In a previous article, I looked at the effects that Saint Johns wort (SJW) has on the SARS2 virus that causes covid, and outlined how it could possibly help in the acute phase of an infection, or with a lingering chronic infection. This post is about how SJW might block mast cell hyperactivity (which is almost universal in Long Haulers), and it is independent of the anti-viral activity of the herb. This could be useful for Long Covid, MCAS, and a variety of other conditions.
“Neurochemical studies with St. John's wort in vitro.” Pharmacopsychiatry, Jul 2001, PMID 11518063.
Here is the sentence that deserves our attention:
“Hypericin showed the most potent binding inhibition of all tested constituents to human CRF1 receptor with an IC50 value of 300 nM.”
The CRF1 receptor is a button that the Corticotrophin Releasing Factor pushes. When this button is pushed, the adrenal cortex produces cortisol. Hypericin binds to the button and prevents it from being pushed… so there is less cortisol produced.
Cortisol is very effective for adapting to certain conditions and it is often referred to as ‘the stress hormone.’ In the short run, it is very useful. But when cortisol levels are chronically elevated, health suffers. And many people have chronically elevated cortisol levels. One good way to induce depression (in lab rats or in people) is to expose them to high levels of chronic stress.
Pushing the CRF button also signals mast cells to fire. 1 2 3
When they do, those cells dump packets of histamine and other inflammatory compounds. Blood pressure can drop (sometimes locally, sometimes system-wide) as the histamine opens blood vessels. Tryptase enzyme is released to chew up proteins - great if they encounter a virus or bacteria, not so good when they only encounter our own tissue. Leukotrienes and prostaglandins are released to put the immune system and local tissues on high alert. The body mobilizes for war. All of this is valuable for an acute infection. But when it continues for weeks and months when there is no invader, it erodes health.
The second part of the quoted sentence is also very remarkable. Translation from the sciency language: At a concentration of 300 nanomolar, hypericin reduces cortisol production by 50%. With a molecular weight of 504.4 grams, this means that hypericin can cut cortisol release in half when present in biological systems at concentrations under 1 part per million.
So at low doses, hypericin can turn down cortisol production. It has the potential to reduce how twitchy mast cells are, and how likely they are to dump their packets of inflammation.
The Modern History of SJW
For decades, scientists have tried to figure out Saint Johns wort (SJW). It was easy to verify that the herb was effective in treating mild and moderate depression - but ideas on how it actually works have been rather scattered and unsatisfactory. When the only model of depression that researchers had was the Catecholamine hypothesis, they tried to pigeon-hole SJW into that idea, but it didn’t really fit. And when Prozac and the serotonin hypothesis came along, it was natural to hypothesize that SJW worked by boosting serotonin - but again, the data didn’t fit.
The article above shows the mechanism of how SJW suppresses chronic arousal and stress that can cause fatigue and depression, but strangely, that article has not gotten much attention. Perhaps this situation is related to the fact that even though there is evidence that SJW is as effective as other anti-depressants with fewer side effects4, it may never be taken into mainstream medicine … so there is less research funding.
Although the CRF1 blocking mechanism has been mostly overlooked, other researchers have documented the consequences of this from a more zoomed out view. There have been several studies that looked at how SJW can improve the HPA axis … the interaction of the Hypothalamus, Pituitary, and Adrenal glands. Consider this article:
“Flavonoids of St. John's Wort reduce HPA axis function in the rat.” Planta Medica, Oct 2004, PMID 15490333.
The article found that hypericin had about the same effect on cortisol as Imipramine (an older antidepressant) - but that 75 times more Imipramine was used to get that effect. Other compounds in SJW like hyperoside and isoquercetin also had the same effect but required somewhat higher doses (3x more).
“Frontline Science: Corticotropin-releasing factor receptor subtype 1 is a critical modulator of mast cell degranulation and stress-induced pathophysiology.” Journal of Leukocyte Biology, Dec 2017, PMID 28684600.
“Corticotropin releasing factor receptor 1 (CRF1) and CRF2 agonists exert an anti-inflammatory effect during the early phase of inflammation suppressing LPS-induced TNF-alpha release from macrophages via induction of COX-2 and PGE2.” Cell Physiology, Mar 2007, PMID 17117478.
“Peripheral Corticotropin-Releasing Factor Triggers Jejunal Mast Cell Activation and Abdominal Pain in Patients With Diarrhea-Predominant Irritable Bowel Syndrome.” American Journal of Gastroenterology, Dec 2020, PMID 32740086.
“Complementary therapies for clinical depression: an overview of systematic reviews.” BMJ Open, 5 Aug 2019, PMID 31383703.
A quite interesting read, thank you. I got here while looking for SJW as a suppressor or blocker of cortisol as a means for testosterone enhancement, since cortisol also interferes with T's social effects. You may want to look into this Ashwagandha research since it seems to work similarly and also thru the HPA axix to block some effects of cortisol, if useful for your purposes: "Adaptogenic and Anxiolytic Effects of Ashwagandha Root Extract in Healthy Adults"