Any extracts used in the following article are for non-commercial research and educational purposes only and may be subject to copyright from their respective owners.
A few days ago, a doc asked me what I knew about valproate toxicity? I’d heard of valproic acid but wasn’t very familiar with its properties. So I started doing a literature search, beginning with drugs.com. At this stage, I had no idea of the scandal that had unfolded over the last 6 decades and a quick read-through left me none the wiser, but the AE’s just hit you in the face (pun intended).
As I read, I was getting a feel for the treatment case “sell” used by big pharma and contrasted these with potential impacts on the patient. In short, it is primarily prescribed as an epilepsy drug but is also useful for those suffering from bipolar disorders or migraines.
Here’s what they say (emphasis mine).
What is Valproate Sodium?
Valproate Sodium is used to treat various types of seizure disorders. This medicine is sometimes used together with other seizure medications.
Valproate Sodium is also used to treat manic episodes related to bipolar disorder (manic depression), and to prevent migraine headaches.
Valproate Sodium may also be used for purposes not listed in this medication guide.
Valproate Sodium side effects
Get emergency medical help if you have signs of an allergic reaction (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).
Seek medical treatment if you have a serious drug reaction that can affect many parts of your body. Symptoms may include: skin rash, fever, swollen glands, muscle aches, severe weakness, unusual bruising, or yellowing of your skin or eyes.
Call your doctor at once if the person taking Valproate Sodium has signs of liver or pancreas problems, such as: loss of appetite, upper stomach pain (that may spread to your back), ongoing nausea or vomiting, dark urine, swelling in the face, or jaundice (yellowing of the skin or eyes).
Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, depression, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.
Call your doctor at once if you have any of these other side effects:
confusion, tiredness, cold feeling, vomiting, change in your mental state;
easy bruising, unusual bleeding (nose, mouth, or gums), purple or red pinpoint spots under your skin;
severe drowsiness;
or worsening seizures.
Severe drowsiness may be more likely in older adults.
Common side effects of Valproate Sodium may include:
nausea, vomiting, stomach pain, diarrhea;
dizziness, drowsiness, weakness;
headache;
tremors, problems with walking or coordination;
blurred vision, double vision;
hair loss; or
changes in appetite, weight gain.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Valproate Sodium can cause liver failure that may be fatal, especially in children under age 2 and in people with liver problems caused by certain genetic disorders.
You should not use Valproate Sodium if you have liver disease, a urea cycle disorder, or a genetic disorder such as Alpers' disease or Alpers-Huttenlocher syndrome.
Do not start or stop taking this medicine during pregnancy without your doctor's advice. This medicine may harm an unborn baby or cause birth defects, but having a seizure during pregnancy could harm both mother and baby.
Do not use Valproate Sodium to prevent migraine headaches if you are pregnant.
Call your doctor at once if the person taking this medicine has signs of liver or pancreas problems, such as: loss of appetite, upper stomach pain (that may spread to your back), ongoing nausea or vomiting, dark urine, swelling in the face, or jaundice (yellowing of the skin or eyes).
Do not stop using Valproate Sodium without your doctor's advice. Stopping suddenly may cause a serious, life-threatening type of seizure.
Before taking this medicine
You should not use Valproate Sodium if you are allergic to it, or if you have:
liver disease;
a urea cycle disorder; or
a genetic mitochondrial (MYE-toe-KON-dree-al) disorder such as Alpers' disease or Alpers-Huttenlocher syndrome, especially in a child younger than 2 years old.
Valproate Sodium can cause liver failure that may be fatal, especially in children under age 2 and in people with liver problems caused by a genetic mitochondrial disorder.
Tell your doctor if you have ever had:
liver problems caused by a genetic mitochondrial disorder;
depression, mental illness, or suicidal thoughts or actions;
a family history of a urea cycle disorder or infant deaths with unknown cause; or
HIV or CMV (cytomegalovirus) infection.
Some young people have thoughts about suicide when first taking Valproate Sodium. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.
Using Valproate Sodium during pregnancy may increase the risk of serious birth defects that can develop early in pregnancy, even before you know you are pregnant. Using Valproate Sodium during pregnancy can also affect cognitive ability (reasoning, intelligence, problem-solving) later in your child's life. However, having a seizure during pregnancy could harm both the mother and the baby.
If you take Valproate Sodium for seizures or manic episodes: The benefit of preventing these conditions may outweigh any risks posed by this medicine. There may be other medications that are safer to use during pregnancy. Do not start or stop taking this medicine without your doctor's advice.
Do not use Valproate Sodium to prevent migraine headaches if you are pregnant or you could become pregnant.
If you are not pregnant, use effective birth control to prevent pregnancy while using Valproate Sodium. Tell your doctor if you start or stop using hormonal contraception that contains estrogen (birth control pills, injections, implants, skin patches, and vaginal rings). Estrogen can interact with this medicine and make it less effective in preventing seizures.
It may not be safe to breastfeed while using this medicine. Ask your doctor about any risk.
Sounds like a right barrel of laughs. Whenever you see a drug with such a broad, serious toxicity profile you are immediately drawn to considering it as a possible systemic poison, similar to the LNP-Spike mRNA gene agents.
Therefore you would expect it to either have been withdrawn at the trial stage, or at least be restricted to specific controlled use cases where nothing else is suitable.
I immediately messaged back saying I had a bad feeling about this.
I didn’t know the half of it…
Discussion
History of sodium valproate
D.F. Scott included a section about the drug in his 1993 book “The History of Epileptic Therapy: An Account of How Medication was Developed”1 .
Key takes:
The history of the discovery of sodium valproate is of considerable interest, not least because it remains a first-line drug, which is effective in all types of seizures including those of absence type - petit mal attacks in childhood.
It was first synthesized as long ago as 1881, but only in 1962 were the therapeutic properties realized. Not long after this, a patent was taken out in France, where the work on the compound had been.
The gap between the original synthesis and the discovery of the anticonvulsant actions was remarkable, being 80 years, indeed the longest interval for any marketed antiepileptic, in striking contrast to carbamazepine, where the time from first synthesis to the pharmacy shelves in most countries of the world was about 10 years.
80 years. 10 years. As long as that? The target now is at most 100 days, or zero days in the case of Novavax as no clinical trials were conducted for this new, adjuvanted version of the drug2:
More recent discoveries, because of detailed requirements of testing before licensing (see Chapter 12), lead to a period which is often longer than that for carbamazepine. This is true, not only for antiepileptic drugs, but in addition for most other pharmaceuticals.
THE DISCOVERY
Valproic acid had been used widely for many years as a solvent for organic chemicals. In the year 1961, its true nature came to light when Mr Pierre Eymard was working under the supervision of Dr Meunier, at the laboratories of Berthier, located in Grenoble in France.
During a screening procedure for antiepileptic activity in a number of compounds, he found that they all showed a strikingly similar, and unexpectedly marked, effect. Such overwhelming success was unusual at this routine screening stage.
They discovered that valproate as a solvent was indeed not inert, in fact it was the active ingredient.
Gazinga! The relevant development of valproate as an epileptic drug was then waved through in only 3 years:
Then it was noted that the solvent, not test compounds, had these beneficial effects. The first clinical trials were quickly underway by 1964. The results were quite clear-cut, and sodium valproate was first marketed in France in 1967.
At least the UK went through the motions:
Other European countries soon followed suit, including the UK in 1974, the last European country where prescription was commenced. Like the US with carbamazepine, this was because of the stringent drug regulations.
This probably meant that pharma had the smell of money, and the means to deal with the troublesome regulators:
Sodium valproate was discovered to be an anticonvulsant at the time when there was a particular interest in research of epilepsy in general, on both sides of the Atlantic.
Not least in importance was the discovery of a new animal model (see below). One other particular advance was in the technology of blood level assessment. It was becoming more generally available. This method, coupled with the clear efficacy of sodium valproate for a wide spectrum of seizure disorders, led to an explosion of publications, estimated by 1991 to be in excess of 5000, whilst over a million individuals worldwide were by then receiving the compound.
A cynic might ask:
Q: If you aren’t clear about its mode of action, how do you know you have a complete safety profile?
A: They didn’t, and they hadn’t, or looked the other way.
In spite of this wide experience and greater volume of research work, its mode of action remains unclear.
THE COST-BENEFITS EQUATION
Sodium valproate is a valuable drug in the treatment of epilepsy, with two-thirds of the patients showing a good response, that is, a 75-100% reduction in seizures*.
Reading this section from 1993 alongside the list of AE’s for children highlights everything that is wrong with the “Willie Sutton” pharma model (i.e. “because that’s where the money is”):
Particularly valuable were the notable effects obtained in children with petit mal. Patients who have drug resistant epilepsy, especially a combination of convulsions — tonic/clonic fits - and complex partial seizures, showed a less dramatic but useful change be for the better.
The author was consultant-in-charge of the clinical neurophysiology department at the London Hospital. Conflict of interest?
From personal experience it seems the dosage may need to high in this type of patient, though generally when sodium valproate is introduced, other anticonvulsants can be curtailed, so that toxic side-effects such as drowsiness, which accrue with large doses of different anticonvulsants given together, can be alleviated.
Yes, it all comes down to money and profits above safety:
There are other considerations: first of all, the cost of a new drug such as sodium valproate is initially high, and indeed, it is still one of the more expensive antiepileptic compounds.
CONCLUSION
Both the discovery of sodium valproate and the baboon model demonstrated once again that empirical factors are acting, chance, luck and serendipity were surprisingly at the forefront of progress.
Such a situation limits regular systematic progress. Perhaps this is changing — with a more rational approach.
Present day, it’s on the WHO’s “Model List of Essential Medicines”. It’s available as a generic medication and is far from being withdrawn. In 2021 over 3 million prescriptions made it the 155th most prescribed medicines in the US.3
Size of the market
The global sodium valproate market size was valued at USD 4.2 billion in 2022 and is projected to reach USD 5.3 billion by 2030, at a CAGR of 4.5% from 2023 to 2030.
This medicine is only available on prescription. It comes as capsules, tablets and a liquid that you swallow. It also comes as granules that you mix with food or drink.
Sodium valproate can also be given by injection, but this is usually only done in hospital.
2. Key facts
You'll usually take sodium valproate once or twice a day. You can take it with or without food.
You'll usually start on a low dose. Your dose will gradually increase over a few days or weeks.
Valproic acid and semisodium valproate are similar to sodium valproate and work in the same way. However these medicines are used to treat different conditions and doses will vary.
There are also brands such as Epilim Chrono, Epilim Chronosphere and Dyzantil which contain mostly sodium valproate, with some valproic acid.
If you're pregnant, or there's a chance you could become pregnant, sodium valproate is not recommended for treating migraine. For epilepsy and bipolar disorder, your doctor will only prescribe sodium valproate for you if there are no other suitable treatments.
4. How and when to take sodium valproate
Sodium valproate is a prescription medicine. It's important to take it as your doctor tells you.
Dosage
The usual dose for treating epilepsy in:
adults and older children (aged 12 years and over) – 600mg to 2,000mg a day, as 1 dose or split into 2 doses. Some people take a higher dose of 2,500mg a day
younger children (aged 1 month to 11 years) – the doctor will use your child's weight to work out the right dose for them
The usual dose for treating bipolar disorder in:
adults – 750mg to 2,000mg a day, as 1 dose or split into 2 doses
children – the doctor will work out the right dose for your child
The usual dose for preventing migraine in:
adults – daily doses vary from a single dose of 400mg to 1,500mg split into 2 doses
If your doctor tells you to take sodium valproate twice a day, you'll usually take half the dose in the morning and half in the evening (to make up your full daily dose).
If you're taking sodium valproate and have kidney problems, your doctor may prescribe a lower dose.
It’s a branched, short-chain fatty acid (SCFA). SCFAs are also produced by gut bacteria. Butyrate is a great example of a beneficial, probiotic anti-inflammatory SCFA, which also helps to inhibit colorectal cancer.
Valproate itself may affect the microbiome, which could help to explain some of its systemic side effects:
During the investigation of VPA on a metabolite profile in a fungus, we found that VPA has significant effects on the production of some fatty acids. Further exploration of VPA on fatty acid profiles of microorganisms, fungi, yeast, and bacteria, as well as representative gut microbiome, revealed that VPA could enhance or reduce the production of some fatty acids. VPA was found to induce the production of trans-9-elaidic acid, a fatty acid that was previously reported to have cellular effects in human macrophages. VPA could also inhibit the production of some polyketides produced by a model fungus. The present work suggests that the induction or inhibition of fatty acid biosynthesis by VPA (100 µM) in gut microbiome could give effects to patients treated with VPA because high doses of VPA oral administration (up to 600 mg to 900 mg) are used by patients; the concentration of VPA in the human gut may reach a concentration of 100 µM, which may give effects to gut microorganisms.
… Fatty acid metabolism has a critical role in human since it sustains balanced homeostasis and the negative perturbations that would lead to disease development.
From: “An anticonvulsive drug, valproic acid (valproate), has effects on the biosynthesis of fatty acids and polyketides in microorganisms“ (2020)
According to research cited by StatPearls, the principal mode of action of valproate is by the inhibition of nerve signalling.
Key takes from “Valproic Acid”4 by Rahman et al., last updated March 19, 2024:
Valproic acid (VPA) was initially synthesized in 1882 by Burton as a derivative of valeric acid, which is a branched, short-chain, and naturally occurring fatty acid present in both plants and animals.
However, the anticonvulsant properties of VPA were discovered by Eymard in 1962 while attempting to synthesize new compounds from VPA. Eymard observed that one of the compounds of VPA, 2-propylpentanoic acid, exhibited a melting point similar to that of phenytoin, the antiepileptic drug.
Later, Eymard decided to conduct experiments on mice and established that the compound possessed a potent anticonvulsant effect against maximal electroshock seizures.
143 years after its discovery, and we still don’t have all the answers:
VPA is a medication with diverse mechanisms of action that are not yet fully comprehended.
It acts in a similar way to some neurotoxins5, such as tetrodotoxin (TTX) from pufferfish. TTX blocks the pore of sodium channels:
… VPA's antiepileptic effects are manifested through the attenuation of high-frequency neuronal firing, achieved through the blockade of voltage-gated sodium, potassium, and calcium channels.
“Gamma-aminobutyric acid (GABA) is a neurotransmitter, a chemical messenger in your brain. It slows down your brain by blocking specific signals in your central nervous system (your brain and spinal cord). GABA is known for producing a calming effect.”6
GABA is produced from glutamate in the glutamate-GABA-glutamine cycle.
As an aside, spike protein from SARS-CoV-2 has a short linear motif that mimics GABA7, contributing to its depletion and likely with neurological disorders associated with Long COVID and Long post-COVID vaccination syndrome:
“Mainly spike, NSP7 and NSP8, also, some other NSP proteins mimic potassium voltage-gated channel subfamily KQT member 1 and 2, gamma-aminobutyric acid type A and B receptor subunits, glycine receptor subunits, metabotropic glutamate receptors, neuronal acetylcholine receptor subunits, dopamine D2 receptor, and adenosine receptor A2a.“8
Aura are associated with some migraines:
The medication influences the biochemical occurrence of aura and impacts nociception by modulating GABA or glutamate-mediated neurotransmission.
We touched on signalling pathways and MAPK cascades in the macrophage priming Substack. This level of interaction helps to explain some of the horrific side effects.
For instance, the Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis.9
Inositol (vitamin B8) is a sugar (carbohydrate) that affects neurotransmitter levels, glucose sensitivity and insulin resistance.
Arachidonate is a polyunsaturated omega-6 fatty acid:
Moreover, VPA also influences signaling systems, such as the Wnt/beta-catenin and ERK pathways, which similarly interfere with inositol and arachidonate metabolism.[20]
This opens up a Pandora’s box of potential pathologies. I can’t add anything more here without knowing the mechanisms in detail. And I suspect there are still huge gaps in our knowledge. However, embryo development and nerve growth stand out as candidates, as well as effects on the proteome and immune function.
Where do you start…?
Valproate use is also critical in expressing multiple genes involved in cell survival, transcription regulation, ion homeostasis, signal transduction, and cytoskeletal modifications.
Valproate as a histone deacetylase (HDAC) inhibitor
A histone is a protein which is abundant in lysine and arginine residues. They provide structural support for chromosomes by binding to DNA in the nucleus and helping to condense it into chromatin:
Nucleosome assembly begins with the binding of acetylated histone H3–H4 complexes to the assembly factor CAF-1. This complex is then recruited to the replication fork by an interaction with the sliding clamp, and a tetramer of histones H3 and H4 is loaded onto the nascent DNA to form half of a new nucleosome. Dimers of histones H2A and H2B are then loaded onto the DNA, probably with the assistance of other assembly factors such as NAP-1, to form the complete histone octamer. Chromatin-remodeling complexes contribute to nucleosome assembly and spacing. The number of histone H3 and H4 subunits that interact with CAF-1 is not clear. These subunits form highly stable tetramers in solution (unlike histones H2A and H2B, which form dimers) and it is therefore thought that CAF-1 loads a complete H3–H4 tetramer as shown here. There is some evidence, however, that CAF-1 can interact with an H3–H4 dimer, in which case the loading of a tetramer would require two CAF-1–histone complexes.[1]By David O Morgan - The Cell Cycle. Principles of Control., Attribution, https://commons.wikimedia.org/w/index.php?curid=89674544
HDACs cause compaction of nuclear chromatin and are primarily associated with transcriptional repression of genes controlling cellular growth and differentiation.
Compaction inhibits gene expression, whereas HDAC inhibitors lead to a less compact chromatin structure by neutralising positive charges on the histone surface.
This makes it more feasible for RNA polymerases to access the DNA, leading to increased gene expression.
HDAC inhibitors as anticancer agents
Valproate does have potential as an anti-cancer therapeutic.
Explain Like I'm Five (ELI5): Valproate opens up DNA and makes tumour cells more likely to die when exposed to radiotherapy.
When a DNA double-strand break(DSB) occurs, such as due to exposure of a cancer cell to ionising radiation (IR), a phosphorylated histone variant called H2AX may promote tumour resistance to IR by contributing to the repair of DSBs, as DSB lesions are highly lethal to a cell1011. The presence of γH2AX also acts as a marker for IR-induced DNA damage.
This means that H2AX is potentially a cancer therapeutic target.
Valproate can make cells more IR-sensitive by mediating histone hyperacetylation, promoting the transition from heterochromatin to euchromatin12,chromatin condensation, and by enhancing the formation of radiation-induced γH2AX, preferentially on euchromatic alleles13.
Euchromatin is also known as “open chromatin”, and is a lightly packed form of chromatin.
“… highly compacted heterochromatin is better protected than euchromatin against indirect radiation DNA damage due to its lower hydration, higher occupation by chromatin-binding proteins, and, in turn, lower accessibility of DNA to harmful free radicals.”14
Distinction between Euchromatin and Heterochromatin. CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=35814557
Valproate and the immune system
As with engineered mRNA Spike protein, research has found that VPA is associated with immune system remodelling, due to immunosuppression and a polarisation from inflammatory M1 macrophages to M2. Similar to the effects of corticosteroids this can have positive and negative effects:
It suppresses the production of pro-inflammatory cytokines, including CXCL1, IL5, IL6, IL10, TNFα and downstream NF-κB.
It can increase antimicrobial action against pathogens including Staphylococcus aureus and Proteus vulgaris at a dose of 100 µg/ml, and other tested organisms at a dose of more than 200 µg/ml.
It can act as a powerful antifungal agent against yeasts such as Candida albicans15.
However, a mouse study found that inhibition of the production of IFN-γ by natural killer (NK) cells stimulated with IL-12 and IL-18 led to significantly increasedmortality when infected by Listeria monocytogenes.
Researchers found that VPA increased bacterial load in the spleen, liver, and blood, associated with decreased levels of IFN-γ in serum and lower splenic indexes16.
It can be used to suppress autoimmune disorders such as Type 1 diabetes mellitus (T1D). A study found that the mechanism involved VPA-induced increased expression of forkhead box P3 (FOXP3) protein. FOXP3 is a transcription factor critical to developing and controlling regulatory T cells (Tregs), which help to suppress autoimmune disorders.
They needed to use a dose of 400 mg/kg VPA in their islet transplantation mouse models to demonstrate this effect. The typical dose in humans is 600 - 2000mg/day. If you weigh 70kg that’s 28mg/kg at the upper end. After correcting for mouse-to-human equivalence by dividing by 12.3 you get 32mg/kg. However, it’s not foolproof to use these conversions and different studies use different factors.
From: “Figure 1. Syngeneic or allogeneic islet transplantation were performed to treat diabetic recipients. (A) Newly isolated islet from male NOD or Balb/c mice were transplanted into the kidney subcapsular space of newly diabetic NOD or streptozotocin (STZ)−induced diabetic C57BL/6 recipients, respectively. Valproic acid (VPA) treatment prolonged islet graft survival in the syngeneic and allogeneic islet transplantation of non−obese diabetic (NOD) or C57BL/6 mice. The recipients were treated with nine dosages of VPA 400 mg/kg. (B) The red arrow indicates the presence transplanted islet graft in the subcapsular space of NOD recipients’ kidney.” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157191/
VPA-induced M2 macrophages produce immune-damping anti-inflammatory cytokines such as IL-4 and IL-13. They also produce an extracellular matrix (ECM) protein called fibronectin.
Positives include wound healing.
Negatives include fibrosis and promotion of tumour progression17.
From: “Fig. 2. The M1/M2 macrophage origin, activation, and functional basis. Macrophages are typically produced from embryonic progenitors and involve inputs from yolk sac macrophages, blood monocytes independent, and adult monocytes originating from bone marrow. Macrophage immune modulation, functional plasticity, and phenotype changes are centered on cytokines, transcription, and epigenetic deviations.” Source: https://www.nature.com/articles/s41392-023-01452-1
A study from 2022 by Zhang et al. suggests that VPA has a magic bullet effect on macrophages. They exposed female rats to cancer-causing, mutagenic and teratogenic polycyclic aromatic hydrocarbons (PAHs) and dosed the animals with VPA at the lower end human-equivalent, at 50mg/kg and 100mg/kg.
They found that although VPA causes macrophages in ordinary tissues to polarize towards the M2 phenotype, with tumours the polarization was towards M1, which helps induce apoptosis via the expression of pro-inflammatory cytokines such as IFN-γ, IL-12 and TNF-α, and activation of Granzyme B-secreting CD8+ T cells18.
So can you get this on the NHS or via your health insurance scheme to treat cancer? A paper from 2023 called “Valproate and lithium: Old drugs for new pharmacological approaches in brain tumors?” by Natale et al19. is not encouraging.
Its use has progressed to clinical trials involving co-administration to see if VPA enhances the antineoplastic activity of chemotherapy used to treat glioblastoma and other brain metastases.
They demonstrated that VPA causes an improved median overall survival in some studies, but not in others. Ordinarily, this would be more than sufficient evidence for pharma to use to progress to full commercial use.
The horrendous side effects profile might also increase the drop-out rates in trials.
Long-term clinical data from Denmark, analysed by Whiting et al. in 2003, not only indicates a lack of efficacy but a doubling of your risk of contracting lung cancer, from 1 in 3177 to 1 in 1388.
For comparison, long-term smoking has an age-adjusted relative risk (RR) for women of 7.48 (95% CI 5.29 to 10.60) and 8.78 for men (95% CI 6.13 to 12.57)20.
The paper was written to evidence the opposite, so it wrong-footed the researchers somewhat. Oops.
Abstract from “Cancer Risk in Long-term Users of Valproate: A Population-Based Case-Control Study”21:
Background: Inhibitors of histone deacetylases (HDAC)have shown promise as targeted cancer therapy. Valproate, an older anticonvulsant, has been shown to possess HDAC inhibitory activity. We undertook this case-control study to clarify whether long-term users of valproate had a reduced cancer incidence. If so, it would support HDAC inhibition as a pharmacologic principle in chemoprevention.
Methods: We identified 149,417 incident cancer cases in Denmark during the study period 2000 through 2005, and 597,668 age- and gender-matched controls. Data on history of cancer, past hospital admission diagnoses, and prescription history were obtained from the Danish Cancer Registry, the Danish National Patient Registry, and the Danish Prescription Registry. Primary exposure to valproate was defined as a cumulative dose of minimum 1,500 g within the past 5 years. Confounders were controlled by conditional logistic regression.
Results: Among the cases and controls, 81 (0.05%) and 260 (0.04%), respectively, were long-term users of valproate. For cancer overall, the crude and adjusted odds ratios were 1.25 [95% confidence interval (95% CI), 0.97-1.60] and 1.21 (95% CI, 0.95-1.56), respectively. Subgroup analyses revealed no dose or duration effect for overall cancer incidence, and nospecific cancer site was found to be inversely associated with long-term use of valproate. For lung cancer, we found a positive but imprecise association (adjusted odds ratio, 2.32; 95% CI, 1.12-4.79).
Conclusion: Long-term valproate use is not associated with a reduced cancer risk. Our study does not support HDAC inhibition as a pharmacologic principle for general chemoprevention. (Cancer Epidemiol BiomarkersPrev 2009;18(6):1714–9)
Note that the relative incidence of colorectal, prostate, and other cancers was also significantly increased in the VPA-exposed group:
As you can see, the authors are quite dismissive of this, and I’m quite confident the study wouldn’t have been funded if they expected these results. They did allow for confounding factors too.
The COI statement is interesting:
Disclosure of Potential Conflicts of Interest
Jasper Hallas, Morten Andersen, and Søren Friis have received fees for teaching from the Danish Association of the Pharmaceutical Industry.
Acknowledgments
The costs of publication of this article were defrayed in part by the payment of page charges. This article must thereforebe hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
A population-level doubling of the risk of lung cancer, and a near doubling of the risk of colorectal cancer by VPA needs further investigation.
On the one hand, we have a study from 2018. “Sodium Valproate Inhibits Small Cell Lung Cancer Tumor Growth on the Chicken Embryo Chorioallantoic Membrane and Reduces the p53 and EZH2 Expression”22by Šlekienė et al. that demonstrated that high dose NaVP can inhibit small cell lung cancer progression:
Abstract
The study aims to test the effect of different sodium valproate (NaVP) doses on small cell lung cancer NCI-H146 cells tumor in chicken embryo chorioallantoic membrane (CAM) model. Xenografts were investigated in the following groups: nontreated control and 5 groups treated with different NaVP doses (2, 3, 4, 6, and 8 mmol/L). Invasion of tumors into CAM in the nontreated group reached 76%. Tumors treated with 8 mmol/L NaVP doses significantly differed in tumor invasion frequency from the control and those treated with 2 mmol/L (P < .01). The calculated probability of 50% tumor noninvasion into CAM was when tumors were treated with 4 mmol/L of NaVP. Number of p53-positive cells in tumors was significantly reduced when treated with NaVP doses from 3 to 8 mmol/L as compared with control; number of EZH2-positive cells in control significantly differed from all NaVP-treated groups. No differences in p53- and EZH2-positive cell numbers were found among 4, 6, and 8 mmol/L NaVP-treated groups. Invaded tumors had an increased N-cadherin and reduced E-cadherin expression. The results indicate the increasing NaVP dose to be able to inhibit tumors progression. Expression of p53 and EZH2 may be promising target markers of therapeutic efficacy evaluation.
It all looks good in vitro using glioblastoma, thyroid, prostate, or non-small lung cancer cell lines:
Sodium valproate is an inhibitor of HDAC and has anticancer properties with a notable effect on cell migration and invasion for both normal and malignant cells, and the treatment with HDAC inhibitors upregulates the metastasis suppressor genes and downregulates the metastasis activating genes in vitro and in vivo.40–42 Sodium valproate has been reported to inhibit tumor growth of different cancers. It significantly inhibits the growth and induces the apoptosis of different glioblastoma cell lines depending on the used doses43; the 8 mmol/L NaVP dose in the U-87 cells tumor on CAM reduced tumor invasion by 90%18; NaVP concentrations of 1 to 3 mmol/L induced cell differentiation and apoptosis of poorly differentiated thyroid cancer cells43,44; NaVP inhibited prostate cancer cell migration by upregulating the E-cadherin expression45; and the 5 to 10 mmol/L NaVP concentrations significantly induced the expression of the tumor suppressor gene IRF-3 in cancer cells, inhibiting non-small lung cancer cell growth.46 Sodium valproate might markedly increase the sensitivity of lung adenocarcinoma cells resistant to erlotinib, thus strengthening NaVP as a potential medicine for resistant cancer therapy.47
On the other hand, it all adds up to zero if real-world population-level clinical data contradicts your lab findings.
A study from 2005 by Stakisaitis et al. used mice with excised ovaries to investigate the effects of NaVP on lung cancers induced by urethane. Urethane is suspected to be a human carcinogen23.
This important work may help to explain the flippantly dismissed “positive but imprecise association” of lung cancer risk doubling for long-term Danish VPA users.
Abstract and key takes from “Sodium Valproate Enhances the Urethane-Induced Lung Adenomas and Suppresses Malignization of Adenomas in Ovariectomized Female Mice“24. Emphasis mine for clarity:
Abstract
In the present study, the possible effect of sodium valproate (NaVP) on urethane-induced lung tumors in female mice has been evaluated. BALB/c mice (n = 60; 4–6 weeks old, females) were used in the following groups: (1) urethane-treated; (2) urethane-NaVP-treated; (3) only NaVP-treated; (4) control. In the same groups, ovariectomized female mice (n = 60) were investigated. Urethane was given intraperitoneally, with a total dose of 50 mg/mouse. In NaVP-treated mice groups, 0.4% aqueous solution of NaVP was offered to mice ad libitum. The duration of the experiment was 6 months. The number of tumors per mouse in ovariectomized mice and in those treated with urethane and NaVP was significantly higher than in mice treated with urethane only (8.29 ± 0.58 versus 6.0 ± 0.63, p < 0.02). No significant difference in the number of tumors per mouse was revealed while comparing the nonovariectomized urethane- and urethane-NaVP-treated groups (p = 0.13). A significant decrease of adenocarcinoma number in ovariectomized mice treated with a urethane-NaVP as compared with ovariectomized mice treated with urethane only was found (p = 0.031). NaVP together with low estrogen may have a protective effect on the malignization of adenomas in ovariectomized mice.
VPA-induced activation of GABA-A receptors is associated with cytotoxic, anti-cancer signalling pathways when co-administered with chemotherapy and radiotherapy25, as discussed earlier.
However, if you have a type of cancer which happens to have GABA-A receptors then the VPA you take may promote tumorigenesis instead of suppressing it. I suspect that is the clinical signal the Danish study accidentally discovered.
From a 2021 review by Bhattacharya et al.:
Importantly, GABA and its varied receptors are found not only in the CNS but throughout the body, including immune cells. Figure 1 illustrates the presence of GABAARs in many human cell types. This ubiquity suggests that the role of GABA and its varied receptors may be far greater than the regulation of firing of action potentials in neurons.
… In addition, GABA signaling may contribute to tumorigenesis within the CNS and in systemic organs, potentially mediating crosstalk between normal and cancer tissue to create an ameliorated microenvironment for the tumor and/or drive metabolic processes resulting in growth of cancer.6–9 The expression of GABA and its receptors combined with their possible functions in disparate cancers suggest that they might be therapeutically beneficial targets for the treatment of cancers.
From: “Therapeutically leveraging GABAA receptors in cancer“ (2021)
An untreated control group, 50:50 male and female.
NaVP treated only, 50:50 M/F.
NaVP plus a peritoneal-injected adenocarcinoma cell line with GABA-A receptors, 50:50 M/F.
As above, but without the NaVP, 50:50 M/F.
Returning to the urethane study:
Urethane-induced lung tumors in mice models were well characterized and accepted for human lung adenocarcinoma investigations [1]. BALB/c mice are considered as susceptible to the development of lung tumor by urethane, and tumors can be modified by the influence of modulatory agents [2, 3]. Recently, it has been shown that NaVP, used together with urethane, synergistically enhances urethane tumorigenicity in lungs of only noncastrated male BALB/c but not in castrated male mice [4]. NaVP increases the turnover of gamma-aminobutyric acid (GABA) and thereby potentiates GABAergic functions [5]. The GABA-A receptor is rapidly activated by NaVP in cells [6]. GABA may affect cancer growth by activating GABA receptors. The gene expression investigation of GABA-A and GABA-B receptors in tissues of non-small cell lung cancers (NSCLC) showed that the gene expression of GABA receptor phenotypes was correlated with gender-related differences in cancerogenesis and clinical prognosis [7]. The GABA-A receptor is an ionotropic receptor; its subunits form a functional chloride channel [8, 9]. NaVP has been shown to enhance the gender-related urinary excretion of chloride in rats [10].
Mice with lung tumors were found neither in intact control nor in the intact NaVP-treated and analogous ovariectomized mice groups. All urethane-treated mice of both groups (ovary-intact and ovariectomized) developed tumors (Table 1). Urethane-caused tumors may be found in any lobe of a lung and are often situated just beneath the pleura and are recognized by their nodular, pearly, and grey-white appearance contrasting with the more pink color of the normal lung parenchyma (Figures 1(a) and 1(b)).
Figure 1 (a) Control.
Figure 1 (b). Lung specimens. (a) Control. (b) Urethane-induced lung tumors (white arrowheads). (c) Adenoma, magnification ×4, H & E staining. There are no signs of pressure to surrounding tissues; alveoli are well preserved (black arrowheads). (d) Adenocarcinoma, magnification ×4, H & E staining. Compression of surrounding alveoli (black arrowheads). Invasion to the lumen of bronchiole (black arrows). (e) adenoma, magnification ×40, H & E staining. All nuclei are of similar size and shape; no nucleoli are present (black arrowheads). Cells are of similar size and shape (black arrows). (f) Adenocarcinoma, magnification ×40, H & E staining. Pleomorphic nuclei (black arrowheads), mitotic figures (black arrow), and different cell shapes and sizes (white arrowheads). Scale bar: (c and d) 200 μm; (e and f) 20 μm.
Tumour size and quantity distribution, grouped by treatment. The light grey column on the right shows that valproate administered to ovariectomized mice generated many more tumours in response to urethane than the non-valproate groups:
Figure 2 (b). Number of tumors in intact and ovariectomized mice groups. (a) Total number of tumors on the surface of the lungs. ∗p < 0.02 in comparison with the ovariectomized urethane-treated group. (b) Tumors in accordance with tumor diameter. ∗∗p < 0.05 in comparison with the ovariectomized urethane-treated group.
Female gender has long been observed to be a positive prognostic factor regardless of the lung cancer type, stage, and therapy. Whether these differences are of a biological, behavioral, or environmental nature remains unclear [19–21]. Sex differences in mouse models of lung cancers were reported [22]. The importance of lung cancerogenesis in both spontaneous and carcinogen-induced gender-related pulmonary cancers and spontaneous pulmonary adenomas in mice is determined by multiple genetic loci [23]. Urethane specifically initiates the development of lung tumors from airway epithelial cells in mice [1]. BALB/c mice are considered susceptible to the development of lung tumor by urethane [2].
The study data show that NaVP causes a significant increase of tumor number in ovariectomized urethane-NaVP-treated BALB/c female mice as compared to ovariectomized only urethane-treated mice, but a significant decrease of adenocarcinoma numbers in ovariectomized mice treated with urethane plus NaVP was found as compared with ovariectomized animals treated only with urethane.
The coup de grâce. I didn’t expect my review to expose this:
Opening the GABA-A receptor chloride channels lead to chloride efflux and cell membrane depolarization [34]. The plasma cell membrane potential influences cell proliferation [35]. GABA has been shown to regulate the proliferation of several cell types including stem cells [36], cortical progenitor cells [37], immune cells [38, 39], and mouse chondrogenic ATDC5 cells [40].
The high level expression of the GABA receptor gene in NSCLC tissues compared with the paired noncancerous ones implicated that the GABA, GABA-B, and GABA-A receptor pathways could be an important factor in NSCLC cell proliferation regulation. NSCLC patients with a high gene expression of the GABA-B receptor subunit 2 and a low expression of the GABA-A receptor subunit A3 had a significantly better prognosis, and the GABA treatment suppressed the proliferation of NSCLC cells in vitro via the GABA-B receptor [7, 41]. A correlation between the high expression of the GABA-B receptor subunit 2 gene and the greater survival rate in females with NSCLC was found [7]. In vitro data show that the high-level GABA-B gene expression is associated with the inhibition of cancer cell proliferation [42–44]. Furthermore, the GABA-A receptor subunit A3 gene overexpression was found in NSCLC tissues [7, 45]. The high level GABA-A receptor subunit A3 gene overexpression is correlated with cancer cell development, and these patients had a worse outcome [12, 46, 47]. The higher gene expression of the GABA-A receptor subunit A3 was mostly detected in male patients who had a worse prognosis [7]. It is possible to suggest that tumor-stimulating effects of GABA-A receptor whether or not GABA itself or NaVP have tumor promotion or inhibiting effects will depend on the expression levels of GABA-A versus GABA-B receptors, which could be affected by sex hormones. The GABRQ is overexpressed in hepatocellular carcinoma cells but not in a normal cell line and GABA in the liver promotes the proliferation of cancer cells through GABRQ [12].
NaVP is recognized as a novel class of HDAC inhibitors that induce the differentiation of transformed cells and show antitumor properties in clinical and preclinical studies by modulating multiple pathways including cell cycle arrest, cell differentiation, and apoptosis [13, 14, 58, 59]. Recent data indicate that HDAC play a dual role in tumorigenesis: oncosuppressive in the early stages and oncogenic in established tumor cells in mice models [15].
Teratogenic effects
“A teratogen is anything a person is exposed to or ingests during pregnancy that's known to cause fetal abnormalities.26”
This review is already quite dark. It’s about to get darker still (black maybe). It has stiff competition from many other pharma products such as engineered mRNA spike, SSRIs, OxyContin, HPV and many other vax’s, stomach acid proton pump inhibitors, and Thalidomide, of course.
I don’t need to go into great depth as we already discussed how VPA affects histones and gene expression.
Our first study is by Phiel et al.: “Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen”27 (2001).
Key takes:
Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown.
We report that valproic acid activates Wnt-dependent gene expression, similar to lithium, the mainstay of therapy for bipolar disorder.
Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC50 for HDAC1 = 0.4 mm).
At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters.
Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription.
Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.
VPA is a potent teratogen in humans (5) and is widely studied as a model teratogen in rodents. Although the target of VPA in this setting is unknown, strict structural requirements have been defined for the teratogenic activity of VPA and VPA-related compounds. Thus, potently teratogenic analogues of VPA contain a tetrahedral α-carbon bound to a free carboxyl group, a hydrogen, and two alkyl groups (6, 7).
We show that VPA potently inhibits histone deacetylase (HDAC), a negative regulator of gene expression in multiple settings, at therapeutically relevant levels.
Furthermore, the teratogenicity of VPA in vertebrate embryos is mimicked by the HDAC inhibitor trichostatin A, whereas non-teratogenic analogues of VPA do not inhibit HDAC. These findings lead us to propose that HDAC is an important target of VPA in the pathogenesis of birth defects.
VPA (valproate) inhibits HDAC1 activity, and this correlates with teratogenic effects on tadpoles:
From: “Figure 7 Inhibition of HDAC correlates with teratogenicity.A, non-teratogenic analogues valpromide (VPM; 5 mm) and 2-methyl-2-propylpentenoic acid (2M2P; 5 mm) do not inhibit HDAC1, whereas VPA (5 mm) and the established HDAC inhibitor TSA (300 nm) do inhibit HDAC1. Assay conditions are as in Fig. 4A. B–E,Xenopus embryos were treated from stage 8 until neurula stage with buffer, VPA, VPM, or TSA, and then scored at tadpole stages.B, control Xenopus tadpole. C, tadpole after exposure to VPA is shorter and lacks anterior structures.D, tadpole after exposure to VPM with normal anterior development. E, tadpole after exposure to TSA is shorter and lacks anterior structures, similar to VPA-treated tadpole.” Source: https://www.jbc.org/article/S0021-9258(20)86757-X/fulltext
VPA is highly teratogenic in humans, causing spina bifida aperta and other neural tube closure defects in 1–2% of offspring of women taking VPA during the first trimester of pregnancy (5). Similarly, VPA causes neural tube defects in rodents, and this has served as a commonly studied model of teratogenesis.
… the HDAC inhibitor TSA causes severe morphological defects in mouse embryos cultured from day 7.5 to 9.5 (52) that are nearly identical to those caused by VPA (53), including anterior neural tube defects, shortening of the anterior-posterior axis, growth retardation, and failure of the embryo to rotate properly.
Furthermore, as presented here, Xenopus embryos treated with TSA show marked defects in anterior development, similar to VPA-treated embryos. These data in mice and Xenopus support our proposal that the teratogenic effects of VPA are mediated through HDAC inhibition.
The normal function of HDAC is essential for healthy embryo development:
A role for HDAC during embryogenesis has been demonstrated in invertebrates. In Drosophila, strong hypomorphic mutations in Rpd3, a gene homologous to HDAC, cause segmentation defects and embryonic lethality. These segmentation defects appear to arise from altered Even-skipped (eve) repressor activity, resulting in an indirect loss of engrailed expression (47).
Additionally, loss of hda-1 in Caenorhabditis elegans causes embryonic lethality at the one-fold stage and rescues endoderm formation in embryos lacking CBP, a histone acetyl transferase (48).
The hda-1 gene product is also a component of a complex involved in regulation of vulva development (49).
Thus, HDACs play an important role during the embryogenesis of numerous organisms, and interfering with the function of these proteins pharmacologically may mimic the effects of loss-of-function mutations in the developing embryo.
Hinted at the drugs.com site, you may also suffer a HIV relapse if you take VPA:
Interestingly, clinical use of VPA in HIV-infected patients causes an increase in the replication of HIV(60). In addition, the HDAC inhibitors TSA and trapoxin induce the transcription of HIV in vivo and in vitro (61). The identification of VPA as an HDAC inhibitor thus offers a plausible explanation for the effect of VPA on HIV levels observed clinically.
A later review “Teratogenicity of sodium valproate”28from 2005 by Alsdorf & Wyszynski gives further insights:
Many factors contribute to the teratogenicity of VPA. These include the number of drugs that are co-administered, drug dosage, differences in maternal and/or infant metabolism, the gestational age of the fetus at exposure, and hereditary susceptibility.
VPA has been associated with a variety of major and minor malformations, including a 20-fold increase in neural tube defects, cleft lip and palate, cardiovascular abnormalities, genitourinarydefects, developmental delay, endocrinological disorders, limb defects, and autism.
It has been suggested that polytherapy treatment in epileptic pregnant women increases the risk of teratogenicity in offspring.
Furthermore, there is an established relationship between VPA dose and adverse outcome. Large single doses of VPA potentially cause high peak levels in the fetal serum resulting in deleterious effects.
Why is there a scandal?
It bears comparison to another, much more well-known scandal. In the 1950s and 60s, the teratogen thalidomide was administered to women who were pregnant or who subsequently became pregnant in 46 countries, primarily as a medication for morning sickness.
It was first introduced in the UK in 1958, primarily under the brand name Distaval. It was withdrawn from the UK in 1961. It is estimated that as many as 100,000 babies were affected in total. Many were still born or died very soon after birth29.
If you weren’t a follower of this series of Substacks then after this health disaster, you would think that the regulators would make damn sure that this could never happen again. But you would be dead wrong.
The scandal is that its teratogenic properties have been known since at least the 1970s. The regulators knew. The doctors knew, yet pregnant mothers were deliberately kept in the dark. In other words, they didn’t have informed consent, and this continued right up until at least 2023.
The official reasons for withholding this information are as bad as those used to sustain the rollout of engineered mRNA gene therapy products.
Unofficially the profit motive must have been a huge factor. After all, it was still under patent and highly profitable back then.
The patent expired in 1993, and derivatives were developed after this, as pharma companies do to try to keep the cash rolling in30.
They couldn’t even do this without breaking the law. Although the fine was large, it was easily absorbed by Abbott Laboratories. No one went to jail, they didn’t lose their license and the pharma reps later got huge financial rewards for acting as whistleblowers. That really showed them, I don’t think.
Note that they pushed this on care homes even after it failed a clinical trial in 1999, due to an increase in adverse events.
From “Abbott pays $1.6bn for promoting off label use of valproic acid” (2012, paywalled, emphasis mine):
The drug company Abbott Laboratories has agreed to pay $1.6bn (£0.9bn; €1.2bn) in penalties for improper promotion of the drug Depakote (valproic acid) in the US. The settlement is the second largest by a drug manufacturer and ends a four year investigation by federal and state officials.
The company acknowledged training a workforce to promote off label use of the drug to nursing homes to control agitation and aggression in older schizophrenia patients and in patients with dementia. The judgment says that Abbott also made illegal payments to doctors and pharmacists to encourage them to promote or prescribe valproic acid outside its licensed indications.
“Not only did Abbott engage in off label promotion, but it targeted elderly dementia patients and downplayed the risks apparent from its own clinical trials,” said Tony West, acting associate Attorney General at a news conference in Washington, DC on 7 May.
Abbott closed a trial of Depakote in patients with dementia in 1999 because ofincreased incidents of adverse events.
It was all harms, with no demonstrable benefits for the condition it was meant to treat:
The Justice Department said Abbott waited nearly two years to tell its sales force that a schizophrenia trial that looked at adding Depakote to another drug failed to show any statistically significant benefit beyond the initial drug. And it waited four years before publishing the trial results. It continued to promote combination use of Depakote to treat schizophrenia throughout the entire period.
“As this criminal and civil resolution demonstrates, those who put profits ahead of patients will pay a hefty price,” said West.
The settlement consists of $800m in civil charges and $700m in criminal charges that will go to the federal government and states. States will receive an additional $100m to resolve consumer protection claims.
Abbott will be on probation for five years, having to regularly report its compliance activities to the court. It also has entered into a Corporate Integrity Agreement with the Department of Health and Human Services, Office of the Inspector General, which holds the company’s board of directors responsible for compliance in these areas.
Former Abbott sales representatives turned whistleblowers will share $84m for helping to uncover and prove the illegal activity, as the law allows.
James Cole, deputy Attorney General, said the settlement is important for what it says about the Obama administration’s “efforts to protect the integrity of programs like Medicare and Medicaid.” A special antifraud unit formed in May 2009 has recovered $8.85bn through settlements and other legal actions.
Abbott issued a brief press release summarising the terms of the settlement. General counsel Laura Schumacher said, “We are pleased to resolve this matter and are confident we have the programs in place to satisfy the requirements of this settlement.”
Industry analysts believe that this will have minimal financial impact on Abbott because it wrote off $1.5bn last autumn towards a potential settlement.
Off-label use was bad enough, first-line use was worse.
From a solicitors website, dated Sep 27th, 2017 (Not a recommendation. Emphasis mine):
How long have the risks of taking Sodium Valproate been known?
Background
Sodium Valproate, which is prescribed to control seizures under a variety of brand names including Epilim, Episenta and Epival, carries a 40% chance of causing developmental problems in the unborn child. These include autism, low IQ and learning disabilities. In addition, it carries a 10% chance of causing physical abnormalities.
In February 2016, the European Medicines Agency (EMA) decided that the information provided to patients required substantial improvement in the form of a new toolkit. Despite that, a very recent survey of female epilepsy sufferers revealed that sixty eight per cent of them had not received any materials from the toolkit.
It has also been revealed that one in six women taking the drug still do not know of the risks and twenty one per cent had not had a discussion initiated by their GP, neurologist or other healthcare professional about the issue.
Epilepsy charities and other support organisations are now calling urgently for all women of childbearing age to have an annual face-to-face consultation with a health professional before their repeat prescription is renewed.
How long have these huge risks been known?
It is now thought that since the 1970s, around 20,000 children have been harmed as a result of their mothers taking Sodium Valproate whilst pregnant. And the terrifying truth is that these risks have been known since the early 1970s.
At a public hearing of the European Medicines Agency, which is conducting a risk assessment of the drug, Catherine Cox of the Fetal Anti-Convulsant Syndrome Association said “these warnings could have and should have been given in 1974. However, there was a deliberate decision not to publish them.”
Documents from 1973 reveal that when considering whether to tell patients about the risks, it was decided that this “could give rise to fruitless anxiety”. A letter to doctors warned that “this compound has been shown to be teratogenic in animals, meaning it could harm the human foetus.” However, the then Committee on the Safety of Medicines said the warning should “not (go) on the package inserts, so that there would be no danger of patients themselves seeing it.”
Sodium Valproate Claim
The leading Sodium Valproate solicitor, David Gazzard, says “even judged by the standards of the time, this is scandalous. This is nothing short of treating people with contempt. How many lives had to be ruined before these clear and substantial risks were taken seriously?”
Teratogenic risks were being deliberately kept from mothers until very recently. It got so bad that one parent even had to act as a medical researcher in her own right to uncover the truth, and later share it. Hat tip to Emma.
From the March ‘24 article posted online: “Doctors 'knew sodium valproate would harm children in 1973', but it was allowed to tear 1,000s of lives apart
'The world knows about Thalidomide... they should know about this'“
Last month, a report by the Patient Safety Commissioner found children “will never be able to live independent lives” after being exposed to the drug. Its author, Dr Henrietta Hughes, said there is a “clear case for redress” for those affected.
Despite this, the issue remains under the radar when compared to other national scandals such as Thalidomide.. But two mothers are hoping to change that.
Emma Murphy and Janet Williams run In-FACT (Independent Fetal Anti Convulsant Trust), an organisation formed to support families and children affected by sodium valproate during pregnancy. Having her first child in 2003 and as a mother of six, Emma noted her first five children were displaying developmental delays and differences compared to their peers.
However, it was only after watching Janet on the news one day that she started piecing her own family's puzzle together. Collating the symptoms and timelines of her first five children, 43-year-old Emma realised they were living with what Janet had been advocating - Fetal Valproate Spectrum Disorder.
Emma with her daughter Lauren outside Downing Street (Image: Emma Murphy)
Realising that night she was the mother of potentially the biggest family in the country dealing with this medical scandal, Emma says she "couldn't just sit by and do nothing". So, she got to work.
The mum, from Salford, told LancsLive: "I was thinking, if I'm in this situation and if Janet's in this situation, there's going to be other women out there. We set up INFACT then and we had two aims.
"The first aim was to get warnings on the patient information leaflets, to warn women of the risks and to get the packaging changed so there's warnings on the packaging. Just awareness about the dangers really.
"So we worked on that in Westminster for a while. The second aim was and still is compensation for the babies who have been affected by this."
Campaigning to the UK Government, using medical support, creating resources and imploring reviews and appeals, Emma and Janet have been working hard to uncover the truth of the so-called Valproate Scandal. "The world knows about Thalidomide and that was classed as the biggest medical scandal," Emma added.
"Whereas with valproate, my work partner and I have been campaigning in Parliament now for 12 years but despite everything we've done, it's still relatively unknown." Whilst working to find out more about valproate and its uses within the medical world, the pair found archive documents involving the drug companies when the medication was brought onto the market.
Emma explained: "The thing with this scandal is, we found archive documents about this. The drug company in 1973 actually warned the Committee of Safety and Medicines, which were the regulators back then - it's called the MHRA today. The drug company actually told them of the risks and told them it would be teratogenic when taken during pregnancy and it would harm the babies."
Emma stated, flatly, that there was a 'conscious decision' to hold information back. She added: "They even sent a letter to the doctors warning them of the risk, but to not warn patients of the risk due to the litigation."
Having spent a long time at the National Archives to uncover the truth, Emma recalls it being "such a surreal moment". She added: "You're looking at these documents, official government documents at that time as well and we're reading them thinking, this can't be. There's no way.
"When I had seen it, I got Janet and we just couldn't believe it, it was there in black and white. We knew at that point we were dealing with a huge medical scandal."
It’s probably no coincidence that public enquiries were only allowed after the patent had expired.
It took 40 years for the contaminated blood scandal to conclude in the UK, long after many victims had died and giving the complicit time to enjoy their retirement.
More than 30,000 people in the UK were infected with HIV and hepatitis C after being given contaminated blood products in the 1970s and 1980s.
A public inquiry described the scale of the scandal as "horrifying" and accused doctors, the government and NHS of repeatedly failing patients.
The government says the first compensation payments to victims will be made by the end of the year.
From “What is the infected blood scandal and what compensation is there?“ (16th August, 2024)
At this rate, it could take another 60-100 years for authentic public enquiries into the SARS-CoV-2 public health disaster to start, if ever.
With valproate, it took nearly 50 years to get the “Cumberlege Review” published in the UK. There wasn’t even a public enquiry and token payments of £25,000 to some of the 24,000 UK victims won’t even begin to be settled until 2025.
Highlights reproduced in full (emphasis mine):
Non-Statutory Inquiry publishes long awaited "Cumberlege Review" in the UK
Last Updated: Wed, 08/07/2020 - 07:02
The outcome of a two-year inquiry in the UK which investigated how the British Healthcare authorities responded to reports of patient concerns regarding the use of sodium valproate (epilim) in pregnancy has today issued their long awaited report.
The inquiry's report is entitled "First Do No Harm" and makes a series of findings concerning the use of sodium valproate (as well as the hormone pregnancy test Primodos and surgical mesh) in the past. It also makes a number of recommendations to be introduced in the UK to ensure the mistakes of the past are not repeated. The key recommendations in the report are as follows:
That the UK Government immediately issues a fulsome apology on behalf of the healthcare system to the families affected by Primodos, sodium valproate and pelvic mesh.
That a Patient Safety Commissioner is appointed. This person would be patients’ port of call, listener and advocate, who holds the system to account, monitors trends, and demands action.
Separate schemes should be set up for Hormone Pregnancy Tests, valproate and pelvic mesh to meet the cost of providing additional care and support to those who have experienced avoidable harm and are eligible to claim.
A Redress Agency for those harmed by medicines and medical devices in future should be established.
The establishment of two types of specialist centres, located regionally – for mesh, and separately for those affected by medications taken during pregnancy.
The regulator of medicines and medical devices in the UK, the MHRA, needs to put patients at the heart of its activity, and to overhaul adverse event reporting and medical device regulation.
That a central database should be created by collecting key details including the patient, the implanted device, and the surgeon.
That the register of the General Medical Council (GMC) should be expanded to include a list of financial and non-pecuniary interests for all doctors, as well as doctors’ clinical interests and specialisms.
Finally, that the UK Government immediately sets up a task force to implement the Review’s recommendations.
The report also made a series of specific findings regarding the use of Sodium Valprate (Epilim) in the UK :
Sodium valproate was known to be teratogenic in animals at the time of licensing. Despite this, no long-term follow-up was conducted at that time.
As concerns emerged about the risk of congenital malformations and neurodevelopmental effects warnings given to patients lagged behind that given to doctors.
Many women were not given enough information about the risks and benefits of their epilepsy treatment and family planning options to make fully informed decisions.
It took over 40 years for the healthcare system to put into place measures to ensure that women were fully informed of the risk prior to becoming pregnant.
The Pregnancy Prevention Programme (PPP) sets out the conditions under which all girls and women of childbearing potential should be treated with valproate. Despite these measures, hundreds of women are still becoming pregnant on valproate while unaware of the risks.
Some additional recommendations concerning families affected by valproate include:
An apology is due, and support is required for those who have suffered avoidable harm.
Specialist centres should be established for all families affected by teratogenic medication, to provide integrated medical and social care expertise to enable those affected to access the services they need in one place.
All women and girls of childbearing potential should be written to, asking them to see their general practitioner or specialist to ensure they are receiving treatment in line with the PPP.
We alongside our colleagues in OACS Ireland are very pleased for our colleagues in the UK who now have more answers as to where the system failed them and are a step closer to justice.
We now need to see an independent inquiry ordered in Ireland so families affected here can receive answers to the many questions they have. In response to today's developments in the UK, we have issued a joint statement with OACS Ireland to the media demanding this inquiry. You can read this statement in the 'News' section of our website.
As you might expect, the real reason for the lack of informed consent:
The only “fruitless anxiety” was that of the clinicians who were being paid off/bribed and didn’t want to miss out or get sued.
From “Disclosure of industry payments to the healthcare sector”, 5th October 2023:
The IMMDS Review, led by Baroness Cumberlege, investigated 3 medical interventions resulting in adverse consequences:
Primodos
sodium valproate
pelvic mesh
The IMMDS report raised concerns about the real and perceived conflicts of interests between clinicians and manufacturers, and how this may influence patient care and, ultimately, patient safety.
Page 34 of the IMMDS report stated:
We have heard particular [patient] concerns that clinicians have been paid or otherwise incentivised by manufacturers. This may influence their practice, and the course of action they recommend to patients, such as preferentially using particular procedures or drugs.
The IMMDS report acknowledged the Association of the British Pharmaceutical Industry’s (ABPI) Disclosure UK system, which publishes information about payments made by certain pharmaceutical businesses to the healthcare sector. In 2022, 145 manufacturers declared payments through Disclosure UK.
I think a lot of the findings and recommendations were ignored, as the MHRA just waved through the teratogenic engineered-mRNA shots just a few months later. This led to a significant decline in the birth rate in many countries, which continues today.
As for the appointment of a “Patient Safety Commissioner” to “be patients’ port of call, listener and advocate, who holds the system to account, monitors trends, and demands action”, if they were appointed then they have been asleep at the wheel for the last 4 years.
The Irish enquiry wasn’t even approved until last year, and it is only getting underway at the time of writing. “Low-key” kind of sums up the media attention to the valproate scandal. One of the reasons I’m putting this out. Please share, as valproate is still being pushed without full informed consent.
Minister for Health secures government approval for inquiry into historical use of sodium valproate in certain groups of women
From Department of Health
Published on 11 July 2023
Last updated on 11 August 2023
Minister for Health Stephen Donnelly has secured government approval to progress an inquiry into the historical licensing and use of sodium valproate in women of child-bearing potential in the State.
While valproate is an effective and essential treatment for some patients, valproate-containing medicines can cause birth defects and developmental disorders in children whose mothers take such medicines during pregnancy.
The purpose of this inquiry is to provide a voice to persons with a diagnosis of foetal valproate spectrum disorder (FVS), their mothers and other family members. The inquiry will also seek to document the evolution of sodium valproate regulation and the practices around the control of this product.
The Chair of this inquiry will be tasked with assessing the health service’s current capacity to respond to safety issues relating to use of anti-seizure medications in women of child-bearing potential.
Minister Donnelly said:
“Today I was delighted to secure government approval for the establishment of an inquiry which will examine the licensing and use of sodium valproate in women of child-bearing potential in the State.
“When I met with the patient groups involved with this issue, I supported their call for an inquiry, and I am very pleased to be able to progress this. This inquiry will be designed to give a voice to patients and their families while looking at the use of sodium valproate in Ireland since it was first licensed.
“There is work to be done before the non-statutory inquiry can commence, but this is an important milestone, and my officials will now work to bring this forward."
Minister Donnelly added:
“Sodium Valproate continues to be an essential part of the treatment plan for some patients and is an effective medication. It is important that people who are currently taking sodium valproate do not make any changes to their treatment without discussing any concerns they have with their doctor in the first instance.”
“The purpose of this inquiry is to provide a voice to persons with a diagnosis of foetal valproate spectrum disorder (FVS), their mothers and other family members.“
The classic exposition of the practice of helping victims of a con adapt to their loss is the sociologist Erving Goffman’s 1952 article “On Cooling the Mark Out.” Like everything by Goffman, it’s worth reading if you want to know what much of life is really all about. (If you don’t, you can skip it.) “After the blowoff has occurred,” Goffman explained, about the operation of a con, “one of the operators stays with the mark and makes an effort to keep the anger of the mark within manageable and sensible proportions. The operator stays behind his team-mates in the capacity of what might be called a cooler and exercises upon the mark the art of consolation. An attempt is made to define the situation for the mark in a way that makes it easy for him to accept the inevitable and quietly go home. The mark is given instruction in the philosophy of taking a loss.” What happened stays out of the paper.
From “Crooked Psychics and Cooling the Mark Out“ (2015)
In the US I couldn’t find any accounts of a public enquiry or report, but in 2011 the FDA issued a safety announcement which reads much like the NHS web page today:
Safety Announcement
[6-30-2011] The U.S. Food and Drug Administration (FDA) is informing the public that children born to mothers who take the anti-seizure medication valproate sodium or related products (valproic acid and divalproex sodium) during pregnancy have an increased risk of lower cognitive test scores than children exposed to other anti-seizure medications during pregnancy. This conclusion is based on the results of epidemiologic studies that show that children born to mothers who took valproate sodium or related products throughout their pregnancy tend to score lower on cognitive tests (IQ and other tests) than children born to mothers who took other anti-seizure medications during pregnancy.
… The benefits and the risks of valproate sodium and related products should be carefully weighed when prescribing these drugs to women of childbearing age, particularly for conditions not usually associated with permanent injury or death. If the use of valproate is not essential, alternative medications that have a lower risk to the fetus of birth defects and adverse cognitive effects should be considered in pregnant women and women of childbearing age. If the decision is made to use valproate in women of childbearing age, effective birth control should be used. (See Data Summary).
If, on reading this, you feel that you or anyone you know may be a victim there are support groups available, along with government-led compensation schemes at various stages of approval.
This isn’t an exhaustive list or a recommendation, but they should be able to signpost you elsewhere too.
If you know of one (other than the FDA, groan) please comment below.
Australia
As above. Both countries have lawyers who may make a claim for clinical negligence. But as with the DeathVax™ shots, this needs careful consideration as to the expenses you may incur, timescales and realistic prospects for success.
Conclusion
It is undeniable that valproate has its uses. Epileptic fits may cause brain damage or prove fatal, giving you no quality of life, being unable to drive or maintain employment, and other drugs may not work as well or be contraindicated. However, whether through the underpinnings of a culture of eugenics, pure greed, or a combination of the two the pharma-medico complex keeps confirming again and again that they are not to be trusted.
Until proven otherwise, our response to any new product or medical device must be to be suspicious of it, every time. We need to treat the captured regulators as nothing more than the sales and promotion office for the industry.
They are all too quick to licence products regardless of real-world safety or efficacy. But when something goes disastrously wrong expect such findings to be hidden from you. You will not be able to give informed consent. Any requests for product recalls are likely to be ignored, as will calls for compensation and public inquiries until many decades have passed and employees are enjoying their retirements.
Thanks for reading DoorlessCarp’s Scientific Literature Reviews! This post is public so feel free to share it.
The joys of retirement. But being famous means having to smile and engage with your fans and autograph hunters when you are out and about.
DoorlessCarp’s Scientific Literature Reviews is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.
Stevens M, Peigneur S, Tytgat J. Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels.Front Pharmacol. 2011;2. doi:10.3389/fphar.2011.00071
Sfera A, Thomas KG, Sasannia S, et al. Neuronal and Non-Neuronal GABA in COVID-19: Relevance for Psychiatry.Reports. 2022;5(2):22. doi:10.3390/reports5020022
Yapici-Eser H, Koroglu YE, Oztop-Cakmak O, Keskin O, Gursoy A, Gursoy-Ozdemir Y. Neuropsychiatric Symptoms of COVID-19 Explained by SARS-CoV-2 Proteins’ Mimicry of Human Protein Interactions.Front Hum Neurosci. 2021;15. doi:10.3389/fnhum.2021.656313
Taneja N, Davis M, Choy JS, et al. Histone H2AX Phosphorylation as a Predictor of Radiosensitivity and Target for Radiotherapy *. Journal of Biological Chemistry. 2004;279(3):2273-2280. doi:10.1074/jbc.M310030200
Tonk ECM, Robinson JF, Verhoef A, Theunissen PT, Pennings JLA, Piersma AH. Valproic acid-induced gene expression responses in rat whole embryo culture and comparison across in vitro developmental and non-developmental models.Reproductive Toxicology. 2013;41:57-66. doi:10.1016/j.reprotox.2013.06.069
Falk M, Hausmann M. A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?Cancers (Basel). 2020;13(1):18. doi:10.3390/cancers13010018
Singh D, Gupta S, Verma I, Morsy MA, Nair AB, Ahmed ASF. Hidden pharmacological activities of valproic acid: A new insight.Biomedicine & Pharmacotherapy. 2021;142:112021. doi:10.1016/j.biopha.2021.112021
Soria-Castro R, Chávez-Blanco AD, García-Pérez BE, et al. Valproic acid inhibits interferon-γ production by NK cells and increases susceptibility to Listeria monocytogenes infection. Sci Rep. 2020;10(1):17802. doi:10.1038/s41598-020-74836-w
Chen S, Saeed AFUH, Liu Q, et al. Macrophages in immunoregulation and therapeutics.Sig Transduct Target Ther. 2023;8(1):1-35. doi:10.1038/s41392-023-01452-1
Zhang Y, Lim D, Cai Z, et al. Valproic acid counteracts polycyclic aromatic hydrocarbons (PAHs)-induced tumorigenic effects by regulating the polarization of macrophages.Ecotoxicology and Environmental Safety. 2022;241:113779. doi:10.1016/j.ecoenv.2022.113779
Natale G, Fini E, Calabrò PF, Carli M, Scarselli M, Bocci G. Valproate and lithium: Old drugs for new pharmacological approaches in brain tumors?Cancer Letters. 2023;560:216125. doi:10.1016/j.canlet.2023.216125
O’Keeffe LM, Taylor G, Huxley RR, Mitchell P, Woodward M, Peters SAE. Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis.BMJ Open. 2018;8(10):e021611. doi:10.1136/bmjopen-2018-021611
Hallas J, Friis S, Bjerrum L, et al. Cancer Risk in Long-term Users of Valproate: A Population-Based Case-Control Study.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2009;18:1714-1719. doi:10.1158/1055-9965.EPI-08-0646
Šlekienė L, Stakišaitis D, Balnytė I, Valančiūtė A. Sodium Valproate Inhibits Small Cell Lung Cancer Tumor Growth on the Chicken Embryo Chorioallantoic Membrane and Reduces the p53 and EZH2 Expression.Dose-Response. 2018;16(2):1559325818772486. doi:10.1177/1559325818772486
Stakisaitis D, Mozuraite R, Juodziukyniene N, et al. Sodium Valproate Enhances the Urethane-Induced Lung Adenomas and Suppresses Malignization of Adenomas in Ovariectomized Female Mice.International Journal of Endocrinology. 2015;2015(1):218219. doi:10.1155/2015/218219
Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen *. Journal of Biological Chemistry. 2001;276(39):36734-36741. doi:10.1074/jbc.M101287200
Delage C, Palayer M, Etain B, et al. Valproate, divalproex, valpromide: Are the differences in indications justified?Biomedicine & Pharmacotherapy. 2023;158:114051. doi:10.1016/j.biopha.2022.114051
Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated
... Abstract. On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate.
... In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age.
![[1]](https://commons.wikimedia.org/wiki/File:Steps_in_nucleosome_assembly.svg#cite_note-1){kind=link}
Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated
... Abstract. On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate.
... In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age.
https://pubmed.ncbi.nlm.nih.gov/39189597/
Generational effects of valproate. A 53% chance of your offspring being affected if you were valproate exposed.
Transgenerational adverse effects of valproate? A patient report from 90 affected families
Marine Martin et al. Birth Defects Res. 2022.
https://pubmed.ncbi.nlm.nih.gov/34866359/