Kava

Kava is a perennial shrub native to islands of the South Pacific. It has been ingested there as part of local culture. It has a relaxing effect.

Kava has been associated with liver toxicity: there have been cases of liver failure necessitating liver transplant, and there have been fatalities. As a result, the sale of kava is restricted in Canada.

Here is a reference about the liver toxicity issue:

http://www.ncbi.nlm.nih.gov/pubmed/15068826

In this 2008 article from a liver disease journal, cases of kava toxicity are reviewed. It is concluded that liver damage is a rare side effect of kava. It also found that many of those experiencing liver toxicity had used higher doses of kava, for longer periods of time, than recommended.

http://www.ncbi.nlm.nih.gov/pubmed/18989142

Effectiveness:

Here is a 2009 prospective, randomized, controlled study from Australia, in which 3 weeks of kava treatment (250 mg kava lactones per day) had minimal side-effects and led to substantial, clinically significant improvements compared to placebo in generalized anxiety symptoms and depressive symptoms:

http://www.ncbi.nlm.nih.gov/pubmed/19430766
As a critical commentary here, I think that 3 weeks is a VERY short study period, and therefore has limited clinical relevance. A great many approaches can relieve anxiety over a brief period of time (e.g. benzodiazepines); it's of much greater interest to see what happens after 3 months, or after 3 years!

Here is a 2003 Cochrane review, showing significant benefits in anxiety symptoms from kava treatment:

http://www.ncbi.nlm.nih.gov/pubmed/12535473

Here is a negative study from 2005, which showed that neither valerian nor kava differed from placebo in relieving anxiety or insomnia. The study participants were recruited on the internet, and were sent the blinded medication or placebo through the mail (another example of an interesting new study design):

http://www.ncbi.nlm.nih.gov/pubmed/16010204

In conclusion, kava seems promising as a treatment for anxiety. But there appears to be a small risk of very dangerous liver toxicity. It will require ongoing study to clarify risks vs. benefits, or to discover ways to minimize the risk of liver damage.

Valerian

Valerian is a perennial flowering plant native to Europe. Its sweetly-smelling flowers have been used to make perfume. Extracts from valerian root have been used as natural remedies in the treatment of insomnia and anxiety since ancient times.

Here is a review of the evidence:


This is a reasonably-done randomized 2009 study showing no effect of valerian vs. placebo in arthritis patients with insomnia:
http://www.ncbi.nlm.nih.gov/pubmed/19114414

This interesting 2007 study--in which subjects were recruited via a TV health program, randomly mailed placebo or valerian, with results collected on-line--showed a very slight improvement in symptoms with valerian, with no differences in side effects, compared to placebo. Subjects in the valerian group took 3600 mg of Valeriana officinalis one hour before bedtime, for 14 days. Perhaps the most significant bottom-line result from the study to report here is that 9.1% of the valerian subjects reported feeling "better or much better", compared to 3.7% of the placebo subjects, after the end of the study period.
http://www.ncbi.nlm.nih.gov/pubmed/17940604


Here is a 2007 review from a sleep medicine journal, concluding that valerian is safe but not effective in the treatment of insomnia:
http://www.ncbi.nlm.nih.gov/pubmed/17517355


Here's a 2006 Cochrane review, showing no evidence of valerian helping with anxiety disorders (mind you, the amount of data is very small):
http://www.ncbi.nlm.nih.gov/pubmed/17054208

Here's one positive 2005 study from Sleep, showing a modest benefit in sleep parameters and quality of life, from 28 days of a valerian-hops combination, compared to placebo, in the treatment of mild insomnia:
http://www.ncbi.nlm.nih.gov/pubmed/17054208

Here's an interesting reference suggesting that valerian could have been the first treatment for epilepsy: but its potential benefit would have been extremely inconsistent, and at this point it is certainly not a practical treatment for epilepsy.
http://www.ncbi.nlm.nih.gov/pubmed/15509234

There are some other articles of dubious quality, which I found in some of the herbal medicine journals.

There could be dangerous interactions between valerian and other medications:
This is a case report of side effects with valerian + lorazepam:
http://www.ncbi.nlm.nih.gov/pubmed/19441067


In conclusion, I am not impressed with the evidence about valerian. It does appear to be quite safe. Mind you, there does not appear to be a good evidence base about possible dangerous interactions with other compounds. I recommend avoiding it, or using it with extreme caution, if you are taking other psychotropic medications. It may have modest benefits for some people, but for the vast majority the evidence suggests that it does not differ from placebo.

Valerian-based perfumes or scented oils might be pleasant and safe to use as aromatherapy for insomnia or anxiety, in conjunction with other relaxing activities.

Herbal Supplements & Vitamins

I'm starting a series of posts based on some questions that were sent in by a visitor (A.E.).

Here's the first question:
1. Herbal supplements and vitamins: What are your views on therapeutic value of multivitamins, Valerian, Kava, Inositol, Passion Flower, and so on?

-I think the risk:benefit ratio of multivitamins is quite favorable. I've written a few other posts about vitamins. With respect to mood or brain function in general, there may be particular benefit from folic acid, thiamine, and higher doses of vitamin D. Standard dose vitamin-mineral supplements are probably harmless at worst (as long as you get a good-quality brand--there's some evidence of dangerous impurities such as lead, in some ). Many people have poor diets, and a supplement could at least help prevent deficiencies in vitamins and iron which may further obstruct recovery from mental health problems. Supplements should not be a substitute for improving the healthiness of one's overall diet (you still need to eat your vegetables even if you're taking vitamins!)

Selling supplements is a huge business: the world market has about $180 billion of annual sales, and is rapidly growing (reference: http://www.nutraceuticalsworld.com/articles/2008/04/dietary-supplements-the-latest-trends-issues).
This is comparable in size to the $440 billion annual market size of the pharmaceutical industry (reference: http://www.valuenotes.com/Prabhudas/pl_pharma_31Mar09.asp?ArtCd=143465&Cat=I&Id=12).

I think we need to be wary of the sales tactics that go on in the dietary supplement business, especially since the quality of research in this area is, for the most part, quite primitive. If you walk into the nutritional supplement area of a health food store or pharmacy, you may be bombarded with advertising, possibly a sales person offering you attention, concern, and apparent expertise--and all of this is in the context of all sorts of other obviously healthy things, perhaps organic vegetables, right next to you. It is a biased environment. Proximity to healthy food and healthy people does not constitute evidence of effectiveness! Yet, there are some supplements that could be helpful. Just be wary of the hype, pseudo-scientific claims, and sales jargon, etc.

I'll write separate posts about valerian, kava, passion flower, and inositol.

In the meantime, here's a reference to a 2006 review in The British Journal of Psychiatry about complementary medicines in psychiatry. I recommend having a look at the whole article at a library:
http://www.ncbi.nlm.nih.gov/pubmed/16449696

Sleep & Napping Improve Memory & Learning

Sleeping after learning improves consolidation of memory. Slow-wave sleep, which tends to occur in the first few hours after you fall asleep, is particularly important for memory consolidation. In one clever 2007 study published in the presitigious journal Science, subjects were exposed to an odor when learning a task. If they were exposed to that same odor during subsequent slow-wave sleep, their retention of the learning task was significantly improved. Here's the reference:
http://www.ncbi.nlm.nih.gov/pubmed/17347444

This suggests a simple aromatherapy technique to enhance your studying: infuse your study environment with a distinct, pleasant fragrance (for example, try an aromatherapy oil) -- then infuse your pillow with the same fragrance afterwards. During an exam or test, try infusing the same fragrance on your skin or clothes (just don't overdo it, or you might irritate the people writing their exams next to you!)

Furthermore, there is evidence that brief naps (60-90 minutes) in the middle of the day can help with memory consolidation, motor learning, and can also prevent the deterioration of mental and physical performance which tends to happen in a long day. Here is one reference about this:
http://www.ncbi.nlm.nih.gov/pubmed/12819785

There's a lot more research on sleep & learning. All of it supports the practice of healthy sleep habits in the life of a successful student. Many students have a very unhealthy, disrupted, perhaps heavily-caffeinated sleep schedule, particularly while "cramming" during the week of exams or other tests. This is hard on the body, physically and emotionally; it also leads to inefficient learning.

So, consider good sleep to be a component of your studying. And a nap after a bout of hard academic work can help you learn better.

Antidepressant Combinations for Resistant Depression

In many cases, a single form of therapy does not relieve symptoms of depression or anxiety. For every person, I recommend a range of healthy lifestyle changes, and I usually would encourage psychotherapy. For many, I encourage trials of antidepressant medication as well. For a significant number of people, a single medication does not relieve symptoms. In these cases of treatment-resistance, it can help to search for an effective combination of several medications. In this post, I will discuss the evidence-based foundation for combining antidepressants.

I find that several different antidepressant combos are worth trying, including an SSRI + mirtazapine, venlafaxine + mirtazapine, or an SSRI + bupropion. Adding trazodone to another antidepressant can be helpful for sleep, although I am less convinced of this combination substantially improving depressive symptoms. Combining newer antidepressants with older tricyclics is another area of interest, which I think we should be open-minded about, but I don't tend to prescribe tricyclics very often, mainly due to concerns about safety and side-effects. There are far fewer careful studies of antidepressant combinations compared to studies looking at single medication treatments, so the level of evidence in this area is not very strong yet. But here are a few references to existing articles from the research literature (I will try to expand my list over time):

http://www.ncbi.nlm.nih.gov/pubmed/19345072
This is a 2009 article from a Montreal group (Blier et al.) showing that a combination of mirtazapine + SSRI (paroxetine) led to significantly more improvement in depressive symptoms over 6 weeks, compared to groups taking either medication alone. The combination was well-tolerated for the most part-- in particular there was little difference in side effects experienced by the combination group compared to the group taking mirtazapine alone. Unfortunately, there are conflict-of-interest problems here: the study was funded by Organon, the mirtazapine manufacturer. And several authors of the study were "consultants" paid by the drug manufacturers for speaking engagements. The continued behaviour of psychiatrists accepting corporate money to give "educational lectures" is unfortunate. Usually large sums of money are involved. Please see my posts on industry-sponsored research: http://garthkroeker.blogspot.com/2008/11/biases-associated-with-industry-funded.html and http://garthkroeker.blogspot.com/2009/05/my-experiences-with-industry.html

Here's another recent article (2010) by Blier et al, again making a strong case for using combination antidepressants right from treatment initiation: http://www.ncbi.nlm.nih.gov/pubmed/20008946

http://www.ncbi.nlm.nih.gov/pubmed/18832958
This is an open study looking at combining escitalopram (Cipralex) with bupropion in chronic depression. There was no placebo or comparison group, so the study has a weak design. But it shows the combination was quite well-tolerated, and led to 50-60% of patients experiencing a remission of symptoms after 12 weeks, which in general is a better result than most single-agent trials, especially in chronic depression. The study was funded by NIMH, which reduces the likelihood of bias.

http://www.ncbi.nlm.nih.gov/pubmed/16165100
This is a 2006 review from Biological Psychiatry looking at combinations of bupropion with SSRIs. It is a good paper, but really most of the evidence presented is of mediocre quality. It does support the idea of using bupropion-SSRI combos, to improve treatment response in depression, and also to reduce SSRI-induced sexual side-effects such as delayed or inhibited orgasm.

http://www.ncbi.nlm.nih.gov/pubmed/15539864
This interesting 2004 paper is looking at the treatment of patients with depression plus chronic headache, using citalopram alone, or amitriptyline (a tricyclic antidepressant) alone, for 16 weeks. Then, a combination of the two medications was given to non-responders, for a further 16 weeks. The combination group showed substantial improvement in both headache and depression.

http://www.ncbi.nlm.nih.gov/pubmed/14744472
This is an important 2004 study from Biological Psychiatry showing that 6 weeks of a fluoxetine (SSRI) + desipramine (tricyclic) combination was more effective than either drug alone, in treating depressed patients admitted to hospital. While similar proportions (about 35-50%) of patients failed to respond to any of the three treatments, those patients who did respond improved much more with the combination. That is, the combination treatment led to a significantly higher chance of total remission compared to either single antidepressant treatment. The study was funded by NIMH.

http://www.ncbi.nlm.nih.gov/pubmed/12172337
This 2002 study looked at several options to treat non-responding depressed patients taking fluoxetine: the first group took a higher dose of fluoxetine (40-60 mg/d), the second group took a combination of regular-dose fluoxetine + desipramine, and the third group took fluoxetine + lithium. The results favoured the first strategy, of maximizing the dose of fluoxetine, instead of combining with something else. However, this result is not very useful, since normally we would maximize the dose of a single agent first anyway, before resorting to a combination. Yet the study does show that combining is not necessarily the best first step in addressing treatment-resistance. It was funded by NIMH.

http://www.ncbi.nlm.nih.gov/pubmed/8988452
This is one of the few studies looking at trazodone combinations: in this case, trazodone+fluoxetine showed some promise in treating resistant depression.

http://www.ncbi.nlm.nih.gov/pubmed/1548249
A weak old study from 1992 showing that trazodone can sometimes help as a combination with an SSRI (in this case, fluoxetine). 3 out of 8 depressed patients in this study improved with the combination (of course, this means that 5 out of 8 did not improve).

http://www.ncbi.nlm.nih.gov/pubmed/19415584
This is a 2009 review article on combining antidepressants. It is in German, which makes it hard for me to read!