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Dr. Dale Bredesen

Sundowning in Alzheimer’s and dementia: melatonin/tryptophan for the agitation, restlessness, anxiety, disturbed sleep and aggression

March 3, 2023 By Trudy Scott 8 Comments

sundowning in alzheimer's and dementia

The terms “sundown syndrome” or “sundowning” are used to describe a wide range of neuropsychiatric symptoms occurring in individuals with dementia in the late afternoon, evening, or night. These symptoms include confusion, restlessness, anxiety, agitation, aggression, pacing, wandering, screaming, yelling, and hallucinations. The treatment of sundown syndrome is challenging, and pharmacological therapies are not particularly effective.

This definition is from a very encouraging case study published as a letter to the editor of the Journal of the American Geriatrics Society – Melatonin for Sundown Syndrome and Delirium in Dementia: Is It Effective?

This case study is very typical in terms of symptoms and a pharmacological approach:

An 81-year-old man with Alzheimer’s disease diagnosed 4 years previously was admitted to the elderly department because of behavioral disturbances, sleep disorders, and wandering. His wife said that his cognitive and functional impairments had gradually worsened over the past 4 years and that, in the last 6 months, her husband had become verbally aggressive, agitated, and restless; wandered; and paced. He did not sleep for long and had difficulty falling asleep. The symptoms increased in the late afternoon and at night. He had no hallucinations or delusions. One month before admission, delirium was suspected, and his general practitioner prescribed haloperidol, but it was not effective.

During admission, sundown syndrome was diagnosed, and he received pharmacological and nonpharmacological interventions for behavioral and sleep disturbances, but none was effective, and some aggravated symptoms. The pharmacological interventions consisted of benzodiazepines, antipsychotics, cholinesterase inhibitors, mood stabilizers, and antidepressants, all given in an optimal dosing schedule.

Melatonin led to much improved symptoms within a few hours

None of the medications were effective and some made his symptoms worse. This case study is atypical in that his doctors were open to the use of melatonin. This led to much improved symptoms within a few hours and complete resolution in 2 weeks with a second dose:

After extensive review of his history, the effect of past treatments, and the published literature, melatonin was started at a dose of 2 mg at 8:00 p.m. for sleep disorders. Not only did his sleep quality improve within a week, but there was also significant improvement in his behavior within 2 hours of initiation of melatonin. A therapeutic trial with an additional dose of 2 mg given at 3:00 p.m. was started, and his symptoms gradually improved over the subsequent 2 weeks (NPI score 20). No behavioral changes were observed in the 2-month follow-up.

These results are powerful and mirror what a number of other studies are showing, for sundowning and to also slow “down the progression of cognitive impairment”). We also see melatonin working clinically for this population.

I share this case study so if you are a carer or have a parent or loved one with Alzheimer’s or dementia, you have a resource to share with the medical team. There is growing awareness of this research and some neurologists are prescribing melatonin with success. Typically 0.5 mg to 5 mg melatonin is used once or twice a day.

My hope is that this becomes the standard of care instead of prescribing psychiatric medications which the authors acknowledge are not particularly effective. And they don’t get to the root cause that is triggering these symptoms: low melatonin and low serotonin (more on low serotonin below).

Melatonin and anxiety

Melatonin also improves sleep quality and reduces anxiety after a TBI (traumatic brain injury). I blogged about a study that used timed-release melatonin here. The study participants used 2 mg of timed-release/prolonged-release melatonin for 4 weeks. This improved sleep quality and melatonin was also associated with a small decrease in self-reported anxiety.

As outlined in this paper, Melatonin as a Potential Approach to Anxiety Treatment, “melatonin’s benefit in anxiety may reside in its sympatholytic action, interaction with the renin-angiotensin and glucocorticoid systems, modulation of interneuronal signaling and its extraordinary antioxidant and radical scavenging nature.”

The serotonin connection and using tryptophan or 5-HTP

Keep in mind the strong serotonin connection: these sundowning symptoms start late afternoon and evening (hence the name sundowning) and serotonin is a precursor to melatonin production.

I look forward to seeing research on the use of tryptophan or 5-HTP for sundowning symptoms too. Until then, based on the above, and the fact that many of these symptoms are classic signs of low serotonin, I feel comfortable recommending either of these amino acids.

As always, we start low, use afternoon and evening doses and increase based on symptom resolution. The typical adult dose of tryptophan is 500 mg and 50 mg of 5-HTP. I recommend starting with 100 mg tryptophan and 10mg of 5-HTP. The amino acid precautions are always reviewed. I would not recommend either tryptophan or 5-HTP if the individual is currently prescribed an antidepressant, unless you are working with a knowledgeable practitioner and always with the approval and monitoring of the prescribing doctor. This is because of the possibility of serotonin syndrome.

Dr. Dale Bredesen recommends tryptophan and melatonin

Dr. Dale Bredesen is the author of The End of Alzheimer’s (my Amazon link) and a number of other books on Alzheimer’s. He is an authority on Alzheimer’s and recommends both tryptophan and melatonin. In this paper, Reversal of cognitive decline: A novel therapeutic program, he reports the use of 0.5 mg melatonin and 500 mg tryptophan used (3 x week) for sleep issues.

Interestingly and surprisingly, he doesn’t mention sundowning in his books or papers. However, if you are new to his work, I encourage you to look into his functional medicine approach, which is extensive and offers results and hope for many.

Low GABA in Alzheimer’s disease and dementia

This paper, Implications of GABAergic Neurotransmission in Alzheimer’s Disease, shares that “of the two major types of synapses in the central nervous system (CNS): glutamatergic and GABAergic, which provide excitatory and inhibitory outputs respectively, abundant data implicate an impaired glutamatergic system during disease progression.” 

The amino acid GABA may also help anxiety, disturbed sleep and restlessness. And it’s common to have both low serotonin and low GABA.

This case study illustrates how using the amino acid GABA can help ease the anxiety often experienced in those with Alzheimer’s disease.

It’s too entrenched in our thinking that there is nothing to be done

It saddens me that it’s too entrenched in our thinking that there is nothing to be done. Unfortunately, many family members and medical professionals consider sundowning a normal part of the disease progression and question whether it’s worth doing anything.

My feedback is this: please don’t discount the power of the amino acids, melatonin and other nutritional approaches to offer some relief and improved quality of life for the patient. And when they are calmer, less aggressive and sleeping better it’s so much easier for the caregivers too.

Resources if you are new to using tryptophan or GABA as supplements

If you are new to using tryptophan or GABA as supplements, here is the Amino Acids Mood Questionnaire from The Antianxiety Food Solution (you can see all the symptoms of neurotransmitter imbalances, including low GABA and low serotonin).

If you suspect low levels of any of the neurotransmitters and do not yet have my book, The Antianxiety Food Solution – How the Foods You Eat Can Help You Calm Your Anxious Mind, Improve Your Mood, and End Cravings, I highly recommend getting it and reading it before jumping in and using amino acids on your own so you are knowledgeable. And be sure to share it with the practitioner/health team you or your loved one is working with.

There is an entire chapter on the amino acids and they are discussed throughout the book in the sections on gut health, gluten, blood sugar control, sugar cravings, self-medicating with alcohol and more.

The book doesn’t include product names (per the publisher’s request) so this blog, The Antianxiety Food Solution Amino Acid and Pyroluria Supplements, lists the amino acids that I use with my individual clients and those in my group programs. You can find them all in my online store. The above oral lavender products are available in my online store too.

If, after reading this blog and my book, you don’t feel comfortable figuring things out on your own (i.e. doing the symptoms questionnaire and respective amino acids trials), a good place to get help is the GABA QuickStart Program (if you have low GABA symptoms). This is a paid online/virtual group program where you get my guidance and community support.

If you are a practitioner, join us in The Balancing Neurotransmitters: the Fundamentals program. This is also a paid online/virtual program with an opportunity to interact with me and other practitioners who are also using the amino acids.

Have you used melatonin to help with sundowning symptoms with your loved one and if yes how much helps?

Was melatonin prescribed or did you research it and bring the information to the doctor?

Have you used melatonin to help with sundowning symptoms in your clients/patients? What ranges have you seen to help?

Have you also found tryptophan, 5-HTP and/or GABA to help?

If you have questions and other feedback please share it here too.

Filed Under: Alzheimer's disease, Anxiety, serotonin, Tryptophan Tagged With: 5-HTP, aggression, agitation, alzheimer's, anxiety, confusion, dementia, disturbed sleep, Dr. Dale Bredesen, GABA, GABA Quickstart online program; and Balancing Neurotransmitters: the Fundamentals program for practitioners, melatonin, pacing, restlessness, serotonin, sundown syndrome, Sundowning, tryptophan, wandering, yelling

Microdose lithium formulation is capable of halting signs of advanced Alzheimer’s and improving cognition

February 7, 2020 By Trudy Scott 59 Comments

microdose lithium formulation and alzheimer

In a new study, a team of researchers has shown that, when given in a formulation that facilitates passage to the brain, lithium in doses up to 400 times lower than what is currently being prescribed for mood disorders is capable of both halting signs of advanced Alzheimer’s pathology and of recovering lost cognitive abilities.

The above snippet is from a press release published in January 2020 on Science Daily: Can lithium halt progression of Alzheimer’s disease? Keep in mind that this is an animal study but the results are so promising.  I’m also very intrigued by the delivery method (more on that below).

In order to give this microdosing context, a typical adult prescription is 900-1800mg lithium carbonate/day.  I reached out to the lead author for clarification about the dosing of this new formulation and lead researcher Dr. Cuello shared this with me:

I calculate that our lithium dosage is 285 times lower concentration than the 900 mg dose (based on 70 kg of body weight) and 570 times lower than the 1800 mg dose.

This translates to around 3.2 mg to 6.4 mg NP03 based on 70kg of body weight (which is around 154.3 lbs).

NP03 is a disease-modifying nano dose formulation of lithium citrate which is used sublingually. I assume it’s not yet commercially available.

Also from the press release: “our findings show that microdoses of lithium in formulations such as the one we used, which facilitates passage to the brain through the brain-blood barrier while minimizing levels of lithium in the blood, sparing individuals from adverse effects, should find immediate therapeutic applications.”

Here is a link to the actual paper: NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats

Can we compare NP03 to low dose lithium orotate?

What is really interesting is that low dose lithium in the form of lithium orotate is commonly recommended by integrative practitioners for anxiety, mild mood swings, brain fog, ADHD and insomnia. I have found it to be extremely beneficial for many of my clients and have used it personally with success (for brain fog and insomnia).

Just how much lithium orotate is low dose? Typical doses are 5-10 mg per day, increasing to 20mg per day.

Can we compare NP03 to low dose lithium orotate? It’s too early to know for sure but we I believe we can start to make extrapolations, especially given that both are very low doses.

Integrative psychiatrist, Dr. James Greenblatt, MD has written extensively about low dose lithium orotate for the above purposes and for Alzheimer’s too. In this article, Lithium: The Cinderella Story About a Mineral That May Prevent Alzheimer’s Disease, he shares that

Scientists first became interested in the use of lithium for treating neurodegenerative disorders when they observed that bipolar patients using lithium therapy seemed to have lower rates of cognitive decline than peers on other medications.

He writes how an enzyme called Glycogen Synthase Kinase-3 (GSK-3) – a serine/threonine protein kinase – normally plays a major role in neural growth and development and how lithium

works as a direct GSK-3 inhibitor… halting inappropriate amyloid production and the hyper-phosphoryation of tau proteins before they become problematic.

If all this fascinates you as much as it does me, Dr. Greenblatt writes more about lithium orotate in his excellent book: “Nutritional Lithium: A Cinderella Story: The Untold Tale of a Mineral That Transforms Lives and Heals the Brain” (my Amazon link).

Lithium deficiency and the onset of Alzheimer’s disease: a 2025 study

Update August 8,  2025:

A new animal study, Lithium deficiency and the onset of Alzheimer’s disease (and published Aug 2025), supports the above, concluding that lithium orotate is “a potential approach to the prevention and treatment of Alzheimer’s disease.” The authors share this about lithium in the brain:

endogenous lithium is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, lithium was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to Alzheimer’s disease. Lithium bioavailability was further reduced in Alzheimer’s disease by amyloid sequestration.

The authors explored the role of endogenous lithium in the brain (i.e. lithium within the brain) by depleting it from the diet of wild-type and Alzheimer’s disease mouse models and found that:

Reducing endogenous cortical lithium by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline.

It’s exciting that they found that lithium orotate, “a lithium salt with reduced amyloid binding, prevents pathological changes and memory loss in Alzheimer’s disease mouse models and ageing wild-type mice.” And this paper also mentions the fact that these “effects were mediated, at least in part, through activation of the kinase GSK3β.”

They conclude that:

These findings reveal physiological effects of endogenous lithium in the brain and indicate that disruption of lithium homeostasis may be an early event in the pathogenesis (cause) of Alzheimer’s disease. Lithium replacement with amyloid-evading salts [such as lithium orotate] is a potential approach to the prevention and treatment of Alzheimer’s disease.

Given the concerns with the toxicity of high dose prescription lithium carbonate, I appreciate that this was addressed:

An important limitation in the treatment of aged individuals with pharmacological doses of lithium [i.e. lithium carbonate] is kidney and thyroid toxicity. It is encouraging that toxicity could not be detected following long-term treatment of ageing mice with a low dose of lithium orotate.

Alzheimer’s and cognitive decline have many root causes

Keep in mind that Alzheimer’s and cognitive decline have many root causes that must be considered. This may include inflammation, stress and candida, and even insecticide exposure.

The best Alzheimer’s book is “The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline” by Dr. Dale Bredeson (my Amazon link). He doesn’t mention lithium orotate so I look forward to hearing his thoughts on this new research. [I’ll come and update the blog when I do]

You can read about some of Dr. Bredesen’s work here: Alzheimer’s disease, mercury and mycotoxins.

Benzodiazepines have also been linked to increased Alzheimer’s risk which is why a nutritional approach for anxiety is the best approach. Let’s use the amino acids like GABA (for physical anxiety), and tryptophan (for worry and fears), as well as dietary changes and improving gut health instead of anti-anxiety medications (more on these below).

Additional resources when you are new to using tryptophan and other amino acids as supplements

As always, I use the symptoms questionnaire to figure out if low serotonin or other neurotransmitter imbalances may be an issue.

If you suspect low levels of any of the neurotransmitters and do not yet have my book, The Antianxiety Food Solution – How the Foods You Eat Can Help You Calm Your Anxious Mind, Improve Your Mood, and End Cravings, I highly recommend getting it and reading it before jumping in and using amino acids on your own so you are knowledgeable. And be sure to share it with the practitioner/health team you or your loved one is working with.

There is an entire chapter on the amino acids and they are discussed throughout the book in the sections on gut health, gluten, blood sugar control (this is covered in an entire chapter too), sugar cravings, anxiety and mood issues.

The book doesn’t include product names (per the publisher’s request) so this blog, The Antianxiety Food Solution Amino Acid and Pyroluria Supplements, lists the amino acids that I use with my individual clients and those in my group programs.

If, after reading this blog and my book, you don’t feel comfortable figuring things out on your own (i.e. doing the symptoms questionnaire and respective amino acids trials), a good place to get help is the GABA QuickStart Program (if you have low GABA symptoms). This is a paid online/virtual group program where you get my guidance and community support. You can sign up to be notified when the next live launch is happening.

If you need serotonin support, the Serotonin QuickStart Program is a good place to get help. This is also a paid online/virtual group program where you get my guidance on using tryptophan and 5-HTP safely, and community support during 5 LIVE Q&A calls. You can sign up to be notified when the next live launch of this program is happening.

If you are a practitioner, join us in The Balancing Neurotransmitters: the Fundamentals program. This is also a paid online/virtual program with an opportunity to interact with me and other practitioners who are also using the amino acids.

Wrapping up and your feedback

I look forward to human clinical trials of NP03. Dr. Cuello “ believes that there is an excellent opportunity to launch initial clinical trials of this formulation with populations with detectable preclinical Alzheimer’s pathology or with populations genetically predisposed to Alzheimer’s, such as adult individuals with Down Syndrome.”

I also look forward to human clinical trials of lithium orotate for Alzheimer’s disease. And  I would love to see lithium orotate compared to NP03 in future research.

In the meantime I feel this research is exciting because it supports so much of what is being seen clinically with lithium orotate.

Have you used lithium orotate with success? How much has helped you and have you seen cognitive benefits? What about a more even mood, better sleep and less anxiety?

And have you or a family member seen improvements with the Bredesen protocol?

Filed Under: Alzheimer's disease, Anxiety Tagged With: alzheimer's, anxiety, benzodizepines, brain fog, cognition, cognitive, Dr. Dale Bredesen, Dr. James Greenblatt, insomnia, lithium, lithium citrate, lithium orotate, low-dose, Microdose, mood swings

Alzheimer’s disease: address the root cause to reverse symptoms (Microbiome summit)

May 7, 2017 By Trudy Scott 4 Comments

Dr. Jill Carnahan’s interview on the Microbiome Medicine Summit 2 covers cutting edge new information about Alzheimer’s disease, based on the work and research of Dr. Dale Bredesen. They start with the gut-brain connection and Dr. Carnahan shares this:

we used to think of early-onset cognitive decline and dementias and mood disorders as being in their own bucket. And so, we saw psychiatrists or neurological doctors or neurologists to treat those diseases. And now we’re finding as we knew for several years with functional medicine that, obviously, it’s all connected.

And the gut is especially important because this reservoir holds so many of our microbes and possibly pathogens and that speaks to the brain through the vagus nerve and through cytokines and through inflammatory molecules of all types.

And so, this conversation between our gut and our brain is very profound and has a huge impact on things like multiple sclerosis or dementia, Alzheimer’s, or even things like bipolar disorder, schizophrenia, depression, anxiety, and sleep disorders.

So what we’re finding is by addressing the immune system and the gut which are intricately connected, we can often get profound effects on areas in the body that are far from that, like the brain.

Dr. Kellman asks Dr. Carnahan to share a study that will be the slam dunk for really believing in this connection and she mentions a paper titled Microbes and Alzheimer’s Disease. It cites pathogens like herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochaete which can affect the brain and play a role in Alzheimer’s disease.

Dr. Carnahan then covers Dr. Dale Bredesen’s subtypes of early-onset dementia which allows you to treat the root cause and actually reverse symptoms. She goes into it in great detail so I’m going to give you the summary version here:

Type #1 is inflammatory

  • This could be from inflammation or infections or other poor dietary habits. And that’s where the microbiome could play into that.
  • You might see elevated CRP, IL-6, TNF-alpha. You might see a low albumin to globulin ratio. You might see high homocysteine, hypothyroid, elevated cortisol

Type #1.5 is glycotoxic

  • The pure pre-diabetic, diabetic
  • That’s kind of the pure elevated insulin, elevated fasting blood sugar, elevated cortisol, low testosterone, high triglycerides, low HDL (and has an element of inflammation)

Type #2 is atrophic: So that’s someone who loses their trophic factor of support like estrogen, testosterone, insulin, and vitamin D3.

And often, these type 1s and type 2s actually have ApoE-4 double mutations which are higher risk for Alzheimer’s.

Type #3 is toxic:

  • Toxic mold exposure, biotoxins from Lyme disease, or heavy metals or other chemicals.
  • Often these chemicals will act on the tight junctions of the gut and increase permeability. And then that permeability leads to massive endotoxemia.
  • Younger onset of symptoms (like 40s and 50s) and reversible once you find and remove the root cause

Type #4 is vascular: inflammation of the blood vessels, high homocysteine

Type #5 is traumatic: wrestlers or boxers or football players that have had multiple head injuries or trauma.

By addressing the various root causes, Dr. Bredesen reports a reduction and in some instances reversal of dementia symptoms.

Of course, we know anxiety is common when it comes to Alzheimer’s and dementia. By addressing many of these above root causes we’re also able to reduce anxiety symptoms at the same time.

It was a fascinating interview and I hope you enjoy it as much as I did. I learned a great deal and find it very useful to group the symptoms into types.

There does seem to be one aspect that Dr. Carnahan didn’t address and I haven’t seen it covered in Dr. Bredesen’s papers: the impact of benzodiazepines on dementia and Alzheimer’s disease.  There is conflicting research on this but I feel there is enough research that does show a correlation – enough for us to be concerned.   Here is a recent paper looking at high-dose benzodiazepine use in Chinese patients , supporting an association.

This 2016 paper – Benzodiazepine Use and Risk of Dementia in the Elderly Population: A Systematic Review and Meta-Analysis states:

Our results suggest that benzodiazepine use is significantly associated with dementia risk. However, observational studies cannot clarify whether the observed epidemiologic association is a causal effect or the result of some unmeasured confounding variable. Therefore, more research is needed.

This may likely fall under type #3 (toxic).  I plan to reach out to them as a follow-up.

UPDATE: May 9, 2017.  I did hear back from Dr. Carnahan and she shared that she always discusses history and physical and lab testing, and history of benzodiazepine use or other neuroactive substances. 

And new research shows that it’s more than the benzodiazepines: SSRIs, SRNIs and atypical antipsychotics increase the risk of dementia in veterans with PTSD and even in those who don’t have PTSD. 

I hope you’ll join the host Dr. Raphael Kellman and all the great speakers on the Microbiome Medicine Summit 2, May 8-15, 2017 to learn more.

If you have questions or comments please feel free to share in the comments.

 

Filed Under: Alzheimer's disease, Events Tagged With: Alzheimer’s disease, anxiety, benzodiazepines, dementia, Dr. Dale Bredesen, Dr. Jill Carnahan, Dr. Kellman, gut-brain, microbiome, microbiome medicine summit, SRNI, SSRI

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