Could a 50-year-old pillar of modern psychiatry be based on a misunderstanding of an ancient herbal medicine and the already available evidence? Some researchers have suggested just that.
Notwithstanding the real and significant personal and social toll that mental health problems play in many people’s lives in the modern world. Our true understanding of what is happening physiologically still seems far from certain.
Perhaps no-one is sure quite where it was first applied as a medicine, likely a long time ago. Though Sarpagandha, aka Snake root, or Rauwolfia serpentina, looks like a relatively insignificant small woody shrub most of the time, but it is showy and distinctive when in flower and is found growing in forested regions from the Indian subcontinent to south-east Asia.
The many historical synonyms and local names attest to the use of this plant in folk and traditional medicine for a considerable time across much of its range in Asia. Though it seems there was added botanical confusion for a while from multiple naming and typos. Rauvolfia or Rauwolfia?
As for many traditional medicines its indications are broad, but often focus on treatment for poisons, gastrointestinal infections including worms and yes even snake bite. One ancient Sanskrit name however, Chandra – the moon, refers to its use in ‘moon’s disease’, aka ‘lunacy’. So that seems to make that an ancient reference to mental illness to me.
It was (re-) introduced to the western world roughly 70 years ago, from the Ayurvedic medicine tradition of India, after the publication by Indian doctors on the effectiveness of the herb in both hypertension and mania in the 1930’s and 40’s. Reportedly a widely utilised and popular herb by the turn of the 20th century in India, Ghandhi is often cited as apparently utilising the relaxing qualities of this herb as a tea on a regular basis. Whilst that may or may not be the case, it certainly seems to have been a significant element of the local herb trade for centuries or millenia by then.
The pharmacological activity of this herb radically altered theories and perceptions of cardiovascular and neurological pharmacology then in the west. Though perhaps mistakenly some of those early ideas have also remained with us and to a large extent have been unquestioned since then.
Early clinical studies in the US reported dramatic results in hypertension, particularly in young “psychoneurotic” patients with tachycardia according to one early review of the herb. Whilst most of the Indian and earlier clinical studies used the whole herb extract, the isolation and identification of reserpine in the root soon led to investigations and clinical trials of this single constituent alone. As has been the case for most of the still used pharmaceuticals derived directly from herbal medicines in the world of pharma science, which includes reserpine.
Even in the mid 1950’s there was recognition that there was a varying mix of alkaloids in Rauwolfia, that could depend on source region and age, plus some early debate on the merits of whole herb versus reserpine alone. Not unexpectedly perhaps, some pharmaceutical companies were marketing the pure alkaloid for treatment by 1954, most widely under the name Serpasil. It soon became evident that long-term treatment with high doses of reserpine induced some serious negative symptoms in people. Causing reduced activity and apparent central nervous system depression.
1956 Serpasil ad from CIBA
Following reports of its use in India for mental disorders, schizophrenics were also treated with reserpine, which didn’t cure them but was sedating and anxiety reducing. It became popularly prescribed for mental disorders for a while.
Along with other findings such as monoamine oxidase inhibitors showing antidepressant action, came the discovery that reserpine acts by permanently inhibiting the transport proteins of our monoamine neurotransmitters (serotonin, dopamine, norepinephrine) into vesicles within neurons. This depletion over time of neurotransmitters caused a general shutdown of what are excitatory pathways of the central nervous system, ie. causes diminished activity. This of course is part of the reason why it is effective in overly excited states like mania.
Stopping reserpine allows the body to regenerate the proteins necessary for neurotransmitter transport over days and weeks, and gradually return to baseline function. This discovery, with other findings, came to be used in part as evidence for the so-called monoamine or serotonin hypothesis. A thesis that an ‘imbalance’ of one or more of these brain messengers is the cause of a whole host of mental disorders, particularly and popularly serotonin for depression in recent times. Though some researchers who have looked back through the data and reports of over 50 years ago are now asking the question about how valid or useful the serotonin hypothesis has been.
There appears to have been few if any reported cases of severe symptoms in the traditional use of the whole herb containing a mixture of alkaloids. It seems unlikely to have been taken endlessly or without reasons, as like many traditional herbal medicine preparations (often a tea) the intense bitterness is a generally a self-limiting factor on consumption for anyone but the ill.
The discovery of these pharmacological actions and the serotonin or monoamine hypothesis spawned whole new classes of psychiatric drugs, anti-psychotics and Selective Serotonin Reuptake Inhibitor (SSRI) anti-depressants in particular. Also reserpine remains in use for some types of hypertension to this day. Setting aside the brawl over the actual diagnosis of depression, so widely given in contemporary times. The hypothesis also saw a boom in the development of pharmaceutical agents targeting serotonin metabolism and action. However the lack of evidence of effectiveness better than placebo for leading SSRI and other antidepressants, despite the marketing and billions spent on research or even the attempts to hide data away, seems to question the whole hypothesis more than support it.
Serotonin of course plays a role in many other aspects of physiology as well, being originally identified both as an agent from blood serum that caused vasoconstriction (sero-tonin) and as a gastrointestinal smooth muscle stimulant (originally named enteramine). Serotonin is also found in many plants, particularly seeds, some of them are common foods – particularly black walnuts, also pecans, banana, kiwifruit, pineapple, avocado and more.
Physiology of all living things seems to be a complex network of different systems, hopefully working in a kind of organised fashion together depending upon the internal and external environment. Although reductionist science appears to be focused on a mechanistic model, the magic bullet or single factor responsible. Life itself seems a lot more complicated than that in practice.
Rauwolfia serpentina from Curtis Botanical Magazine 1804
Rauwolfia serpentina has been listed in the CITES Annex for trade in medicinal plants. Though it seems to remain unknown how endangered it is, it’s continuing use in traditional medicines or as a source of reserpine and dramatic changes across its habitat in a world full of people are risk factors for unsustainability and loss of wild populations. Tissue and cell culture have been tried, synthesis of reserpine is complex and expensive. Cultivation projects in some countries (India, Pakistan) have been undertaken. Other plants also contain reserpine but it seems are not currently used as a source. Other related alkaloids from Rauwolfia and some closely related genera continue to see use in medicine or in research of treatments for mental health and other disorders.