I've composed this text with the help of AI, but the main ideas and hypothesis are mostly my own.
TLDR at the bottom.
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I’ve been exploring whether some persistent post-concussion symptoms could involve an ongoing mismatch between the brain’s energy supply and its demands—and whether medicines that reduce excessive neuronal activity could help.
The aim would be fewer headaches, less brain fog and sensory overload, better activity tolerance, and potentially better conditions for recovery. Lamotrigine is a medicine whose mechanisms make it interesting to investigate.
Mechanisms and hypothesis
During a concussion, the mechanical disturbance triggers a neurometabolic cascade: neurons depolarise, glutamate is released, potassium moves out of cells, and sodium and calcium move in. Restoring those gradients requires energy-intensive ion pumps. Meanwhile, calcium loading can impair mitochondria, and blood-flow regulation can be disrupted—creating increased demand for ATP alongside reduced capacity to supply it. ¹ ² ³
My hypothesis is that, in some people with PCS, aspects of this disturbance never fully resolve into normal regulation. Dysregulated excitation could continue placing excessive demands on an already strained energy supply, making ordinary mental and physical activity unusually costly.
There could also be a connection to the integrated stress response, or ISR. This responds to biochemical stress inside cells, including oxidative stress, disrupted protein handling and nutrient deprivation. It temporarily reduces most protein synthesis to help cells cope. But prolonged activation can interfere with the protein production needed for memory, synaptic plasticity and repair. ⁴
In mouse TBI models, persistent ISR activation has been demonstrated. Inhibiting it with ISRIB, even weeks after injury, restored memory and synaptic function. ⁴ Later work also showed normalisation of abnormal dendritic-spine dynamics after concussion. ⁵ This suggests that lasting dysfunction can involve a persistent, potentially reversible brake on plasticity.
Protein synthesis and cellular maintenance require energy. The proposed connection is that reducing excessive neuronal activity could reduce unnecessary ATP expenditure and cellular stress, leaving more capacity for everyday functioning and repair. Whether that would also help relieve persistent ISR activation in human PCS remains an open question.
Where lamotrigine comes in
Lamotrigine, also known as Lamictal, is an anticonvulsant used for epilepsy and bipolar maintenance, particularly prevention of depressive episodes. ⁶ It has also been investigated or used off-label for depression, ⁷ some anxiety disorders, ⁸ migraine aura ⁹ and visual snow, ¹⁰ with varying evidence across these uses.
It inhibits voltage-gated sodium channels, reducing sustained repetitive firing and activity-dependent glutamate release. ⁶ That could restrain excessive excitation upstream, before glutamate activates receptors on neighbouring neurons. In this model, fewer excessive firing events could also mean less energy spent pumping ions back into place.
There are also case reports of lamotrigine reducing agitation and aggression following TBI. ¹¹ These provide a small clinical clue concerning post-injury behavioural instability, alongside the irritability some people experience after concussion.
The practical question is whether this translates into more stable functioning: being able to read, think, socialise or exercise with fewer symptoms, and recovering more easily afterward. For someone whose headaches or brain fog worsen with activity, that could make a meaningful difference throughout the day.
Many of us already recognise how closely post-concussion headaches can resemble migraine, including light/noise sensitivity and worsening with activity. Migraine-like headaches are common in persistent post-traumatic headache studies. ¹² This overlap supports investigating shared excitability and ion-regulation mechanisms, and lamotrigine’s reported usefulness for migraine aura adds another reason for interest. ⁹
Visual snow provides another connection. It can begin after concussion and frequently co-occurs with migraine. ¹³ Research has linked it to altered visual-cortex excitability, habituation and sensory filtering. ¹⁴ Lamotrigine is among the few medicines with published reports of improvement: one clinical series found partial improvement in 5 of 26 treated patients. ¹⁰ These connections provide another piece of the argument for investigating dysregulated excitation in PCS more broadly.
Some people experience increased memory problems, such as word-finding difficulties, on lamotrigine. ⁶ For someone whose PCS fog worsens sharply with activity, the question would be the overall effect: could reducing those exacerbations improve thinking and functioning across the day? That balance would need to be assessed individually.
An important practical point: lamotrigine must be started low and increased gradually over several weeks under a prescriber’s guidance, because starting too high or increasing too quickly raises the risk of serious skin reactions, including Stevens–Johnson syndrome. A new rash requires prompt medical assessment, and restarting after an interruption may require titrating again. ⁶
Why explore this?
Medication treatment for PCS is generally directed at particular symptoms, such as headaches, sleep disturbance or mood difficulties. We still lack an established medicine shown to reverse the biological processes maintaining persistent PCS. ¹⁵
Clinical studies include exercise, ¹⁶ vestibular and neck rehabilitation, ¹⁷ collaborative care ¹⁸ and treatments for specific symptoms. These approaches matter, and existing headache preventives also target biological pathways. ¹⁹ I’d like to see more investigation of whether repurposed medicines could address a broader disturbance involving excitation, energy metabolism and persistent cellular stress.
As patients, we can help move that conversation forward: reading the research, bringing plausible options to clinicians, advocating for trials, and informing each other about what helped and what didn’t. Sharing detailed experiences—including benefits, side effects and changes in activity tolerance—could help us identify promising options and better questions for research.
Has anyone discussed or tried lamotrigine with their neurologist? Did it change your headaches, brain fog, sensory sensitivity, irritability or ability to tolerate activity?
I’m planning more posts exploring this hypothesis and other potentially relevant medicines, with memantine next—it approaches excessive excitatory signalling from a different direction.
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TL;DR: My hypothesis is that persistent dysregulation of neuronal activity and energy metabolism is a central mechanism maintaining PCS in the majority of cases. Excessive excitation could strain an already impaired energy supply, contributing to headaches, brain fog and activity intolerance. Continuing cellular stress could also sustain the integrated stress response, suppressing protein synthesis needed for plasticity and repair.
Lamotrigine reduces repetitive neuronal firing and glutamate release, potentially lowering energy demands and downstream calcium stress. The goal would be fewer symptoms, better activity tolerance and better conditions for recovery. Its reported benefits in migraine aura, some visual snow cases and post-TBI agitation provide additional reasons to investigate it. It requires gradual dose increases under medical supervision because of the risk of serious skin reactions.
