Botanicals and nutraceuticals could have a potential role in slowing progression of cognitive impairment and/or dementia including Alzheimer’s disease, improving cognition and memory, and improving behavior in those with dementia.
Alzheimer’s disease accounts for 60-80% of all dementias, and is one of the most frightening, life altering and deadly diseases of our time. Not all Alzheimer’s disease is in the elderly and over 200,000 U.S. adults have early onset (< 65 y) disease. There is no cure at this time. Any role of botanical and nutraceuticals for risk reduction, prevention, and disease alteration must be considered.
Mild cognitive impairment involves problems with memory, language, thinking and judgement and is at a stage that is greater than normal age related changes but not as serious as dementia. Mild cognitive impairment may increase the risk of dementia, with approximately 10-15% going on to having some kind of dementia. While hypertension, sleep apnea and depression should be addressed, as these conditions can affect memory as well, mild cognitive impairment should be taken seriously, including the use of dietary supplements that can improve memory and slow or prevent progression.
Acetyl-L-carnitine
Acetyl-L-carnitine is derived from L-carnitine, an amino acid found naturally in the human body. L-carnitine is made in the brain, liver and kidneys from lysine and methionine and we convert the L-carnitine to acetyl-L-carnitine, and the reverse as well. The primary function of L-carnitine is to transfer long chain fatty acids in their ester form across the mitochondrial membrane prior to beta-oxidation. This process turns fat into energy. As a dietary supplement, one should take L-carnitine and acetyl-L-carnitine specifically as needed as we do not know if the two are interchangeable.
Acetyl-L-carnitine is used for a wide range of conditions but the focus here is its use in improving Alzheimer’s disease and age-related cognitive impairment. But there are many uses ranging from age related fatigue and exercise performance to serious issues such as diabetic neuropathy, hepatic encephalopathy, and more.
Acetyl-L-carnitine might slow the rate of Alzheimer’s disease (AD) progression as well as improve memory, and improve measures of cognitive function and behavior in individuals with AD.
A 1996 double-blind, placebo-controlled, randomized, parallel-group study of one year compared acetyl-L-carnitine hydrochloride (ALCAR) with placebo in patients with probable AD. [1] Four hundred thirty-one patients 50 or older entered the study who had probable mild to moderate AD were given 1 gm three times daily of ALCAR or placebo for 12 months, and 83% completed the 1 year of treatment. The Alzheimer’s Disease Assessment Scale cognitive component and the Clinical Dementia Rating Scale were the primary outcome measures. At first glance, both ALCAR and placebo-treated patients declined at the same rate on all primary measures and most secondary measures. But when comparing early-onset patients (aged 65 years or younger at study entry) with late-onset patients (older than 66 at study entry), there was a trend for the early-onset patients on the acetyl-L-carnitine to decline faster than the early onset AD patients on placebo. In addition, in the placebo groups, early-onset patients tended to decline more rapidly than older patients and late-onset AD patients on ALCAR tended to progress more rapidly than the ALCAR treated early-onset patients. The study suggests AD patients aged 65 or younger may benefit from treatment with ALCAR whereas older individuals might do more poorly.
In a small pilot study of 30 mild to moderately demented patients with probable AD, an acetyl levocarnitine hydrochloride at 2.5 g/day for 3 months followed by 3g/day for 3 months was compared to placebo. [2] Tests of memory, attention, language, visuospatial and constructional abilities were administered along with measuring the spinal fluid for acetyl levocarnitine hydrochloride. At the end of 6 months, the treatment group had significantly less deterioration in several measurable tasks although no differences were found in any other neuropsychological test results. A small subgroup with the lowest baseline scores and who received the supplement, had significantly less deterioration on the verbal memory test and a significant increase in the cerebrospinal fluid acetyl levocarnitine levels compared to placebo. Again, we may be seeing an ability of acetyl levocarnitine to retard the deterioration in some cognitive areas in patients with Alzheimer’s disease.
In 130 patients with a clear diagnosis of AD, a double-blind, placebo-controlled, parallel-group, randomized clinical trial, studied the efficacy of a one–year oral treatment with acetyl-L-carnitine. [3] There were 14 outcome measures to assess functional and cognitive impairment. After 1 year, both the treatment group and the placebo group worsened, but there was a slower rate of deterioration in 13 of the 14 outcome measures in the treatment group, better scores in all outcome measures in the treatment group, including a statistically significance difference for the Blessed Dementia Scale, logical intelligence, ideomotor and buccofacial apraxia, and selective attention.
In another small but randomized, double-blind, placebo-controlled, parallel-group clinical trial, 36 individuals with AD were given either 1 g acetyl-l-carnitine twice daily or a placebo for 24 weeks. [4] A total of 20 patients completed the full 24 weeks with 7 in the active group and 13 in the placebo group. In the end, there was an apparent trend for more improvement in two short term memory tests in the acetyl-l-carnitine. There was also a trend for less deterioration in reaction time in the active treatment group. Particularly in the area of short term memory, this study suggests an improvement in the AD patients receiving this dose of acetyl-L-carnitine.
A meta-analysis of acetyl-L-carnitine in mild cognitive impairment (MCI) and mild early AD, investigated only double-blind, placebo-controlled prospective, parallel group comparison studies of at least 3 months duration. [5] Studies ranged in duration from 3 to 12 months and the daily dose varied in the studies but with a range of 1.5-3.0 g/day. An overall summary effect was significantly better with the acetyl-L-carnitine compared to placebo and the benefits were seen in clinical results and psychometric tests. These benefits were seen as soon as 3 months in all the studies.
A Cochrane review from 2003 identified 11 double blind randomized trials of people with AD and using acetyl-L-carnitine. [6] While there was evidence for benefit of ALC on clinical global impression, there was no evidence using objective assessments in any other area of outcome.
Dosages, Side Effects, Toxicity, Contraindications
For age related cognitive impairment, oral acetyl-L-carnitine dosages range from 1500-2000 mg daily. For Alzheimer’s disease, 1,500 mg-3,000 mg daily has been used.
Acetyl-L-carnitine is generally well tolerated, although it may cause nausea, vomiting, gastrointestinal upset, dry mouth, anorexia, agitation, headache, and insomnia. Less common reports include hiccups, abdominal distension, paresthesia, and pain. When acetyl-L-carnitine is taken orally in combination with alpha-lipoic acid, there are reports of rash, diarrhea, constipation, dyspepsia, and foul-smelling urine.
One major drug interaction should be avoided, acenocoumarol, which is a shorter acting drug similar to warfarin. Caution is warranted with warfarin itself.
Using acetyl-L-carnitine may increase the risk of mania in those with bipolar disorder. It also may increase symptoms of neuropathy in those taking the supplement with taxane based chemotherapy medications. It is also beset to avoid acetyl-L-carnitine in those with hypothyroid as it seems to inhibit the activity of thyroid hormones in target tissues, and in those with seizure disorders, an increase has been reported when using acetyl-L-carnitine.
Phosphatidylserine
Phosphatidylserine is a phospholipid synthesized in the body and is a component of the phospholipid bilayer of the cell membrane. Phosphatidylserine is found in high quantities in the brain and particularly in myelin.
Phosphatidylserine has been used orally for dementias, including Alzheimer’s disease, and in age-related cognitive decline. This will be our focus here in this report. But, it has also been used to improve cognitive function in young people, attention deficit-hyperactivity disorder (ADHD) and depression with additional uses in preventing exercise-induced muscle soreness, and improving athletic performance.
Several clinical studies show that phosphatidylserine improves attention, arousal, verbal fluency, and memory in aging people with cognitive deterioration.
One double-blind study assessed the efficacy and safety of oral phosphatidylserine (PS) 300 mg/day for 6 months vs placebo in a group of elderly patients with cognitive impairment. [7] A total of 494 elderly men and women with moderate to severe cognitive decline and between the ages of 65 and 93 were recruited in clinical care units in Italy. Patients were examined at baseline, 3 and 6 months. There were statistically significant improvements in the phosphatidylserine-treated group compared to placebo in both behavioral and cognitive parameters.
Another 149 patients with age-associated memory impairment (AAMI) were treated with 100 mg three times daily of phosphatidylserine or placebo for 12 weeks. [8] Patients treated with the PS improved compared to placebo in tasks of daily life and those with the poorest initial performance at baseline, were the best responders.
In patients who have a diagnosis of Alzheimer’s disease, taking phosphatidylserine could increase cognitive function, improve in global rating scales and behavioral rating scales. Observations may be seen in 6-12 weeks although it may be most effect in those with less severe symptoms. One observation is that treatment effects may last only 16 weeks, and then the progression of the disease may dominate over any benefit of phosphatidylserine. [9], [10], [11], [12], [13]
Dosages, Side Effects, Toxicity, Contraindications:
Sources of phosphatidylserine available are from bovine or plant sources and likely soy or cabbage derived. Both bovine- and plant-sourced phosphatidylserine 100 mg three times daily for up to 6 months have been used in age related cognitive impairment. For Alzheimer’s disease, bovine sourced phosphatidylserine 300-400 mg/day in divided doses has been used.
Oral phosphatidylserine is usually well-tolerated although some patients may experience gastrointestinal upset, flatulence, nausea, headache, or insomnia, although most likely to occur in higher doses such as 600 mg/day.
Moderate drug interactions include acetylcholinesterase inhibitors, anticholinergics and cholinergics. Caution is warranted due to the theoretical possibility that phosphatidylserine might increase acetylcholine levels and potentially cause cholinergic effects.
Other nootropics agents not mentioned in this article can include bacopa, rhodiola, ginkgo biloba, L-theanine, Panax ginseng, resveratrol and even caffeine. Lifestyle factors must also be considered and one diet, the MIND diet (vegetables, fruits, nuts, fish and other brain healthy foods) has been able to slow brain aging and reduce the risk of Alzheimer’s disease.
References
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- Montgomery, S.A., et al. Int Clin Psychopharmacol. 2003 Mar;18(2):61-71.
- Hudson, S., et al. Cochrane Database Syst Rev. 2003;(2):CD003158.
- Cenacchi., et al. Aging1993 Apr;5(2):123-33.
- Crook, T.H., et al. Neurology. 1991 May;41(5):644-9.
- Heiss, W.D., et al. Dementia. 1994 Mar-Apr;5(2):88-98.
- Crook, T., et al. Psychopharmacol Bull 1992;28:61-6.
- Delwaide, P.J., Acta Neurol Scand 1986;73:136-40.
- Engel, R.R., et al. Eur Neuropsychopharmacol 1992;2:149-55.
- Amaducci, L., et al. Psychopharmacol Bull 1988;24:130-4.
