I WANT MY NZT!
Limitless was my favorite movie last year. For those of you who missed it, Bradley Cooper used his chemically enhanced super-brain to conquer the stock market, his landlady, and the Russian mob. He even learned to fight like Bruce Lee… by, like, osmosis or something. Wow! Obviously, after the movie I stayed up all night researching where we stand in the quest to find a ‘genius pill.’ Here’s what I learned:
- NZT doesn’t exist. (Damn!)
- but… not for lack of trying! And we’re making progress.
The search for cognitive enhancers has been going on for decades (having begun, no doubt, approximately three hours after the invention of the dunce cap). By one report, the Pentagon spends $20 million per year exploring ways to “expand available memory” and to build “sleep-resistant circuitry” in the brain13 …and that sounds low to me, considering the potential payoff. In any event, the hunt has not been fruitless! A number of supplements have been found to improve various parameters of cognitive function. We refer to these as nootropics. Some say that piracetam was the first nootropic drug, and it is true that the concept and definition of a “nootropic” was first proposed in 1972 by C.E. Guirgea, the principal piracetam researcher for UCB Pharmaceutical Company of Belgium. He coined the term from the Greek words “noos” (mind) and “tropein” (to turn or to change), to mean enhancement of learning and memory. Awkward, in my opinion; most of you will prefer the term “smart drug.” The main features defining a nootropic drug are:
- The enhancement of learning and memory, as well as enhanced resistance of learned behaviors to agents that tend to impair them
- Protection of brain function against various physical or chemical injuries
- Facilitation of interhemispheric flow of information
- Absence of the usual negative pharmacologic effects of psychotropic drugs
The chart below shows most of the major players:
When I worked at PhysioAge Medical Group, we designed the PhysioAge NeuroPacks to include five of the supplements on this chart: acetyl-l-carnitine, alpha lipoic acid, vinpocetine, phosphatidylserine, and ginkgo. We also included a specialized preparation of curcumin. Though curcumin is not a nootropic, it is probably the best anti-Alzheimer’s supplement available (assuming you use a formulation that is well-absorbed). Our goals are preventative as well as nootropic, and thus including curcumin was an easy decision. As always, it’s not just the ingredient that matters, but the source:
- We used a particular form of PS, from Enzymotec. Unlike soy-based PS, Enzymotec’s PS is complexed with DHA to improve incorporation into cell membranes. They have a number of small human trials showing efficacy in improving cognitive function.
- Our alpha lipoic acid is from GeroNova Research, because they have human pK studies proving better absorption than any other brand.
- We chose Longvida brand curcumin. For an extensive review of why I think Longvida is currently the only brand of curcumin worth using for brain health, see my blog post on curcumin.
Clearly there are a number of conversations worth having with regard to nootropics (raw material for future posts!), but for now let’s start with a look at vinpocetine. Two points stand out from the chart above:
- Vinpocetine’s “niche” is in improving cerebral blood flow, oxygenation and metabolism (meaning glucose consumption), and it is the only supplement on the list that affects all three of those. This is why it has been studied for the treatment of vascular dementia.
- Vinpocetine affects more of the relevant mechanisms than any other supplement on the list– so if you are going to try a brain supplement, it’s a great place to start. Also note: it does not affect Dopamine, Serotonin or Acetylcholine, which may be why it is so well-tolerated in human studies.
Why am I so interested in vinpocetine? Take a look at the two positron emission tomography (PET) scans below:
As you can see, our brains lose the ability to metabolize glucose and efficiently maintain energy levels as we age. Vinpocetine is remarkable in that it can counteract this in two ways: it increases blood flow in certain regions of the brain, and it increases the brain’s metabolism of glucose. Vinpocetine was first synthesized in the late 1960s, extracted from the leaf of the lesser periwinkle plant. It was made available under the trade name Cavinton in 1978, and has been used widely since then in Japan, Hungary, Germany, Poland, and Russia, for the treatment of cerebrovascular-related pathologies.
Taking a supplement through its’ paces: my checklist
One of the themes I frequently harp on regarding supplements is: How do you know that what you’re taking is being absorbed?? When it comes to vinpocetine, that question has been quite elegantly answered. Using radioactively labeled vinpocetine (which can then be tracked in the body), researchers have shown that vinpocetine crosses the blood-brain barrier and is taken up by cerebral tissue.1,2 In humans, vinpocetine is preferentially absorbed in the central nervous system at twice the level that would be expected according to total body distribution.3 (In other words, our brains seem quite fond of the stuff.) For the neurologists among you, the highest uptake of vinpocetine is seen in the thalamus, putamen, and neocortical regions:
Radioactivity uptake and distribution in the brain were demonstrable from the tenth minute after the oral administration of the labelled drug. Brain distribution was heterogeneous (with preferences in the thalamus, basal ganglia and occipital cortex), similar to the distribution previously reported by the authors after intravenous administration.
CONCLUSIONS: Vinpocetine, administered orally to human volunteers, readily entered the bloodstream from the stomach and the gastrointestinal tract and thereafter passed the blood-brain barrier and entered the brain. Orv Hetil. 2003 Nov 16;144(46):2271-6. [Article in Hungarian] [/dropdown_box] So: we know it is taken up in the brain. What does it do once it gets there? As it turns out, it has a number of interesting effects:
Effects on blood flow Vinpocetine lowers blood viscosity,4 dilates blood vessels,5 decreases platelet aggregation,6 and increases and maintains red blood cell flexibility under oxidative stress,7 all of which are potentially beneficial in cerebrovascular disease. Amazingly, vinpocetine is able to selectively increase cerebral blood flow, and also increases your brain’s metabolic rate.8,9 Here is a study looking at cerebral perfusion in stroke patients after Vinpocetine: 43 patients with ischemic stroke were randomized into vinpocetine or placebo groups in a double blind, placebo-controlled study of the effect of a single-dose i.v. infusion of vinpocetine on cerebral blood perfusion and oxygenation.
CONCLUSION: Vinpocetine increases cerebral perfusion as well as parenchymal oxygen extraction.
Vinpocetine increases cerebral blood flow and oxygenation in stroke patients: a near infrared spectroscopy and transcranial Doppler study. Eur J Ultrasound. 2002 Jun;15(1-2):85-91.
Unlike curcumin, vinpocetine is probably not of great benefit in Alzheimer’s disease– but studies like the one above suggest that it could certainly help in vascular dementia (which is caused by the cumulative effect of small strokes and poor circulation). So: does this improved blood flow and metabolism provide clinically beneficial results? Are there any controlled clinical trials?
Luckily, vinpocetine has been prescribed for decades outside of the U.S. (trade name Cavinton), so there are a number of double-blind, placebo-controlled, human clinical trials we can look at: In the following two studies of older adults with memory problems due to poor brain circulation or dementia, oral vinpocetine produced significant improvement in performance on cognitive tests reflecting attention, concentration, and memory: Back in the early ’90s, two hundred and three patients were included in a placebo-controlled, randomized double-blind, multicentre trial. Every day for 16 weeks they received (by mouth) either 10mg of vinpocetine, 20mg of vinpocetine, or placebo, three times a day. Patients were assessed on ratings of clinical global impression, cognitive performance and on quality of life measures including depressive illness.
Significant improvements were found [with] vinpocetine [but not with placebo] in both Global Improvement and cognitive performance. Vinpocetine was also superior to placebo in ratings of the severity of illness. This study demonstrates the usefulness and efficacy of vinpocetine in the management of patients with moderate organic psychosyndromes.
Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes. Int Clin Psychopharmacol. 1991 Spring;6(1):31-43.
In another double-blind, placebo-controlled trial, forty-two patients received 10 mg vinpocetine three times a day for 30 days, then 5 mg for 60 days. Matching placebo tablets were given to another 42 patients for the 90 day trial period.
Patients on vinpocetine scored consistently better in all evaluations of the effectiveness of treatment including measurements on the Clinical Global Impression (CGI) scale, the Sandoz Clinical Assessment-Geriatric (SCAG) scale, and the Mini-Mental Status Questionnaire (MMSQ). There were no serious side effects related to treatment.
A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. J Am Geriatr Soc. 1987 May;35(5):425-30.
Can younger people use it as part of a preventive regimen? My intention is to use the NeuroPack in patients who have not yet experienced significant decline, as either a nootropic or a preventative; thus I was gratified to find this small study using healthy young pre-menopausal women, which showed memory improvement at 40mg/day: Twelve healthy female volunteers received pre-treatments with vinpocetine 10, 20, 40 mg and placebo for two days according to a randomised, double-blind crossover design. On the third day of treatment, 1 hour after the morning dose, subjects completed a battery of psychological tests including Critical Flicker Fusion (CFF), Choice Reaction Time (CRT), Subjective Ratings of Drug Effects (LARS) and a Sternberg Memory Scanning Test.
Memory as assessed using the Sternberg technique was significantly improved following treatment with vinpocetine 40mg when compared to placebo.
Psychopharmacological effects of vinpocetine in normal healthy volunteers. Eur J Clin Pharmacol. 1985;28(5):567-71.[dropdown_box expand_text=”” show_more=”Click for more studies, including ones over a longer period of time…” show_less=”Close this section please.” start=”hide”]More studies on vinpocetine (a.k.a Cavinton): Because vinpocetine has been around for so long, there are a number of other papers to look at: _____________ 10-year experience with using Cavinton in cerebrovascular disorders.[Article in Russian] Cavinton was used for 10 years in 967 patients with different cerebrovascular diseases. The greatest benefit was seen in patients with early forms and primarily chronic forms: vascular (neurocirculatory) dystonia, initial manifestations of cerebral blood supply insufficiency, and circulatory encephalopathy in the first and second stages. Improvement of the subjective status and a decrease of the intensity of vestibulocerebellar disorders were recorded by the end of the treatment in 75-85% of such patients. Zh Nevropatol Psikhiatr Im S S Korsakova. 1992;92(1):56-60. ______________ Ethyl apovincaminate therapy in neurovascular diseases. Of a series of 100 patients, 46 were given combined (intramuscular and oral) treatment with ethyl apovincaminate (Cavinton) in daily doses of 10-30 mg; 54 were put on oral Cavinton (30-45 mg daily). Significant and relatively quick improvement was obtained in reversible vascular diseases, such as hypertensive encephalopathy, intermittent vascular cerebral insufficiency, in the early stage or light cases of cerebral endarteriitis and cerebral arteriosclerosis. On Cavinton, hypoxic character of the EEG improved, and so did performance in psychodiagnostic tests, alertness and memory. The doses administered did not damage parenchymal organs, and did not accumulate. Arzneimittelforschung. 1976;26(10a):1984-9. ______________ Rheoencephalographic and psychological studies with ethyl apovincaminate in cerebral vascular insufficiency. The effect of ethyl apovincaminate (RGH-4405, Cavinton) on the rheoencephalogram and memory functions was studied in 50 patients with ischaemic disturbances of cerebral circulation. The drug was administered in a single i.v. dose of 10 mg, and 5mg orally three times daily for a month. Improvement of cerebral circulation was observed after i.v. and oral medication. Blood flow was most markedly increased in the gray matter. The effect on arterial pressure was negligible.
Improvement of memorizing capacity evaluated by psychological tests was recorded after one month of Cavinton treatment, associated with alleviation or complete disappearance of symptoms. No side effects attributable to the drug were observed.
Cavinton is indicated in the treatment of ischaemic disorders of the cerebral circulation, particularly in chronic insufficiency. Arzneimittelforschung. 1976;26(10a):1947-50. _______________________ Investigation of the effect of vinpocetine on cerebral blood flow and cognitive functions.[Article in Hungarian]
The authors found a significant improvement in cognitive function and blood flow velocity after 12-weeks of oral vinpocetine therapy using psychometric tests. The general condition of patients also improved significantly according to both the investigator’s and the patients’ opinion; patients with mild cognitive impairment judged the improvement higher. The authors recommend the use of vinpocetine for the treatment of patients with mild cognitive impairment.
Ideggyogy Sz. 2007 Jul 30;60(7-8):301-10. ________________________ The role of vinpocetine in the treatment of cerebrovascular diseases based on human studies.[Article in Hungarian] The aim of this review was to summarize the indications and the potential effects of vinpocetine in acute and chronic cerebrovascular diseases based on clinical studies. RESULTS: In chronic cerebrovascular patients after single dose and long-term vinpocetine therapy, PET, TCD, SPECT and NIRS examinations showed increasing perfusion and elevated glucose and O2 consumption of the examined areas; furthermore, significant improvement of rheologic factors was detected.
A meta-analysis of international clinical studies showed a significant improvement in cognitive achievement in chronic stroke patients after oral therapy.
CONCLUSION: The cited studies showed the potential multi-pharmacological effects of vinpocetine and its beneficial hemorheological potential. The drug also improves the blood flow and metabolism of the affected brain areas.
There is increasing evidence that vinpocetine improves the quality of life in chronic cerebrovascular patients.
Orv Hetil. 2007 Jul 22;148(29):1353-8.
_____________ I include this next paper with an important caveat: Every review of vinpocetine mentions it, because the results sound impressive, but I was not able to get my hands on it despite multiple attempts. Having never read the “fine print”, I can’t actually vouch for the methodology or conclusions. A meta-analysis of six randomized, controlled trials involving 731 patients showed that vinpocetine was highly effective in the treatment of senile cerebral dysfunction. Using several psychometric testing scales in addition to physical symptoms (speech and movement capacity, muscular coordination and strength, sensory-perceptual ability) the researchers were able to show a highly significant effect of vinpocetine on both cognitive and motor functions. Nagy Z, Vargha P, Kovacs L, et al. Meta-analysis of Cavinton. Praxis 1998;7:63-68. [/dropdown_box] Aside from its’ effects on blood flow and metabolism, vinpocetine seems to have a number of other tricks that contribute to its effectiveness. To wit: Antioxidant Effects Like vitamin E, vinpocetine is an effective scavenger of hydroxyl radicals.10 It has also been shown to inhibit lipid peroxidation in mouse brain tissue, and to protect against anoxia and hypoxia in animals: during experimentally-induced stroke (in animals), Vinpocetine decreased areas of brain necrosis up to 60 percent.11
Stimulates Neurons of Locus Cereuleus: Vinpocetine stimulates locus ceruleus (LC) neurons, which decline in number with age.12 The reduced number and activity leads to a reduction in concentration, alertness and information processing speed and ability. Vinpocetine’s ability to improve the cerebral cortical activating power of the remaining LC neurons makes it a potential cognition enhancer.
In summary: It is rare to find a supplement with strong basic science and clinical trial data that complement each other. Vinpocetine is a standout in that regard, considering the lack of pharmaceutical company backing. It appears to be effective, and at a dose requiring just a small pill or two; it’s inexpensive, and it has an almost negligible side effects profile. In the world of supplements, that’s just about as good as it gets. More posts to come on the fascinating topic of nootropics. Stay tuned! [dropdown_box expand_text=”” show_more=”Show me the REFERENCES.” show_less=”Hide references, please.” start=”hide”]REFERENCES: 1. Polgar M, Vereczkey l, Nyary I. Pharmacokinetics of vinpocetine and its metabolite, apovincaminic acid, in plasma and cerebrospinal fluid after intravenous infusion. J Pharm Biomed Anal 1985;3:131-139. 2. Gulyas B, Halldin M, Karlsson P, et al. Brain uptake and plasma metabolism of vinpocetine: a preliminary PET study in a cynomolgus monkey. J Neuroimaging 1999;9:217-222. 3. Guylas B, Halldin C, Farde L. PET studies on the brain uptake and regional distribution of [11C]vinpocetine in human subjects. Acta Neurol Scand. 2002 Dec;106(6):325-32. 4. Osawa M, Maruyama S. Effects of TCV-3B (vinpocetine) on blood viscosity in ischemic cerebrovascular diseases. Ther Hung 1985;33:7-12. 5. Tamaki N, Kusunoki T, Matsumoto S. The effect of vinpocetine on cerebral blood flow in patients with cerebrovascular disorders. Ther Hung 1985;33:13-21.
6. Kuzuya F. Effects of vinpocetine on platelet aggregability and erythrocyte deformability. Ther Hung 1985;33:22-34. 7. Hayakawa M. Comparative efficacy of vinpocetine, pentoxifylline and nicergoline on red blood cell deformability. Arzneimittelforschung 1992;42:108-110. 8. Imamoto T, Tanabe M, Shimamoto N, et al. Cerebral circulatory and cardiac effects of vinpocetine and its metabolite, apovincaminic acid, in anaesthetized dogs. Arzneimittelforschung 1984;34:161-169. 9. Szilágyi G, Nagy Z, Balkay L, Boros I. Effects of vinpocetine on the redistribution of cerebral blood flow and glucose metabolism in chronic ischemic stroke patients: a PET study. J Neurol Sci. 2005 Mar 15;229-230:275-84. Epub 2005 Jan 8. 10. Stolc S. Indole derivatives as neuroprotectants. Life Sci 1999;65:1943-1950. 11. Bonoczk P, Gulyas B, Adam-Vizi V, et al. Role of sodium channel inhibition in neuroprotection: effect of vinpocetine. Brain Res Bull 2000;53:245-254. 12. Olpe HR, Steinmann MW, Jones RSG: Locus coeruleus as a target for psychogeriatric agents. Ann NY Acad Sci, 1985, 444, 399–405. 13. Healy, M. Sharper Minds. Arthur Magazine. 2004 December 19; [cited 2007 August 4]. From: http://www.arthurmag.com/magpie/?m=2004&w=51. [/dropdown_box] P.S. Vinpocetine should be taken twice daily, as there are no studies on once-daily dosing. For people who don’t want to take a NeuroPack twice a day, I would suggest supplementing with an additional 20mg vinpocetine in the evening.