Can medicines help persistent memory problems after brain injury?
What drug studies found, who took part, and what to ask your care team
It has been months since the crash. The headaches have eased. But you still forget what you went into the kitchen for. Work tasks slip away halfway through. Someone at a support group mentions a medicine that helped their memory. You wonder whether you should ask for it too.
That is a fair question to bring to your care team. A few medicines have been tested for thinking problems after brain injury. The results depend a great deal on who was studied.
Most of these trials involved people with moderate or severe injuries, often months or years earlier. Very little research has been done in people whose only injury was a concussion. Knowing those details can help you have a clearer talk with the person who prescribes for you.
Why no pill is approved for memory after brain injury
Military and veterans’ health systems follow a VA/DoD guideline for mild TBI, most recently updated in 2021. It states that no medicines have FDA approval for the brain or behavior symptoms that follow a concussion [1]. So a prescriber who uses a medicine for memory after a brain injury is using it “off label.” That means the FDA has not approved the drug for that purpose.
With off label use, you and your prescriber rely on smaller studies, clinical judgment and close follow up.
Memory problems rarely have one cause
Thinking problems after an injury can come from several sources at once. The VA/DoD guideline lists sleep, pain, mental health, headache and balance problems as factors to manage before or alongside memory treatment [1]. The INCOG 2.0 international guideline, updated in 2023, adds hearing, vision, fatigue, substance use and medicines to the list of things to check [3].
Some of those factors respond to their own treatment. A person whose memory slips because of poor sleep may need sleep care first. Someone taking a sedating medicine for another reason may need a review of that drug. A medicine aimed at memory would not fix either problem.
That is one reason guidelines put assessment first. Some people with mild TBI still have memory, attention or planning problems after these factors are managed. For them, the VA/DoD guideline recommends trying a few sessions of cognitive rehab with a clinician [1].
Donepezil: what a 2024 trial found
Researchers have studied donepezil as a possible memory medicine after brain injury. A trial published in 2024 tested it at four sites, using a randomized, double blind design [2, 7]. “Double blind” means neither participants nor researchers knew who got the real drug until the end.
Who took part
The trial enrolled 75 adults, with an average age of 37. Three in four were men [7]. All had been injured at least six months earlier [7]. Most had a severe TBI that needed a hospital stay [7]. The trial also accepted moderate injuries and milder ones with complications [7].
To join, people needed serious, lasting problems with verbal memory, the kind that makes it hard to learn and recall spoken or written words [2]. Those problems had to limit daily life [2]. The trial ran for 10 weeks [7].
What it measured and found
The main test asked people to learn a word list over several tries. People taking donepezil improved more on this test than those taking a placebo, an inactive pill [7]. About 42% of the donepezil group met the bar for a meaningful response, compared with 18% of the placebo group [2]. Among those who responded, delayed recall and processing speed also improved [2].
Researchers summed this up with a figure called the “number needed to treat.” For roughly every three or four people who took donepezil, one more person responded than would have on placebo [2].
Side effects
Side effects were reported by 46% of people on donepezil and 8% on placebo [2]. Diarrhea and nausea were the most clearly linked to the drug [2]. Neither group had any serious adverse events [7].
The study was funded by a federal disability research institute [7]. Reports on the study noted limits. The sample was small. The results may not apply to people with other levels of injury [7]. The trial also lasted only 10 weeks [7]. It cannot tell us whether the gains hold up over many months, or what happens after someone stops the drug.
The 2023 INCOG memory guideline, written before this trial was published, said only limited evidence supports medicines called acetylcholinesterase inhibitors for memory [8]. It called for more research on medicines for memory after TBI [8].
Methylphenidate: more about speed than memory
INCOG 2.0 recommends methylphenidate to improve information processing speed after TBI, which is how quickly you take in and respond to information [3]. The recommendation sits in the part of the guideline that covers attention and speed.
A 2025 meta analysis, which pools results across studies, looked at 25 studies with 666 adults [4]. Injuries ranged from mild to severe. People were anywhere from 4 days to 8.6 years past their injury [4].
The pooled results showed a benefit on only one timed attention and speed test. Other thinking tests did not show a clear difference [4]. There was not enough data to combine the memory results at all [4]. The review did find improvements in depression and fatigue [4].
The authors described real limits. Eleven of the 25 studies carried some to high risk of bias, samples were small. Results were reported in inconsistent ways [4]. The review did not examine side effects. It did not report results for mild TBI separately [4].
For you, that means methylphenidate might help some people who think slowly after a TBI. Whether it helps everyday memory is still unclear.
Slow thinking and poor memory can look alike in daily life. If you process information slowly, you may miss parts of a conversation and then seem to forget them. Detailed testing can help sort out which problem is driving your trouble, which in turn shapes which treatment makes sense [9]. Any medicine like this has risks that your prescriber needs to weigh against your heart health, sleep, mood and other medicines.
Amantadine: a common choice with a disappointing trial
Amantadine is often prescribed to help thinking and memory after TBI [6]. A multisite trial published in 2018 put that practice to a direct test [5].
The trial included 119 adults whose injuries had happened more than six months earlier [5]. Injuries ranged from milder ones with complications to severe [5]. Everyone also had irritability. Each person scored well below average on at least two thinking tests [5]. They took amantadine or a placebo for 60 days [5].
At 28 days, the placebo group did better on overall thinking and on learning and memory [5]. By day 60, the groups no longer differed [5]. Side effects were similar in both groups [5]. The authors concluded that their results do not support using amantadine to improve thinking in people with chronic TBI [5]. Everyone in the study also had irritability, so the findings may not cover every person with a brain injury. Still, it was a multisite trial with a placebo group. It found no thinking benefit.
A TBI Model Systems summary of the trial notes that there is little evidence for this use, even though clinicians still commonly prescribe it [10].
Comparison compiled by Safety Behind the Wheel Foundation
Medicines tested for thinking problems after TBI
| Medicine | Who was studied | What was found | Main limits |
|---|---|---|---|
| Donepezil | 75 adults, mostly severe TBI, at least 6 months after injury | Better verbal learning; 42% responded vs 18% on placebo | More side effects; small study; little data for concussion |
| Methylphenidate | 25 studies, 666 adults, mild to severe TBI | Faster on one timed test; less depression and fatigue | Memory not pooled; side effects not reviewed |
| Amantadine | 119 adults with chronic TBI and irritability | No thinking benefit; worse at 28 days | Done in people with irritability |
Sources: Arciniegas and colleagues 2024 [2]; MDedge 2025 [7]; Rees and colleagues 2025 [4]; Hammond and colleagues 2018 [5].
Why the evidence is thinnest for concussion
Look closely at who joined these trials. The donepezil study enrolled mostly people with severe TBI [7]. The amantadine trial included injuries from milder ones with complications up to severe [5]. The methylphenidate review included some people with mild TBI but did not report their results on their own [4].
That matters because a concussion and a severe TBI are very different injuries. Most people who have concussion symptoms get better within a week to a few months [11]. Some take longer and benefit from treatment aimed at their particular symptoms [11]. A medicine that helps one group may not help the other. It may carry risks that are not worth taking.
Age matters too. All three bodies of research described here studied adults [7, 4, 5]. None of them tells us how these medicines work for a child or teen after a concussion. Parents should raise that gap with a specialist who treats young people with brain injuries.
The VA/DoD guideline, written for mild TBI, makes no recommendation for any medicine to treat memory [1]. Its suggested treatment for lasting memory, attention or planning problems is a short trial of clinician directed cognitive rehab, after other contributing factors are addressed [1].
Medicines that can make memory worse
The medicines you already take deserve a look too. A TBI Model Systems factsheet on thinking problems advises watching for side effects that may affect thinking [9].
The VA/DoD guideline advises care teams to avoid medicines that can cause confusion after mild TBI, such as benzodiazepines, lithium and anticholinergic drugs [1]. A 2024 military guidance document on sleep after concussion goes further. It calls benzodiazepines contraindicated after TBI, meaning they should generally not be used, because they may slow recovery and harm thinking [12]. It also urges caution with anticholinergic drugs in the first three months after injury [12].
Never stop a prescribed medicine on your own. Bring a complete list to your prescriber or pharmacist and ask for a review.
Some sleep medicines carry a risk of slowed reactions the next day [12]. If you drive, ask whether any medicine you take could affect you behind the wheel.
Bring this to a medicine review
Checklist from Safety Behind the Wheel Foundation
- Every prescription you take, with the dose written on the label.
- Over the counter products, including sleep aids, allergy pills and pain relievers.
- Vitamins, supplements, cannabis and alcohol use.
- When each medicine started, and whether memory changed around that time.
- Any daytime sleepiness, dizziness or slowed thinking you have noticed.
- Whether you are driving, and how far.
Getting a specialist assessment
A medicine for memory is a decision for someone who knows brain injury well. A neuropsychologist usually evaluates changes in thinking after TBI, using detailed testing [9]. A physiatrist, a physician trained in rehabilitation medicine, can help you sort out symptoms and treatment options [9].
A good assessment covers more than memory tests. It should include how your injury happened, what your memory was like before, how you sleep, your mood, your pain, and every medicine you take [1, 3]. Only then does it make sense to weigh a medicine against rehab and other steps.
If a prescriber does suggest a trial of medicine, ask how success will be judged. Test scores are one measure. Changes in daily life, such as fewer missed appointments or less time redoing work, matter more to most people.
It helps to keep simple notes for two or three weeks before the visit and during any trial. Write down what you forgot, when it happened, and how you slept the night before. Notes like these give your team something concrete to compare. They make it easier to spot side effects early.
Imagine a 52 year old truck driver who had a moderate TBI in a highway crash two years ago. His neuropsychology testing shows a clear problem learning new information. His team first treats his sleep apnea and reviews a sedating medicine. Only then do they talk about a medicine trial, with a set end date and a plan to track missed tasks at work.
Cognitive rehab remains the main treatment in guidelines. Thinking often improves with it [1, 9].
Questions to ask your care team
Question checklist from Safety Behind the Wheel Foundation
- Could anything I already take be affecting my memory?
- Have my sleep, mood, pain and headaches been checked as possible causes?
- Was my injury similar to the people studied in the trials for this medicine?
- What benefit should I expect, and how will we measure it in daily life?
- What side effects should I watch for, and what should I do if they happen?
- How long will we try the medicine before deciding whether it helps?
- Could this medicine affect my driving, my sleep or my heart?
- Should I see a neuropsychologist or a rehabilitation specialist before we decide?
- Would cognitive rehab help me alongside, or before, any medicine?
Frequently asked questions
Will a memory medicine help if I only had a concussion?
There is very little research to say. The main trials mostly enrolled people with moderate or severe TBI. No medicine is FDA approved for symptoms after a concussion [7, 1]. Most people with a concussion recover within weeks to a few months [11].
Is donepezil now a standard treatment for memory after TBI?
Not yet. The 2024 trial was promising for some adults with severe, persistent memory problems, mostly after severe TBI [2]. It was a small study. Its results may not apply to other injury levels [7].
Can a medicine replace memory rehabilitation?
Guidelines for mild TBI recommend a trial of clinician directed rehab for lasting memory problems. They make no medicine recommendation for memory [1]. Medicine studies mostly measured test scores, so rehab remains the main way to build strategies for daily life [9].
What if my prescriber already has me on one of these medicines?
Keep taking it as prescribed and raise your questions at your next visit. Ask how the team is judging whether it helps. If a side effect seems to cloud your thinking or worries you, call your prescriber or pharmacist [9].
The bottom line
Recommendation from Safety Behind the Wheel Foundation
Medicines can help some people with brain injury, but the evidence is narrow. Donepezil has the strongest recent trial, mainly in people with severe memory problems after severe TBI. Methylphenidate is better supported for thinking speed than for memory. Amantadine did not help thinking in a multisite trial.
If you had a concussion and memory problems linger, start with an assessment that checks sleep, mood, pain and current medicines, and ask about guided rehab. A specialist can tell you whether a medicine trial makes sense for your injury and your goals.
Sources and further reading
- 1Management and Rehabilitation of Post-Acute Mild Traumatic Brain Injury Work Group. VA/DoD clinical practice guideline for the management and rehabilitation of post-acute mild traumatic brain injury, provider summary. Version 3.0. U.S. Department of Veterans Affairs and Department of Defense; 2021. healthquality.va.gov/…/VADoDmTBICPGProviderSummary…
- 2Arciniegas DB, Almeida EJ, Sander AM, et al. Multicenter evaluation of memory remediation in traumatic brain injury with donepezil: a randomized controlled trial. Journal of Neuropsychiatry and Clinical Neurosciences. Published online December 4, 2024. PMID 39628282. doi.org/10.1176/appi.neuropsych.20230055
- 3Ponsford J, Velikonja D, Janzen S, et al. INCOG 2.0 guidelines for cognitive rehabilitation following traumatic brain injury, part II: attention and information processing speed. Journal of Head Trauma Rehabilitation. 2023;38(1):38-51. research.monash.edu/…/incog-20-guidelines-for-cog…
- 4Rees JLC, Saunders R, Krynicki CR, et al. Methylphenidate for the cognitive and neurobehavioural sequelae of traumatic brain injury in adults: a systematic review and meta-analysis. Frontiers in Neurology. 2025;16:1546080. frontiersin.org/…/full
- 5Hammond FM, Sherer M, Malec JF, et al. Amantadine did not positively impact cognition in chronic traumatic brain injury: a multi-site, randomized, controlled trial. Journal of Neurotrauma. 2018;35(19):2298-2305. doi.org/10.1089/neu.2018.5767
- 6Brain Injury Association of America. Amantadine did not positively impact cognition in chronic traumatic brain injury (TBI Model Systems research summary). Accessed October 2026. biausa.org/…/amantadine-did-not-positive…
- 7Chaphalkar A. Donepezil shows promise in TBI recovery. MDedge, Federal Practitioner. January 7, 2025. mdedge.com/…/donepezil-shows-promise-tbi…
- 8Velikonja D, Ponsford J, Janzen S, et al. INCOG 2.0 guidelines for cognitive rehabilitation following traumatic brain injury, part V: memory. Journal of Head Trauma Rehabilitation. 2023;38(1):83-102. doi.org/10.1097/HTR.0000000000000837
- 9Neumann D, Lequerica A. Cognitive problems after traumatic brain injury. Model Systems Knowledge Translation Center; 2020. msktc.org/…/cognitive-problems-after-tr…
- 10Model Systems Knowledge Translation Center. Amantadine and cognition in chronic traumatic brain injury (research quick review). Accessed October 2026. msktc.org/…/amantadine-and-cognition-ch…
- 11Hanks R, Bell K, Dreer L. Concussion recovery. Model Systems Knowledge Translation Center. Accessed October 2026. msktc.org/tbi/factsheets/concussion-recovery
- 12Traumatic Brain Injury Center of Excellence. Assessment and management of sleep disturbances following concussion/mild traumatic brain injury: guidance for the primary care manager. Defense Health Agency; revised September 2024. health.mil/…/Management-of-Sleep-Disturb…
This article reflects the safety priorities of brain injury recovery and road safety education. It is general education and does not replace medical advice. Medicine research changes over time, so check official sources and talk with your own care team before making any decision about treatment. Reviewed October 2026.
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