aged meats and cheeses or over-the-counter cough and cold medications, with two of them acutely developing flushing and pounding headaches from the combination. One blacked out after combining it with alcohol.

St. John’s Wort traditionally had many uses, and in some areas it was used against the melancholy of winter, probably an early name for seasonal affective disorder.

The rationale was that it flowered on the summer solstice at the time of the feast of St. John the Baptist. Since winter caused depression from lack of sunlight, this yellow flower captured sunlight from the summer solstice that could be administered during winter.

Brain serotonin levels are primarily determined by exposure to light. This lines up well with serotonin’s primary role being to support mitochondrial function during hypoxia because when we rise from sleep we are instantaneously experiencing “relative hypoxia” until our mitochondrial function can rise to adapt to the higher metabolic demand of wakefulness.

If St. John’s Wort indeed activates the sigma-1 receptor, it would be expected to increase brain serotonin and thereby act similarly to sunlight.

The fact that one of its principal adverse effects is photosensitivity also lines up with this: by providing too much biochemical similarity to sunlight, one overdoses on the sunlight.

These collectively support the traditional concept that the flower captured sunlight as it bloomed on the summer solstice and then delivered it during winter to those who consumed it.

The photosensitivity of St. John’s Wort can include sun-induced pain, paresthesia, and rashes.

SSRIs can cause various forms of photosensitivity as well, including hyperpigmentation, epilepsy, and skin rashes.

Since photosensitivity is shared across these substances, it probably results from their main mechanisms of action regarding serotonin synthesis and transport.

This might be due to driving tryptophan into the synthesis of serotonin and away from the synthesis of NAD+. Sunlight exposure causes DNA damage, which requires the irreversible loss of NAD+ to repair, thereby synergizing to aggravate NAD+ deficiency in the tissues most exposed to sunlight, such as the skin and the eyes. This principle underlies the photosensitivity of classical pellagra expressed as the “dermatitis” of the “three D’s” (or four, if you include “death”).

Alternatively, elevated catabolism of serotonin to 5-hydroxyindoleacetic acid (5-HIAA) could cause photosensitivity because this compound becomes cytotoxic when exposed to light.

If we put the St. John’s wort data into historical perspective, it seems that traditional flower concoctions probably had lower doses, and use for the melancholy of winter limited the duration of use to twelve weeks.

This is in gross contrast to the modern diagnostic framework that identifies people as depressed instead of identifying “melancholy” as something that occurs due to “temporary deficiency of sunlight,” that demanded a temporary fix. The modern treatment framework then puts people on SSRIs for years, which has no basis whatsoever in the randomized controlled trial literature and is tied to horrific imprisonment of people with the threat of severe and protracted withdrawal.

While randomized controlled trials should indeed be used as the gold standard for inferring causation between a strategy and its outcome, they should not provide the boundaries of safe use in most cases except to potentially restrict them beyond the traditional use of an herb.

While the pharmaceutical-medical industrial complex claims to follow randomized controlled trials to make treatment decisions, this is mostly fake. For example, SSRIs are mostly studied up to twelve weeks but SSRIs are on average prescribed for five years.

Ironically, the medieval European use of St. John’s Wort better conformed to the boundaries of modern randomized controlled trials without even knowing about them, since its use lasted for one season rather than being used indefinitely for years.

Since St. John’s Wort has equivalent efficacy and superior tolerability to SSRIs, it is better to use St. John’s Wort than SSRIs.

However, since it does work in much the same way and it does pose a similar risk of withdrawal-induced mitochondrial dysfunction, it should be used toward the lower end of the effective dose range and for no longer than twelve weeks. It should be used only if still needed after addressing nutritional deficiencies, idiosyncratic mitochondrial dysfunction, and the low-hanging fruit of depression prevention such as boosting protein intake up to the range that powerfully protects against depression.

This is exactly how I have positioned it in the Depression Protocol.