Reference
Small GW, Siddarth P, Li Z, et al. Memory and brain amyloid and tau effects of a bioavailable form of curcumin in non-demented adults: a double-blind, placebo-controlled 18-month trial. Am J Geriatr Psychiatry. 2018;26(3):266-277.
Design
Randomized, double-blind, 2-group parallel design comparing placebo to proprietary form of curcumin (Theracurmin)
Objective
To assess whether a proprietary curcumin formula has a measurable effect on cognitive performance in older adults without frank dementia.
Participants
Forty-six adults aged 50 to 90 years with objective cognitive performance scores and clinical histories consistent with normal aging or mild neurocognitive disorder and inconsistent with dementia (major neurocognitive disorder) were randomized to receive curcumin or placebo; all agreed to participate for the entire study duration (18 months), had adequate visual and auditory acuity for neuropsychological testing, and had screening laboratory tests and electrocardiograms that did not show significant medical abnormalities that might interfere with the study. A total of 40 participants (age 51-84 years; 21 in the experimental group and 19 in the placebo group) ultimately completed the trial and were included in the data analysis.
Study Medication and Dosage
The experimental group took Theracurmin (containing 90 mg of curcumin) twice a day (ie, 180 mg curcumin/day) for 18 months.
Study Parameters Assessed
The following tests were used to assess cognitive performance:
- Verbal performance—Buschke Selective Reminding Test (SRT)
- Visual performance—Brief Visual Memory Test-Revised (BVMT-R)
- Attention—Trail Making A (secondary outcome measure)
To assess brain effects, investigators used a specific type of positron emission tomography (PET) scan that provides in vivo images of brain plaques and tangles: 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile positron emission tomography (FDDNP-PET). Thirty participants, 15 in the intervention group and 15 in the placebo group, completed the FDDNP-PET testing.
All assessments were performed at baseline (before intervention) and at the end of the 18-month intervention.
Outcome Measures
Improvement in cognitive performance tests from baseline; changes in brain amyloid and tau accumulation as determined by PET testing (for 30 participants) from baseline.
Key Findings
Significant differences between groups were seen on a number of the tests. Long-term memory retrieval improved in the curcumin group but not in the placebo group. Total long-term memory recall, visual memory, and attention also improved significantly in the curcumin group, with no significant improvement in the placebo group. The FDDNP testing showed significantly decreased binding in the amygdala in participants on curcumin compared to those on placebo. (Higher FDDNP binding values have been positively associated with dementia.) In the hypothalamus, FDDNP binding did not change with curcumin but increased with placebo.
Practice Implications
This study is long overdue. Researchers have thought that curcumin should, could, and would improve cognitive function for years but have been unable to prove it.
The belief that curcumin, the active constituent in turmeric, might be protective against Alzheimer disease (AD) dates back to the early 1990s. Much of the early research was done by Sally Frautschy and Greg Cole. In 2001 they put forth the idea that curcumin might be useful in preventing or treating AD. During the 1990s about 20 studies had been published suggesting that people who took nonsteroidal anti-inflammatory drugs (NSAIDs) long-term lowered their risk of developing AD. These medications couldn’t be used in a clinical trial because of their potential side effects. Seeking a “safer drug,” Cole and Frautschy experimented with curcumin. Curcumin was well-known for its anti-inflammatory properties and was assumed to be safe to take long-term. Unlike NSAIDs, curcumin also acts as an antioxidant; it stops damage caused by free radicals. Reactive oxygen damage is considered a main contributor to AD.
In their 2001 paper published in the Journal of Neuroscience, Cole and Frautschy reported on several early experiments. They tested curcumin on mice who had been forced to develop amyloid plaques in their brains similar to those seen in AD. The mice who ate food spiced with turmeric developed about half the volume of brain plaque as mice not eating turmeric.1
Though they initially tested curcumin hoping to find a safe alternative to ibuprofen, Frautschy reported in the November 2001 issue of Neurobiology and Aging that curcumin was actually more effective at protecting experimental mice than ibuprofen.2
The theory in those days was that AD was caused by small bits of protein called amyloid that tangled together in the brain into toxic plaques, which kill brain cells by triggering inflammation. The plaques also produce free radicals that cause oxidative damage to nerve cells. Ibuprofen apparently slows this process by slowing the inflammatory reactions. Curcumin acts to decrease inflammation and also acts as an antioxidant.
Frautschy and Cole then asked the question: If curcumin protects against AD, does AD risk vary with diet? The answer was published in 2001; people in India, who consume the most turmeric, have the lowest incidence of AD in the world. Chandra et al reported in Neurology that only 0.47% of older people in Ballabgarh, India, showed signs of AD, while 1.75% farmers living in Pennsylvania showed signs of AD. Thus, turmeric consumers in India had about one-fourth the risk of the Americans and the lowest incidence of AD seen anywhere in the world.3 A 2006 study conducted in Singapore that looked at curry consumption also reported lower AD risk with increasing turmeric consumption. In this second study, the more curry people ate, the lower their risk for AD. The study was conducted in Singapore, a place that customarily uses lots of turmeric in their curry.4
Curcumin does more than act as an antioxidant in the brain. Yang et al reported in 2005 that curcumin actually prevents these plaques from forming in the first place.5
Additionally, Ono et al reported that curcumin triggers the dissolution of amyloid plaques.6 Structurally, curcumin resembles the chemicals used as contrast material in CT (computed tomography) brain scans to enhance plaque visibility. Because of this similarity, curcumin apparently binds to the amyloid. This binding ability may explain why curcumin interferes with plaque formation and degrades existing plaques.7
In April 2005, John Ringman along with Cole, Frautschy, and other colleagues from UCLA began a clinical trial using curcumin in patients with AD. Ringman’s study compared 2 doses of curcumin, either 2,000 or 4,000 mg per day, in a double-blinded placebo-controlled trial with 33 patients.8 We impatiently awaited the results. Five years later, this writer contacted Ringman to ask what happened. Dr Ringman admitted that, “Our initial study did not reveal any evidence of benefit in AD, possibly because inadequate amounts of curcumin were absorbed into the bloodstream” (private communication with John Ringman, MD, on June 17, 2010).
These new enhanced forms of curcumin appear to be both well-absorbed and capable of reaching the central nervous system.
In a 2010 paper, Cole and Frautschy explained why there was “no evidence of benefit” in the 2005 study. They first explained that AD has a long prodromal period in which damage builds up before any changes in mental symptoms are apparent; in their words, “much of the pathology occurs preceding rather than in parallel with cognitive decline.”9 Thus, even if curcumin were to reverse amyloid deposition, the disease progression may be too far advanced to slow down.
The second reason they thought curcumin had not been a miracle cure was that it is poorly absorbed in humans. In a clinical trial in which patients received either 2 or 4 grams per day, no curcumin was detected in their blood plasma.10
If the curcumin didn’t get into the blood, it certainly wouldn’t get into the brain and so it is no surprise that curcumin had no benefit in Ringman’s study.
There was another curcumin failure at about the same time. In 2008, results were published from a phase II trial at the University of Texas MD Anderson Cancer Center, which explored the effects of 8 grams of curcumin per day on pancreatic cancer; the outcomes were less than exciting.11
These failures in human trials led researchers to reevaluate curcumin absorption and led the way to the development of highly absorbable forms of curcumin. Typically, we refrain from talking about specific products by names in these commentaries but making an exception is appropriate in this situation. At this point in time, we should pay attention to specific products by name.
Cole and Frautschy, the UCLA Alzheimer researchers, developed and patented an enhanced form of curcumin that is now sold under the brand name Longvida.12
Other competing products also claiming enhanced absorption are now available and sold as “liposomal curcumin” and water-miscible curcumin. The 2 most often used in clinical research trials are Meriva and Theracurmin, respectively.
A trial of curcumin by Rainey-Smith et al published in 2016 gave either curcumin or placebo to 96 older adults for 12 months. A battery of clinical and cognitive measures was administered at baseline; the 6-month and 12-month follow-up assessments revealed no significant changes in those who received the curcumin, but declines were observed in those who received placebo.13 The curcumin product used in that trial was Biocurcumax, more commonly known as BCM-95. PubMed lists only 3 clinical trials under a search for BCM-95. Eleven trials are listed for Meriva, 8 trials for Theracurmin, the product used in this current trial, and 2 for Longvida, the UCLA product.
In 2012, DiSilvestro reported on blood changes measured in a group of 19 healthy middle-aged volunteers who took Longvida for a month. Those who took curcumin, but not those who took placebo, experienced the following statistically significant changes: decreased plasma triglyceride values; decreased salivary amylase levels; increased salivary radical-scavenging capacities; increased plasma catalase activities; decreased plasma beta amyloid protein concentrations; decreased plasma sICAM (soluble intercellular adhesion molecule) readings; increased plasma myeloperoxidase without increased C-reactive protein levels; increased plasma nitric oxide; and decreased plasma alanine aminotransferase activities.14
These new studies are exciting, as they are reporting significant results, in contrast to earlier, disappointing trials using older, less absorbable forms of curcumin. These new enhanced forms of curcumin appear to be both well-absorbed and capable of reaching the central nervous system.
Debate continues as to which, if any, of these enhanced curcumin products might prove to be superior. Patients often switch between these products to see if they have a preference, then they select the one they perceive as best.
