The Effects of Ethanol on Histamine

The following is a guest post by Dr. Andrew Hill, Lead Neuroscientist at truBrain. Click here for a fascinating audio podcast that accompanies this article. featuring Ben Greenfield and Dr. Hill.

Dr. Hill received his PhD in Cognitive Neuroscience from UCLA in 2012, studying how attention operates in the brain. He has been employed as a Lecturer at UCLA over the past few years, teaching multidisciplinary courses on both Healthy Brain Aging and courses in Neuroscience and Psychology. Dr. Hill has published chapters on measuring and modulating human attention, and continues to research self regulation.

Prior to UCLA, Dr. Hill obtained extensive experience working with both psychiatric and developmental populations as well as gaining experience in high technology areas. He received his B.S. in Psychology/Neuroscience from UMass Amherst, and is a key adviser in the formulation of the truBrain’s cognitive blend (get 20% off on your purchase with the code BEN20).

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The Limitless Pill

In the 2011 movie Limitless, Bradley Cooper’s character gets his hands on a smart drug (NZT-48) that enables him to be cognitively super human. The only known side effect is that his eyes change color while he is on the drug, but that changes over the course of the movie as side effects, including withdrawal symptoms, begin to get worse and worse. It’s a sci-fi thriller with a not-so-feel-good message about addiction and performance enhancing substances. And goons chasing you. Makes smart drugs sound dangerous, right? Like any good sci-fi , this movie questions our assumption on the limits of science. And some of what it is suggesting is not science fiction today. Smart drugs and nootropics are a current reality, being used more and more not to treat or remediate any active condition or complaint but towards boosting already typical or superior performance, in colleges, board rooms, military theatres, and by forward thinking gerontologists. With the wide variety of compounds available today that have some research support for cognitive effects, it is important for you to understand the risks and benefits associated with usage, or at least how to choose smarter, when choosing things that affect your brain. For example, one of the most popular misconceptions about smart drugs is that they are the same as nootropics. This may be due to similar benefits that people use them for, but ultimately they do not share the same range of effects, mechanisms of action, safety and side effects. So - what are smart drugs? What are nootropics? How do we know if something is safe or effective? What are these drugs actually doing to my brain? Why am I asking so many questions without answering them? Keep reading to get this and more information you need to understand these questions, and start formulating your own answers - and your own strategies for selecting nootropics.

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Smart Drugs vs. Nootropics

A smart drug is generally a prescribed medication or off-label drug used primarily to treat some kind of mental or cognitive disorder. The most common are drugs such as Adderall (dextroamphetamine) or Ritalin (methylphenidate) in the stimulant class used to treat symptoms related to ADHD - although legal and illegal off-label use is rampant. And while they may promote focus and energy in some people, others have dramatic side effect, to body and brain. Smart drugs in the stimulant class also tend to be reinforcing, producing spikes in dopamine and norepinephrine. This leads to tolerance and habit formation, including adverse effects on appetite, mood stability, cardiac function, stress levels and possibly many other unwanted effects - especially on younger brains such as teens and young adults. Irritability and mood swings, anxiety, sleep issues, and other forms of emotional or cognitive regulation problems can crop up over time with stimulant use, as well. A popular atypical stimulant “smart drug” includes the narcolepsy agents Modafinil / Adrafinil, although their effects on cognition beyond wakefulness are unproven, and side effects - while rare - can be life threatening. If attention problems are already present the side effect risk appears to be significant increased, as well. (Kumar, (2008), Approved and Investigational Uses, Drugs. 68(13):1803-39.). In contrast to a smart drug, a nootropic is generally a non-prescribed compound, including vitamins, herb, other supplements, natural or synthetic compound that may increase or protect cognition in some way. The preponderance of research in the past 40 years shows some effects on focus, attention, effects on aging, and possibly cellular metabolism. To paraphrase the definition of “nootropic” as initially coined in this article by the researcher Girugea in 1972, it is something that improves cognition without appreciable side effects, or provides from protection to the brain. In a modern context we think of nootropics as something used not to treat any mental condition or pathology directly, but instead to provide support to peak function, protect against long term risk, and provide daily boost. Across the field, true nootropic ingredients and full blends can now be found largely sourced from natural ingredients. Nootropic blends are designed to leverage synergy effects suggested in the research and subjective experiences. The goals with nootropics should always be to allow for greater and more consistent cognitive effort and flow, without the side effects of a stimulant or other harsh substance.

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How Do I Know If A Smart Drug Is Safe?

As a rule of thumb, it is the nature of science to be wrong at times. We’ve come a long way since we accepted that the theory behind the Earth being the center of the universe was wrong. We understand that new research may overturn old knowledge. So how can we truly know the risks and benefits of long term use of nootropics or smart drugs? A red flag in understanding the harm of a substance is the body’s ability to handle an overabundance of this substance. Small amounts of toxic substances may be beneficial in the short term, but the magic happens when we look at what is happening in the body when we get too much. Something as simple as a cup of coffee may seem harmless, but caffeine in high amounts can cause dizziness, anxiety, and even cardiac arrest or death. Caffeine mimics the action of the neuromodulator adenosine in the body. This leads to higher adrenaline and cortisol levels. Even in typical doses caffeine can deeply affect our sleep and cause heart arrhythmias for some people. Alcohol has even worse short and long term toxicity symptoms at non-moderate doses, and some people struggle to keep their dosing moderate. In better doses - perhaps a couple cups of coffee a day (without sugar) and a drink or so per day on average, these substance are actively health promoting, and reduce risk for many brain and cardiac diseases. When you are picking substances and compounds, dosing should be cautious at first. From this, a couple rules come out - 1) don’t take any compounds, substance, or blends of substances that don’t list all their ingredients out in plain amounts. Proprietary blends with lump-sum amount hiding buzzword-compliant list of magical ingredients known as “fairy dusting” in the supplement industry. Don’t be fooled. Read the ingredients. Figure out why and what is in there, and if you want it. 2) don’t chase suspicious research chemicals without much history of use or safety profile. Experiment on yourself if you like, but you only have one brain - make rational and cautious choices. There are nootropic, smart drug, and cognitive enhancers that have been around for decades - something released last week as a “Research Chemical” with a bunch of numbers and letters for a name and no human studies isn’t worth the risk to you. Not for years.

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What About Adderall & Modafinil Safety?

Smart drugs such as Adderall can cause dangerous lows, psychosis with extreme use, rebound fatigue, and depression, even at lower use levels. As an amphetamine, Adderall can act as a reuptake inhibitor, meaning that it can compete with other neurotransmitters for reuptake. Specifically it is thought to block the uptake of dopamine and norepinephrine, which are associated with reward behaviors and our nervous system functions, respectively. This causes a flood of these neurotransmitters onto multiple receptors, causing neurotransmitter depletion and overexcited receiving neurons. This large “signal” is the reason for the focus, but also responsible for some of the side effects that go along with this class of prescription drugs. Existing research is also a bit weak on any improvement that Adderall or other stimulants may have on short term memory or cognitive function, and some actually may impair function. Modafinil, also known as Provigil, is an example of a smart drug that has been used like a nootropic. Modafinil is prescribed to treat sleep disorders, but when combined with a normal functioning brain, can potentially cause increases in cognition and awareness. Just like Adderall, the use of these drugs outside the medical field does not make them a nootropic. Modafinil is also a reuptake inhibitor for dopamine, causing the same type of neurotrasmitter flood as Adderall. However, Modafinil may also affect the histaminergic pathway, which deals with wakefulness and the delicate immune response of the body. Histaminergic neurons in the brain are more active during wakefulness and slow their firing pattern as we rest or sleep. Modafinil’s “beneficial” side effects may come from this heightened histaminergic neuronal activation, but too much activation can cause apoptosis, or cell death. In addition, this has been shown to cause adverse skin reactions that required hospitalization since the histamine pathway also deals with our immune system. Modafinil may increase your intelligence, but can be extremely dangerous to the health of your brain and body.

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Enter Nootropics

Nootropics, like truBrain’s cognitive blend, and a few other products on the market, have dose-toxicity levels much lower than salt, caffeine, and especially Adderall. There doesn’t seem to be any neurotransmitter depletion, tolerance or habit forming potential, adverse body side effects, or impaired brain function, from most true nootropics, by Girugea’s definition. The mechanisms for nootropics lie within the structural connectivity of the brain, the optimization of blood flow and oxygenation, and the fortification of brain regions over long term consistency. Nootropics act more as a super supplement to protecting the brain. Girugea’s own first synthesized nootropic (in 1964) is still in use today and has been shown to have effects on mitochondrial metabolism, cell membrane fluidity, and functional connectivity in the brain. Piracetam is this poster child for nootropics, and one of the main ingredients in truBrain nootropic blends. It is one of the only compounds used in that formulation that can not be found in nature, however it was originally derived from - and has structural similarities to - the neurotransmitter GABA. Since Girugea bought piracetam to light in 1964, there has been lots of research to support the benefits of piracetam. It has been shown to positively affect our cell membranes and to have neuroprotective and pro-metabolism effects on cells. The fluidity in our membranes changes with stress and old age, as well as moment to moment as one method of regulating receptor activity. By keeping our membranes healthy we can promote the cells ability to communicate. For example, truBrain combines other membrane oriented supplements - including choline. The cell membrane - especially in the brain - relays ongoing control signals and messages from other cells to the inner processes of the cell. Neurons’ membranes in the axon (wiring) and soma (cell body) help generate and propagate electrical signals, sum distant signals, and even have computational and complex learning functions related to changes in membrane function.Healthier and more active cell membranes bring us increased activity and cell communication, and hopefully better cognition. Piracetam along with other truBrain ingredients such as magnesium, choline, and DHA, increases in brain plasticity and are designed to improve cognition and efficiency under processing load - or peak performance, versus remediation. Nootropics may support increased cognitive potential as well as long term protection. The truBrain team added L-Theanine and L-Tyrosine to support neurotransmitters of GABA and Dopamine, respectively. You can use a similar or different strategy when building your own nootropic regimen, but use a strategy. Know why you are putting an ingredient in, know how it might interact with the others, and be sure that dosing is safe. When you are planning your nootropic or nutraceutical regimen, think in terms of nutrition support to cell metabolism and function, amino acids, natural or near-natural compounds, and avoid bad fats and harsh chemicals that give a momentary boost at the cost of later crashing or having other more serious side effects, such as excess sugars and caffeine. And don’t forget what else you put in your mouth - additional DHA and other omega-3 fatty acids (in grass fed meats, deep sea fish) are excellent for brain health. Craft your diet like you craft your brain supplement regimen - or have both catered / curated for you in a high end product. If you do create your own blend, think precise selection, not shotgun approach, and add slowly to your regimen.

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The Problem With Instant Gratification

As a culture, we often hear false marketing claims or create mindsets about what is possible with our health. We see ads that advertise a pill that gets rid of “stomach fat fast”. Truthfully, fat is lost uniformly in the body and the fastest and healthiest way to lose weight it about 1-2 pounds uniformly a week. So we eat poorly and don’t exercise for 2 years and then criticize our healthy workout plans and diet 1 month in when we don’t get the results we want. The healthiest and most effective things in life are often the ones that we do routinely. Consistency is key. This is true if you are talking about athletic performance, academic or intellectual training, or nutrition and supplement support. While not “necessary” like supplements or medicines, nootropic use follows this principle as well. There is another rule, emerging. If something is strongly “felt” dose to dose - if it gets you high, or wired, or sedated...it’s a smart drug, recreational drug, or something that may enhancing some aspect of performance (perhaps at the expense of another), but is definitely not a nootropic. And finally, nootropics should be sustainable. With some nootropics there is an initial loading phase followed by a maintenance phase, and while subtle, results can be felt fairly quickly on the timescale of a few days. The contrasting quick highs / crashes of coffee, alcohol, smart drugs, and even quickly digesting carbs are definitely experienced more immediately, but have consequences that make them unsustainable for many people.

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Summary

So in summary - here are a few initial rules to help select your own nootropic or cognitive enhancing blend:

• Know your ingredients, and their amounts.
• Don’t spend your money on obfuscate fairy dusting or expensive blends that are full of caffeine or random research chemicals.
• It’s not a nootropic if it has side effects.
• Your nootropic solutions should focus on mild nutritive and metabolic support, for long term gains and protection. Break the cycle peak and crash that you get with too many stimulants, and avoid the more serious side effects that you risk with smart drugs.
• Nootropics don’t get you high, altered, or wired.

And don’t forget the other accessible and evidence-based brain and cognition improving methodologies we have at our disposal today: meditation, yoga, and other contemplative (attention training) practices, biofeedback and neurofeedback, diets high in good fats, and other modifiable behaviors you can implement to take control of your brain health and performance. So take care of your brain - the tools are out there, to support health and shift performance.

Leave your questions, comments and feedback at BenGreenfieldFitness.com. Also, if you want to try the nootropic that Dr. Hill helped design, grab truBrain and get 20% off on your purchase with the code BEN20.

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