The piece below’s something I’ve written while trawling the literature on herbal supplementation and Alzheimer’s Disease. As always, I’m open to alternative points of view and if you have anything to say on the piece then drop me a comment below! It’d be good to have a discussion with some of you. 🙂
In the UK, there is a moving trend from the top ten causes of death being physical, infectious issues such as lower respiratory tract diseases (currently the top cause of mortality in low, developing areas) towards behavioural and mental health problems. Dementia makes up 4.1% of these deaths, making it the fourth biggest killer in high-income, developed countries (The top ten causes of death, June 2011).
While various types of dementia exist, such as vascular dementia that occurs from lack of blood to the brain and dementia with Lewy bodies, Alzheimer’s disease is the most prevalent and effects up to 496,000 people within the UK alone. This number is expected to rise exponentially to almost 34 million in 2025 (Iliffe, 2011). Thus, there is no lack of research regarding this ailment, with many different fields converging and producing papers to fuel the ever expanding literature. It is within the body of this essay that some of these papers will be considered, with specific regards to the psychopharmacological research on food supplements and herbal drugs.
Dementia itself is an acquired global impairment of intellect, memory and personality, but without clouding of consciousness (Longley & Warner, 2002). While there is currently no way of ascertaining whether or not an individual will develop Alzheimer’s, there are risk factors that will significantly increase an individual’s chance of developing it. Of these, three well-researched areas are the degradation of acetylcholine, (ACh) developing of amyloid plaques (plaques) and neurofibrillary tangles (tangles) within the brain, and ageing (Selkoe, 1997). The last of these hypotheses is simply a correlation noted between the age of a patient and their likelihood to develop dementia. Dementia itself, including Alzheimer’s, is typically noted in elderly groups though it is not unseen in younger people, with early onset dementia affecting up to 10% of the dementia population (Evans et al., 1989).
Plaques occur between neurons within the brain. Consisting of beta amyloid protein particles, parts of the amyloid precursor protein that have fragmented, these harden to form insoluble plaques in the brain of an Alzheimer’s patient. In a healthy brain, these particles would be broken down and eliminated through natural processes. Tangles, on the other hand, consist mainly of a protein termed tau. In healthy brains, these form microtubules that transport nutrients and substances from one nerve cell to another, though in an Alzheimer’s patient these microtubules collapse and form insoluble, twisted fibers (Hardy & Higgins, 1992). However, while these are the most visible markers of Alzheimer’s the only way of locating these in a patient’s brain is through an autopsy making any treatment or intervention based upon these structures difficult, at best. This is chiefly because an invasive brain procedure such as a biopsy carries the inherent risk of causing damage at a much faster rate than Alzheimer’s, and so this is ethically unsound. However, autopsies of Alzheimer’s disease patients has revealed another interesting faucet: massive destruction of ACh pathways.
Before going on to explain this further, though, some knowledge of the cholinergic system is required. ACh was the first neurotransmitter to be studied systematically and was isolated in 1867 (Feldberg, 2006). Consisting of two main receptors, the muscarinic – a metabotropic receptor; slower firing, utilizing a G protein – and nicotinic – an ionotropic receptor; directly linked to the ion channel – nAChR – this system has been linked to almost every aspect of behaviour from aggression to sleep. The Ascending Reticular Activating System (ARAS; Moruzzi & Magoun, 1949) is an almost entirely cholinergic system that is responsible for regulating levels of arousal and sleep-wake states through activation of the thalamus and basal forebrain (Fuller, Sherman, Pedersen, Saper & Lu, 2011). In the Alzheimer’s population, however, dysfunction in all ACh systems can be noted; perhaps most notably in the processes of learning and memory (Garcia-Rill, Kezunovic, Hyde, Simon, Beck & Urbano, 2012).
These findings have collectively given way to what is known as the cholinergic hypothesis of Alzheimer’s Disease (Terry & Buccafusco, 2003). It is theorized that due to acetylcholinesterase (AChE) hydrolysing ACh and a reduction in nAChR, there is cholinergic system destruction. This malaise then causes the associated issues observed in Alzheimer’s. The most prevalent method of demonstrating this in the literature utilises ACh antagonists (drugs that compete with and block the actions of other neurotransmitters without having a chronic effect) to mimic the effects of Alzheimer’s in animals. Scopolamine, one such mentioned antagonist, impairs acquisition and maintenance of learning in terms of destroying the encoding process between short term and long term memory (Wesnes & Warburton, 1984). This drug has also been shown to affect declarative memory, the ability to recall facts and knowledge, but not non-declarative memory, such as unconscious skills (Caffaro, Suárez, Blake & Delorenzi, 2012). This is seen in a real world capacity in that scopolamine is often used as a hypnotic, sedative “date rape” drug (Adamowicz & Kała, 2010).
It would not be improper, then, to assume that a drug that agonises the cholinergic system and inhibits AChE could halt, or reverse, the effects of Alzheimer’s type dementia. Research into this, however has produced mixed results. “Choline loading” via a precursor to ACh, in this case choline alfoscerate, has shown significant improvements over a range of psychometric tests (De Jesus Moreno Moreno, 2003) though this specific procedure allowed for participants to continue using various other drugs that had been previously prescribed to them by a doctor. Both experimental groups, too, were comprised mainly of Hispanic participants (97.7%) which raises various questions about how generalizable the results may or may not be (Tate & Goldstein, 2004). Another point worthy of note is that patients suffered from various other ailments such as central nervous system issues, (10% of the sample) cardiovascular, (23%) and peripheral vascular problems (5%). In previous research, damage to the central nervous system, cardiovascular and peripheral vascular systems has been shown to affect brain functioning and so the question of how much these affected the outcome of the study should be raised (Schmidley, 1990; Aronow & Ahn, 1994; McAuley, Kramer & Colcombe, 2004).
There is no question that cholinomimetic treatment has some form of effect on Alzheimer’s disease, and is certainly superior to a placebo (Birks, 2012) but the actual benefits of using such a drug are debateable; only six to nine months of delay in the progression of Alzheimer’s occurs, and reversal of the disease has not been noted at all (Kaduszkiewicz, Zimmermann, Beck-Bornholdt & Van Den Bussche, 2005). Coupled with the toxicity of some of the drugs originally used, such as tacrine and physostigmine carbamate that cause hepatic and cardiovascular functioning detriments in patients, do the costs really outweigh the benefits?
Current NICE guidelines support the usage of ACh agonists in the early stages of Alzheimer’s, but recommends their withdrawal in mild, moderate and serious cases, (Tadros, Bullock & Isaac, 2012). It is no surprise, then, that more current research is focusing on alternate methods of treating dementia. The use of herbal medicines has a long and significant history, though lacks major scientific work into it’s efficacy (Sumner, 2000). Though indexes exist that catalogue range of herb effects, (Schhultz, Hansel & Tyler, 1998) more research is needed to fully understand the extent of herbal applications. Thus, more research is examining the role herbs play with regards to Alzheimer’s. While cholinomimetic drugs target only one suspected cause of Alzheimer’s, the degradation of ACh, dietary and herb supplements target many, including poor diet, hormonal status, amyloid abnormalities and compromised metabolism alongside ACh degradation (Schhultz, 1998).
Salvia officinalis (salvia) is one strongly researched herbal supplement that may have an effect upon Alzheimer’s. Known for it’s anti-cholinesterase abilities, (Savelev, Okello, Perry, Wilkins & Perry, 2003) early research first focused upon documenting it’s antioxidant, anti-inflammatory, oestrogenic and CNS depressant functions. Perry, Perry and Ballard (2003) commend salvia for it’s tolerability, especially in comparison to first generation anti-cholinesterases (see Birks, 2012) – though there were noted increases in systolic and diastolic blood pressures in participants with pre-existing hypertension – and conclude that there are pharmacological activities relevant to dementia therapy. While statistically significant increases were seen in patient’s abilities to detect digits, as well as an increase in false alarms in a vigilance task and a lower neuropsychiatric inventory score, the study does acknowledge that it was not “originally designed to assess efficacy in terms of cognitive function or behavioural features” (p. 658). Thus, these results should be taken only as an indication of potential beneficial effects and as a suggestion for more directed future research. Akhondzadeh et al. (2003b) studied 39 dementia patients bi-weekly for 18 weeks upon administration of either 60 drops of saliva or a placebo control. It was found that there was a progressive, significant improvement in ADAS-Cog and CDR-SB scores. Though it should be noted that in this study patients are monitored for less time than the observed effective period of other, already examined anti-cholinesterase drugs (Kaduszkiewicz et al., 2005) and so it is entirely possible that the differences in scores seen between the placebo and salvia group may not be present after six months, in line with findings from Birks (2012). Further research should examine this closer, as it does appear as if ADAS-Cog and CDR-SB test battery scores are markedly similar to previous findings (Birks, 2012).
Another herb researched for the purposes of treating Alzheimer’s is melissa officinalis (melissa). Melissa acts in the same manner as saliva and other anti-cholinesterase drugs, and has also been suggested as a potential herbal treatment for depression due to it’s calming and sedative effects (Schhultz et al., 1998). As agitation and altered mood is often observed in dementia patients, (Reisberg, Borenstein, Salob & Ferris, 1987) this could be an added bonus of treatment. In a protocol that mirrored Akhondzadeh et al. (2003b), Akhondzadeh et al. (2003a) found comparatively similar results: participants experienced significant benefits in cognition after 16 weeks of treatment. The study was, again, limited by the short period in which participants were followed for, though.
This touches upon a very important criticism of the design, however; both studies (Akhondzadeh et al., 2003a; Akhondzadeh et al., 2003b) were published in the same year and were published by the same team. While it cannot be ascertained whether the sample is the same in both studies due to the steps taken for anonymity reasons, there are indicators that would suggest this is the case: the mean participant age is the same, as is the male-to-female ratio and amount of participants used. If this did indeed occur, then both studies are forfeit of any concise data for two main reasons. The first is that participants would have undergone the same measures four times, and so the potential for order effects is unquestionable. Secondly is that any gains noted from taking either salvia or melissa could just be an extension of the benefits noted from the study undertaken previously; outcome measures would be “polluted” via the previous experiment’s drug.
More current research is investigating the potential effects herbs have on amyloid beta proteins, the substance responsible for the development of plaques within the brain. Crocus sativus (saffron) is commonly used in cooking and food preparation. What it is probably less known for, though, are it’s behavioural and psychological effects; saffron aromas have been linked to relieving incidents of premenstrual stress (Fukui, Toyoshima & Komaki, 2010) and lowering chronic stress in rats (Ghadrdoost et al., 2011). Akhondzadeh et al. (2010) theorise that saffron may inhibit the development of plaque deposits in the brains of Alzheimer’s patients. In a sixteen week, double-blind and placebo controlled study, measures of Alzheimer’s severity and dementia rating scales decreased, indicating an improved global cognitive and clinical profile in patients that received a saffron tablet over a placebo pill. This suggests that saffron is an effective treatment of mild to moderate Alzheimer’s, though larger, randomised controlled trials are required to reaffirm this.
Another herb that has been studied is curcumin, a specific component of turmic. Previously linked to having an effect on cystic fibrosis, various ulcers and liver diseases (Ringman, Frautschy, Cole, Masterman & Cummings, 2005), attention turned to the effects it may have on Alzheimer’s after it was found to also have an impact on beta-amyloid pathology in rats, effecting the development (Lim, Chu, Yang, Beech, Frautschy & Cole, 2001) and in some cases, even clearing plaques altogether (Garcia‐Alloza, Borrelli, Rozkalne, Hyman & Bacskai, 2007). Research applied to Alzheimer’s in a human population, though, is somewhat lacking. Curcumin appeared to have no effect on Alzheimer’s patient’s scores in the Mini Mental State Examination (Baum et al., 2008) though it was concluded that due to slight, non-significant changes in comparison to a placebo group participants should be monitored for a longer duration in order to better assess any effects upon cognition. Baum et al.’s participants were also administered 120g of gingko biloba during the course of the study, and so any future research needs to account for this within their methodology.
It would appear, then, as if herbal supplements could be a potential panacea for a lot of conditions if it were not for methodological flaws: melissa was noted for the effect it had on mood, saliva for it’s antibiotic capabilities and turmeric for antioxidant properties (Schhultz et al., 1998). But the very premise of herbal medicine is the treatment of a wide range of possible causes as opposed to single symptoms of illness. While a drug designed to treat an infection would target the virus specifically, herbal medicine acts more as a buffer, preventing side effects as well as targeting the virus. This is problematic for science; by the very definition of the scientific method, the way in which things are investigated should be empirical and measurable (Popper, Popper & Popper, 1972). If research can not be specific enough about effects, then it is not developed enough to be used as a legitimate treatment. This can be seen in a broader sense, too, between differing species of plant. The herb ginseng has 11 different species, two of these being panax schinsen (K-ginseng) and eleutherococcus senticosus (S-ginseng). The former, K-ginseng, increases cerebral blood flow and lowers blood sugar levels in patients with type 2 diabetes (Kim, Park, Kim, Chang, Ryoo & Jeon, 2002), whilst the latter, S-ginseng, has been shown to be effective in treating herpes simplex 2 and relieving effects of the common cold (Vogler, Pittler & Ernst, 1999). Current NICE guidelines reflect this; herbs are only ever advised to be used alongside current anti-cholinesterase drugs and, much like the drugs themselves, be withdrawn in late, severe cases of Alzheimer’s (Tadros, Bullock & Isaac, 2012). Food supplements however can be more rigorously controlled by researchers and can be created in more uniform process so that scientists can be sure of the contents (Dwyer et al., 2007).
In Alzheimer’s, homocysteine levels may be increased in patent’s blood levels and it is theorised by some that hyperhomocysteinemia contributes to the development of the disease (Seshadri et al., 2007). Vitamin’s B6, B12 and folate contribute to lowering levels of homocysteine and so to determine the efficacy of this as a method of treatment, Aisen et al. (2008) administered these to 409 participants with mild-to-moderate Alzheimer’s. While homocysteine levels were seen to drop in all active groups, there was no benefit on the rate of change in ADAS-Cog scores. Similar observations were noted in the application of vitamin E and donepezil to patients with mild cognitive impairment, (Peterson et al., 2005) which is often seen as the precursor to a dementia. Tabet et al., (2000) analysed The Cochrane Dementia Group Register of Clinical Trials for double blind, randomised and placebo-controlled vitamin E experiments only to conclude that “there is insufficient evidence of efficacy of vitamin E in the treatment of people with Alzheimer’s disease” (Conclusions, para. 1).
Another approach taken by the literature is the development of medical foods; items developed for the “specific dietary management of a disease or condition that has distinctive nutritional requirements, established by medical evaluation and based on recognised scientific principle” (Medical foods, 2009, Overview para. 1). Axona, Souvenaid and CerefolinNAC are three of the most prevalent medical foods designed to treat Alzheimer’s disease, though few thorough studies have been conducted in vivo into their efficacy (Alzheimer’s Association Medical and Scientific Advisory Council, 2011). Axona provides ketone as an alternative energy source, Souvenaid administers neurotransmitter precursors and CerefolinNAC reduces the impact of oxidative stress. Thaipisuttikul and Galvin (2012) conducted a meta-analysis of the currently published research and found that ‘the potential benefit of medical foods is unclear… an important issue to reiterate is that the FDA does not require high level testing for approval [of] medical foods [in comparison to prescription medicine]’ (p. 207). It was concluded that CerefolinNAC requires further study to confirm efficacy as all established work regards either case reports or series; Axona demonstrates clinical significance only in a specific subgroup of patients, though longer research would help clarify this, and in the case of Souvenaid, a less skewed sample is required in research as 40% of patients scored 0 on a baseline, delayed memory recall test.
When the literature on supplementation is considered hermetically, it does not require an academic point of view to understand that it is somewhat lacking. Promising, though unsuccessful results have been demonstrated in highly regulated drug trials and while comparable research has been produced utilising herbs it appears as if this field is suffering from a lack of thorough research methodologies. Studies into medical food supplements is in the stages of infancy, though no results of significance have been produced yet. None of the literature regarding supplementation mentions an effective or lethal dose level, nor is there, in most cases, a detailed mention of how the drug in question is metabolised into the body. More research into the chronic effects of supplements is required too, and so it appears as if the most sensible approach to collectively raising the standards of these fields appears to be the tightening of regulations. Such an outcome would cause an increase in the efficacy of these types of studies, though it would need to be carefully handled in order to avoid increasing bureaucracy and warding off further scholarly interest.