Archive for April, 2012


DISCLAIMER:  I debated for a long time about whether or not to post this entry.  This entry is about my personal experiences with an herbal remedy. I am not advocating St. John’s Wort as an alternative to prescription anti-depressants or advocating self-medicating.  I was young when I did this, and, honestly, very stubborn and very stupid, and I got lucky; I would not treat my depression, or any other disorder from which I suffered, without professional help now.  If you are feeling depressed, I strongly recommend that you seek professional help, starting with your personal physician.

Everyone suffers from depression at some point in their life.  Like many of you, I have had my bouts with mild depression here and there, mostly in reaction to life events.  Normally, I just get through it, because it never gets so severe that I cannot see better days ahead.  I think I am a reasonably happy, well-adjusted person, and when I do feel depressed, it is usually in reaction to something going on in my life rather than a chronic state.

Blue MeaniesThere was one point in my life, however, where the depression, although mild, was protracted and began to become disruptive.  I was working on my dissertation, and also running a laboratory, working many hours a week.  I was experiencing depression over the state of my dissertation, because it felt like I could not make any significant headway on it.  Compounding those feelings were what a good friend of mine referred to as “the 3am blue meanies.”  Every night, I would wake up with an anxiety attack about my dissertation, at around 3am.  I would lie in bed and worry about how I was not going to finish my dissertation in time, that the experiments I had designed were not going to work anyway, and how I would flunk out of graduate school and be a total failure for the rest of my life.  Images of myself as a sad bag lady filled my head, and there would be no sleep for me for the rest of the night.

I did not have any health insurance at the time, so going to see a counselor was out of the question, since I could not afford it.  In desperation, I looked around on the internet (I know, right?) for some solution to my problem.  I focused on depression, since I was convinced my nightly anxiety was related to depression (I do not know why, I am not a clinician, but that is where my mind went).  I came across several references to an herbal remedy called St. John’s Wort (pronounced “wert” by the way), which was touted as a remedy for depression.

St. John's WortAt the time, there was little in the way of information, but most scientific sources said that it was probably no more effective than a placebo.  Several European journals, however, reported that it was effective in treating depression, and had relatively few side effects.  St. John’s Wort (Hypericum perforatum) is a yellow-flowering plant with many chemical properties that are not, to date, well understood.  It has been used for centuries to treat various disorders, including depression and anxiety.  It is a prescription medication in many places in Europe, but is available over-the-counter here from many health food stores.  Delivery methods include capsules and teabags.

I was admittedly dubious, but also desperate.  At the very least, I told myself, as I bought a bottle of the stuff, I hoped that my extensive reading on the subject would not negate a placebo effect, and there were few reported side-effects from taking it.  Dutifully, I began taking my two capsules of St. John’s Wort a day and waited for results.

At first, nothing happened.  I still kept waking up at night, I still felt depressed and anxious, and, on top of that, now I was disappointed, because this stuff obviously did not work.  However, I had read that it sometimes took a couple of weeks to work, and I knew enough about anti-depressant medication to know that that was also the case with those.  So I stuck it out, and continued taking the pills.

Lo and behold, the 3am blue meanies went away, more or less.  I still felt anxious and depressed about the state of my dissertation, but less so.  The lessening of the anxiety and the better sleeping at night led to more productivity, and I actually began to make progress on my studies again.  My general mood improved over the first few months that I took it.

Feeling like I had been cured, and definitely making headway on my dissertation, I stopped taking St. John’s Wort.  Cold turkey.  Just quit one morning, and tossed the bottle into the dumpster on my way to work.  Within a few days, I developed an absolutely crushing headache that lasted for several days, I began sweating profusely, and was nauseous.  I also developed a horrible tremor.  I had to leave work one day, I felt so awful.  Being young and stupid, it did not occur to me that I was going through withdrawal from the St. John’s Wort until I mentioned that I had stopped taking it to my mentor and she looked at me like I was a complete idiot, which she followed with a lecture on the dangers of withdrawal from anti-depressant medication.

So, do these herbal remedies really work?  As I mentioned, at the time, the general consensus was that they do not, that any beneficial responses that occur while taking it are due to a placebo effect.  My experience, both as I took it and when I quit taking it, however, would suggest that St. John’s Word does something, but I’m not willing to say, definitively, that it does since I could have experienced a placebo effect, or simply gotten better due to the passage of time.  Over the years, I’ve checked in on the literature with respect to St. John’s Wort, and it is still mixed, but the idea that it is an effective treatment for depression is gaining traction in the United States.  NIH’s National Center for Complementary and Alternative Medicine (NCCAM) still regards St. John’s Wort as no better than a placebo.  A recent systematic review of many studies by Klaus, Berner, and Levente (2009) suggest that St. John’s Wort is more effective than a placebo for treating symptoms of depression.  A list of studies over the last decade continue to produce a mix of results.

If St. John’s Wort does work (and I do not take the fact that it worked for me as definitive proof that it does), I would predict that it probably works much like prescription SSRIs, such as Prozac, work, by blocking reuptake of Serotonin, making more of that neurotransmitter available to synapses in the nervous system.  I will say that the withdrawal symptoms I experienced when I stopped taking St. John’s Wort match up almost perfectly with the symptoms of SSRI withdrawal.

So, the jury is still out on these medications, which is why, despite my story, I cannot advocate their use.  I strongly suspect that the reason behind the mixed results is that St. John’s Wort is being tested in these studies on a variety of levels of depression.  I am no expert on the subject, but I do not believe I was experiencing major depression when I began taking it.  I was depressed, undoubtedly, but I would not characterize my symptoms as extreme.  It may be, and this is pure speculation on my part so take it with a grain of salt, the effectiveness of St. John’s Wort may be as a treatment for low to moderate levels of depression, as a sort of weaker SSRI, rather than as something that can be effective against full-blown major depression.  I do not know for sure, but I will continue to check in on the literature about St. John’s Wort from time to time, just see what progress is being made.  These remedies serve to remind us that there are probably many such remedies for various ailments out there, in nature, either as part of local tradition, or waiting to be discovered.  But caution and research are also needed to make certain they are safe and effective.

Reference

Klaus, L., Berner, M., and Levente, K. (2009). St. John’s wort for major depression. Cochrane Database for Systematic Reviews, 4, DOI: 10.1002/14651858.CD000448.pub

As an undergraduate I took a seminar on feeding behavior in my senior year.  We covered a variety of topics during the semester, including some of the physiological mechanisms involved in feeding behavior, and emotions evoked from feeding.

I remember my professor once talking about cravings.  We of course asked her if there was any truth to the adage that pregnant women have strange cravings.  She told us that that was probably not the case, that everyone has strange food cravings from time to time, and that people just notice the cravings of pregnant women more.  This actually made a lot of sense to me.  We pursued the subject with her, and learned that research suggests that salt is the only biologically driven craving.  What this means is that when you crave something salty, your body actually needs salt.  Given what you know about how the nervous system works, this should hardly be surprising.  But we were kind of amazed at the idea that other cravings, like a craving for oranges, were probably not caused by a deficiency in vitamin C, but more likely the product of an aversion to a specific diet.  In other words, you do not crave grapefruit because you need vitamin C; you crave it because you are tired of all the stuff you normally eat.  I always meant to pursue the question of what cravings actually are, since I think they are very interesting, but, as always, it is hard to find the time.

As I was thinking about this blog entry, however, I decided to do a literature search on cravings, and discovered a 2002 article authored by the very professor I took the feeding behavior seminar with, Dr. Marcia Pelchat, who is now at the Monell Chemical Senses Center in Philadelphia, PA.    Marci played an integral role in my life in terms of my career, so it was a pleasant surprise to come across that, and a few others from her on the very topic long in the periphery of my interests.

In this particular article, Dr. Pelchat reviewed the similarities between food addictions and drug addictions, with emphasis on physiological substrates.  A craving is defined as an intense desire for a specific food or a drug, and, according to Dr. Pelchat, it is no accident that the word links two apparently different types of cravings.  Her research has shown that food cravings, while often viewed  negatively, may actually promote more variability in the diet, and thus serve an adaptive function.

Many links between food cravings and drug cravings are apparent.  Preferences for sweets and the self-administration of certain drugs are also linked.  Alcoholics prefer more concentrated sweeteners than non-alcoholics, as well as exhibit a preference for sweets, and treatment programs for people attempting to stop smoking involve chewing various types of gum.  Opioid neurotransmitters, dopamine, and serotonin are also involved in cravings.  Endogenous opioids and dopamine are most likely involved in rewarding addictive behavior (be the addiction for food or drugs) and serotonin may affect cravings for carbohydrates.  Indeed, activity of the orbitofrontal cortex is implicated in obsessive-compulsive disorder, and this area is linked to the reward circuitry of the midbrain.    Though this area has not, to date, been directly implicated in food and drug cravings, this area does receive significant sensory information associated with food intake, notably gustatory and olfactory information.  The hormone leptin may also play a role in cravings for alcohol in individuals going through withdrawal.

In general, then, cravings, regardless of what is actually being craved, all activate the same architecture in the nervous system.

References

Pelchat, M. (2002). Of human bondage:  Food craving, obsession, compulsion, and addiction.  Physiology and Behavior, 76, 347-352

Writing up an article summary (which appears below and was the original plan for this week’s blog entry), I find myself thinking quite a lot about the novel The Strange Case of Dr. Jekyll and Mr. Hyde, by Robert Louis Stevenson. For those of you not up on your literary references, the novel tells the story of a doctor who manages to invent a potion that separates and personifies his darker impulses. The result, Mr. Hyde, is a destructive monster with no conscience, who brutally murders several people.

The metaphor Mr. Stevenson was writing about is pretty obvious. We each contain dark impulses that are a part of us, just as we all have a desire to be good and do good. The concept applies to so many things, not the least of which are the two chemicals at the center of this blog entry, glutamate and ketamine. Each of these substances can produce good effects or bad effects, depending on the circumstances.

For example, did you know that glutamate at high levels can become toxic? It kills brain cells, and abnormal levels of it have been linked to degenerative diseases like Alzheimer’s. At the same time, as the major excitatory neurotransmitter in the central nervous system, it is critical to life. Similarly, ketamine, as a glutamate blocker, produces extremely beneficial effects on the symptoms of depression, and does so extremely quickly. It’s also safely used as a sedative for children and animals. But did you also know ketamine is derived from PCP, and because of its hallucinogenic properties, is a popular “club drug” that is often abused and can have serious side effects?

So while Mr. Stevenson was interested in a metaphor about human nature, the very fact that his protagonist creates a potion, a chemical substance, to produce the alteration, is appropriate and prescient. Each of these chemicals, glutamate and ketamine, cause changes in perception and behavior, thus altering us in the eyes of others. They can, in certain situations, turn us into different people, much like Dr. Jekyll was turned into Mr. Hyde by drinking his potion. Too much glutamate kills brain cells and is one of the causes of dementia; ketamine is an hallucinogen that alters our perceptions and our mood. Both alter our behavior and our thought processes.

Now, I’m not suggesting that anyone suffering from Alzheimer’s Disease is in any way like Mr. Hyde. I do not mean it in that negative fashion, merely that certain aspects of people suffering from the disorder are profoundly affected. I know this first hand, as my mother has been suffering from Alzheimer’s Disease now for several years. She is not the person I used to know, at all; in many ways, she is as much a stranger to me as I am now to her.

Anyway, that is a topic for another entry (perhaps). In the meantime, here is a brief summary of the article I mentioned. If anyone would like a copy, please let me know. It’s a little complex, but you should be familiar enough with enough of the terms and concepts to follow it.

Maeng, S., and Zarate, C. (2007). The Role of Glutamate in Mood Disorders: Results from the Ketamine in Major Depression Study and the Presumed Cellular Mechanism Underlying its Antidepressant Effects. Current Psychiatry Reports, 9, 467-474, DOI: 10.1007/s11920-007-0063-1.

Millions of people world-wide suffer from mood disorders, such as major depressive disorder and bipolar disorder. Little about the physiological mechanisms underlying mood disorders is known, making successful treatment difficult. Treatment plans, including many drugs on the market, are often only marginally successful and relapse rates are high. Some promising work has been done looking at the effects of neurotransmitters such as serotonin, dopamine, and norepinephrine, with medication working as agonists for these neurotransmitters at the synaptic level, to increase effectiveness. Monoamine agonists often take weeks to become effective, however. It seems reasonable to assume that while the monoamine neurotransmitters play an important role in mood disorders, the time it takes them to become effective suggests that the focus of research should be deeper in the system, at the targets for these monoamine systems rather than the direct synapses themselves.

More recent research has focused on the amino acid neurotransmitter glutamate, the major excitatory neurotransmitter of the central nervous system. Glutamate plays a major role in synaptic plasticity, facilitating changes in axonal and dendritic architecture that form the basis of learning and memory. Imaging studies of individuals suffering from mood disorders show a variety of anomalies, including decreases in the gray matter of the pre-frontal lobes, less glia, and changes in the amounts of neurotransmitters, including glutamate. Abnormalities in glutamate (which can be toxic at certain levels) levels also play a role in degenerative disorders such as Huntington’s Chorea and Alzheimer’s Disease. Recent research suggests that current drugs used to treat depression decrease the activity of the NMDA glutamate receptor, and that when these NMDA receptors are directly targeted, the symptoms of major depression are alleviated much faster than with conventional medication.

Ketamine, an NMDA antagonist and derivative of PCP, has been administered to patients suffering from depression, with symptoms diminishing within 72 hours of administration. The administration of ketamine causes neurons to release glutamate, but blocks NMDA receptors while leaving AMPA receptors unaffected to cause increased post-synaptic potentiation. Since AMPA receptors are ionotropic, they respond much faster than the metabotropic NMDA receptors. Though the onset of the effects of ketamine on depression is short, some changes in synaptic plasticity, most likely due to the activity of the AMPA receptors is also thought to be a factor. The rapid and sustained effects of ketamine on depression are very promising, with up to two-thirds of patients becoming symptom-free from this treatment.