We have officially reached 1500 views! Thank you to everyone who has taken the time to read this blog so far. Truly appreciate the support.
This week’s question comes from Joe, who asks “I’ve heard of certain medications, like Adderall and Provigil, that give people a tremendous boost in focus and work ability. Provigil is especially becoming popular with the Wall Street types. How do these drugs work and are there any major negative side effects?”
I think most people have heard of stimulants becoming popular with the big city finance types, starting with cocaine in the 80’s and moving to more sophisticated pharmaceuticals like these as the years progressed. More recently, these types of drugs have become popular with otherwise normal college and even high school students looking to get more done in less time. The military has been using pills like this to keep pilots and other essential personnel awake for days at a time since the early 20th century.
Before we start, one comment: contrary to what some people may believe, no pills as of yet actually make you “smarter” or otherwise enhance your pre-existing function. What they actually do is alter your perception of reality, directly in the brain and/or by systemically suppressing signals of fatigue. The same ability is present no matter what you take, just the drugs can temporarily ease the natural feelings of fatigue that would ordinarily hold back full function.
So to answer the question generally, we can split the drugs into two basic categories. The first category, which most people are familiar with, are stimulants. Stimulants are defined as any chemical that temporarily increases physiological function. Obviously this is a very wide definition that can apply to a wide variety of things. Some drugs we encounter every day are weaker stimulants, like nicotine, than others, like caffeine. Many stimulants are illegal, like cocaine and methamphetamine. Stimulants can and often do cause addiction. Likely the strongest widely available class of stimulants are amphetamines. Adderall is actually a mix of two different types of amphetamine salts, amphetamine and dextroamphetamine. Lets explore how amphetamines work in more detail.
Amphetamines function by causing a large rise in the levels of dopamine and norepinephrine in the brain and prevent their reuptake, allowing these chemicals to continue to exert influence longer than normal. The specifics of this action are not important to this discussion but are described very well in this article. We have already talked about the function of norepinephrine in the brain (here), so I won’t repeat myself. Take a peek at that other article if you need a refresher.
The changes in dopamine are also tremendously important. Dopamine is a neurotransmitter in the brain responsible for a wide variety of functions. One major function is control/ heavy influence over the reward and alertness centers of the brain. So when a substance causes a major release of dopamine, one effect is you feel really good, have a very positive mood, and are very alert. MDMA, the active ingredient in the drug ecstasy, exerts its influence largely by this mechanism (it also happens to be an amphetamine). This is also where amphetamines give us the ability to remain awake. High levels of dopamine can also have an impact on higher level brain functions such as motor control, causing abnormally high motor activity and low threshold for movement. This is possibly the source of the “jitters” people get when they take dopamine releasing drugs like amphetamines. It is also the reason movement is so difficult with Parkinson’s Disease, as the dopamine producing center of the brain is damaged and dopamine levels are lower than normal.
As you might imagine, amphetamines are incredibly addictive due largely to their reward center influencing mechanism of action. They also have negative side effects such as appetite suppression that can cause longer term health effects if left unchecked. As such, their use should be limited only to those instances where their value outweighs the cost.
The second category of drugs are non-stimulants. These are drugs that seek to mimic the individual effects of the stimulant drugs without similar side effects, including addiction potential. For the treatment of ADHD, sometimes SNRIs (selection norepinephrine reputake inhibitors) are used as an alternative method to amphetamines. This seeks to produce the increase in norepinephrine found in amphetamine medication without the associated addiction potential from dopamine-related activity.
The drug you mentioned, Provigil, attempts to do a similar thing by influencing dopamine levels without a massive increase all at once. By upticking the dopamine transporters in the brain, the levels are increased more gradually and causes the desired alertness without the dose of euphoria that underlies the addictive nature of amphetamines and other stimulants. Mind you, amphetamines do a similar thing, but they also cause a massive release and prevent reuptake so it is likely that transporter alteration is the least negative of the three effects. It also has an impact on norepinephrine, serotonin, and histamine levels in various areas of the brain through its impact on neurons in the hypothalamus, though this effect is much less well understood. However, unlike amphetamines, it seems to have some potential for real cognitive enhancement. There have been basic studies that show some value to this end, and as such this drugs and future drugs like it may actually start to approach a “brain pill” rather than simply tricking your body into not being fatigued.
On the face of it, Provigil seems to work for its intended purpose and is well tolerated, however its full mechanism of action is not well understood. Based on its known mechanism of action, it is likely much less addictive than amphetamines and other stimulants. However, because it is also much less well understood it is something that should also be treated with caution and used only as indicated/prescribed.
In sum, these different types of drugs often work as marketed, but each has their own positives and negatives. You should only use these drugs under the regular care of a physician who prescribes them to you for a legitimate condition. But, should you decide to obtain them outside of that, I would advise you tread carefully. While they may seem innocent at the time and certainly useful in many contexts, you may be making a deal with the devil in the process. There are much more beneficial methods of increasing alertness (exercise, meditation, etc.) than taking a potentially dangerous pill. I would suggest trying those before jumping to a pharmaceutical solution.
Hope this helps, Joe! Thank you for the question. As always, feel free to submit questions to me directly at the link above.
Till next time, tread lightly.
Hello readers! Sorry for the delayed post, been a hectic last few days getting my life arranged for my jaw surgery on Friday. This week’s question comes to Desiree, who asks “I’ve noticed I get sick more often when I’m really stressed about school. What exactly is happening that causes this and how can I avoid it in the future?” Well Desiree, I think most of us have experienced this phenomenon at one point or another. For some people, it can cause nastier problems than just more frequent colds. But, you’re spot on in your assessment that stress plays tricks on the immune system. Before we get to your question, we should first explore the relevant physiology of stress.
This response, commonly referred to as “fight or flight,” is meant to save your life in the event of an imminent threat or direct attack. It involves many different body systems and is a truly systemic in its effect. The complex interconnectedness is beyond the scope of this article, but the following is the basic rundown. I highly encourage independent research of this topic for a more complete picture.
The stress response is generated in the brain based on sensory input (ie. you see something scary coming towards you). The relevant signals are collected, processed, and travel to one or both of two locations. One is the locus coeruleus, which is responsible largely for initiating the stress response via production of norepinephrine in the brain. The other is the collective Raphe nuclei, which are responsible for, among other things, anxiety and are major serotonin producers in the brain. The subsequent release of neurotransmitters from one or both of these areas of the brain produce the stress response cascade throughout the rest of the body.
The signal produced by the brain has two major parts. First, direct neurological stimulation of the adrenal glands produces adrenaline very quickly. Second, the neurological signal initiated in the locus coeruleus is translated into hormonal signal by the hypothalamus. This then affects the pituitary gland and causes the release of ACTH, or adrenocorticotropic releasing hormone. This hormone enters the blood stream and stimulates the production and release of cortisol into the blood. Together with norepinephrine, which is also released by the adrenal glands along with adrenaline, these molecules are the dominant effectors of the stress response across the body. These molecules also feedback with the brain structures that originate them, creating a very complex web of effects that are not yet fully understood (ex. cortisol has an effect on serotonin production in the Raphe nuclei).
Adrenaline and norepinephrine (collectively a part of a group of molecules known as catecholamines) affect the sympathetic nervous system. It is not important to know what this is for the purposes of this discussion, just know it as one half of the body’s automatic systems. These molecules have a number of functions, namely opening the air passages, altering blood flow throughout the body, slowing digestion, and increasing heart rate. Many of the immediate physical effects you feel during a stressful situation are due to these because their release is much quicker than cortisol. This is also why adrenaline is used during anaphylaxis (allergic reaction), as it can open the narrowed airways and control the potentially deadly swelling.
Cortisol’s role is much different. Like the catecholamines, its job is to keep you alive when fighting for your life, but by a vastly different mechanism. Instead of priming the body to fight or move, cortisol’s main function is to augment its ability to produce and release glucose into the blood stream. It does this by both encouraging the breakdown of more complex storage sugars as well as increasing the processes that convert other molecules, such as proteins and fats, into glucose (known as gluconeogenesis). In other words, it provides the fuel you need to do whatever is necessary to survive, via the slash and burn method if necessary. It also has some inhibitory effects on body systems unnecessary in the short term, such as bone formation. Unfortunately, another one of cortisol’s inhibitory effects makes it the focus of this discussion for the remainder: immune system depression.
While it may seem counterintuitive to curtail the immune system when stressed, the reason for this is fairly simple once we understand the different nature of stress responses. The body has two basic types of stress: acute and chronic. Acute stress, caused by immediate stressors like being attacked or frightened, causes the release all of these molecules in tolerable amounts that temporarily empower us without a tremendous long term downside. Suppressing immune function in acute stress is smart because it holds off inflammation. As anyone who has injured themselves under stress can attest, function can be maintained through the injury until the stressful situation resolves. If the immune system were not held at bay during that time, the injury would quickly become immobile and hinder survival efforts.
However, chronic stress, with which many in graduate school or in dangerous/busy professions are intimately familiar, tips this balance towards the negative. If cortisol levels remain elevated continuously, the effects on the body due to continued suppression can cause a myriad of problems, including more frequent infections.
The immune suppressing function of cortisol has been utilized in medications for decades. Steroids (not the work out kind) such as prednisone and dexamethasone are commonly used in medicine to reduce inflammation, swelling, and the negative effects of autoimmune diseases. However, long term use of these drugs can have similar side effects as chronic stress. Thus, just as long term steroid use is often avoided due to its negative effects on the body, so too should chronic stress be avoided to prevent the same.
Unfortunately, cortisol is a natural part of the body and to attack it pharmacologically could be disastrous. So, stress management techniques are key to controlling its release by controlling the stimuli presented to the brain. Exercising, meditation, massage, acupuncture and other similar activities have been shown clinically to be beneficial for stress reduction. Given that they have minimal downside and often benefit quality of life, they are also the most advisable methods of stress control. If these prove ineffective, low doses of anti-depressant medications that affect the serotonin and/or norepinephrine in the brain may be helpful for this purpose (as it already is shown to be for people with severe anxiety).
Hope this helps, Desiree! Thank you for the question. As always, I encourage question submission via the link at the top of the page!
Till next time, que le vaya con Dios.
David DJ, et al. “Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of Anxiety/Depression.” Neuron. 62(4); 2009 May: 453-455.
Laaris L, et al. “Stress-induced alterations of somatodendritic 5-HT1A autoreceptor sensitivity in the rat dorsal raphe nucleus — in vitro electrophysiological evidence.” Fundamental and Clinical Pharmacology. 11(3): 1997 May: 206–214.
Tsigos C, et al. “Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress.” Journal of Psychosomatic Research. 53; 2002: 865 – 871.
Valentino RJ, et al. “The Locus Coeruleus as a Site for Integrating Corticotropin-Releasing Factor and Noradrenergic Mediation of Stress Responses.” Annals of the New York Academy of Sciences. 697; 1993 Oct: 173-188.
Welch WJ, et al. “Mammalian stress response: cell physiology, structure/function of stress proteins, and implications for medicine and disease.” Physiology Review. 72(4); 1992 Oct: 1063-1081.
Before I begin, a big thank you to all of my readers. We are officially well past the 1000 view mark. Not bad for a blog only shared with my friends, family, and their friends!
This week’s question comes from my friend Brock, who asks, “I have Bipolar Disorder. It is currently being treated by use of lithium salts (specifically lithium carbonate), but no one has a straight answer about how it all works. What is known about the lithium’s action in the human brain?”
Before I launch into what I could find on the subject, I would first like to give some background on Bipolar Disorder, especially the symptoms and biological origin. Bipolar Disorder is one of the most well known mental illnesses, and over the years has held many different names. Many of you may recognize it as manic depression/manic depressive disorder or bipolar mania. Generally, people tend to understand it as a radical emotional shift: one moment someone is as happy as they can be and the next they’re in the deepest pit of despair. In fact, the term “bipolar” tends to be used informally to describe someone who is emotionally volatile or erratic.
However, Bipolar Disorder is far more complicated than people realize. The main elements, mania and depression, have tremendous variability and can be punctuated with long bouts of seeming normalcy. Also, its source is often difficult to understand, as symptoms may manifest long before people experience their first “manic break,” or severe bout of psychosis where they break from reality. Distressingly, it is known to have a strong genetic component and heredity is not uncommon.
The grey areas are vast, but generally begin with the concept of hypomania. A hypomanic state makes someone very high energy, restless, erratic, irritable, and easily excited and distracted. Often people in a hypomanic state have reduced inhibitions, an inflated sense of self, and cannot sleep well. These symptoms can progress in severity to the point where the person becomes entirely detached from reality, the aforementioned “manic break.” Though not all of those with Bipolar Disorder present with such severe symptoms, for some even a relatively mild hypomanic state can be life altering and require intervention.
On the other side of the coin, as high as people can get in the manic state is how low they can get in the depressive state. It is almost the polar opposite of the manic state, including lethargy, loss of energy, disinterest in life, problems with concentration and memory, and even suicidal tendencies.
However, it is not even essential to have them discretely or even at all. Some people can experienced mixed symptoms, where elements of one appear in the other type of episode.
The main line treatment for this mental illness is a group of drugs known as “mood stabilizers,” of which lithium carbonate is one. The goal of these drugs is to control in some way the levels and/or use of norepinephrine (NE), a neurotransmitter that has far reaching effects in the brain; it is also deeply tied into the function and release of other neurotransmitters in the brain and around the body. NE especially influences general arousal (including fight or flight mechanisms), attention, and the reward system. Other more common antidepressants (SSRIs, SNRIs, etc.) and antipsychotics (sodium valproate, etc.) can also be used for control of less severe symptoms in either direction of the mood spectrum.
Specifically, it is thought that the manic state is caused by a dramatic increase in NE, and the symtoms seem to correlate well with NE’s function in the brain. The depressive state, then, is the opposite neuro-chemical environment, where there is not enough NE to support normal mood. Unfortunately, it is not known by what exactly mechanism this process works and to what extent the changes in NE alter other neurotransmitter levels–the systems remain too linked to effectively show cause and effect. Even genetic analysis has not provided any greater answers for the biological source of the disease.
Sadly, the reason for lithium’s effect is also not very well understood. For its anti-depressant qualities, two competing theories exist. Both affect signaling pathways far away from the release of neurotransmitters and instead focus on neuroprotective (brain cell protecting) mechanisms. In the first theory, lithium blocks an enzyme pathway responsible for ultimately allowing for the destruction of cells in a region of the brain known as the hippocampus. Damage to the hippocampus (as evidenced by reduced size) is known to be present in depression patients. In the second mechanism, lithium blocks an enzyme responsible for the creation of a cellular messenger known as inositol. Depleting inositol slows down the improper signaling between cells and prevents similar problems with the hippocampus.
The mania is thought to be controlled by lithium’s effects of NE in the brain. Primarily, this is theoretically accomplished by binding to the NE receptor and reducing NE’s ability to bind to it. Secondarily, lithium encourages lithium to be taken back into the cell and stored in elements that are not involved in neurotransmission. Systemically, it is also thought that lithium causes increased release of acetylcholine in the blood, which can have a calming effect generally.
Unfortunately, none of these mechanisms are definitively outlined and proven and thus remain difficult to target more specifically. Things are made much more difficult by the fact that a significant percentage of patients do not respond effectively to lithium. The unreliability makes it just that much harder to definitively prove a mechanism applicable to the disease biology as a whole.
On the whole, it appears that the theories all seem to lay claim to some general alteration of neurotransmitters or signaling pathways, but without further in depth research the mechanisms will remain largely speculative. It certainly appears that Bipolar Disorder is complex disease that involves far more than just NE levels in the brain. Only time will tell exactly what these complexities are and hopefully will yield a more effective treatments.
Hope this helps, Brock! As always, if you have any questions feel free to submit them directly.
Till next time, have a good one!