Benefits and Risks of Zinc Supplementation in Eating Disorders, ADHD, and Depression

Zinc supplementation may help treat anorexia nervosa, ADHD, and treatment-resistant depression.

Zinc is a metallic element involved in multiple aspects of human cellular function, metabolism, growth, and immune function. It is required for the function of about 100 human enzymes. The human body contains about 2000-3000 mg of zinc, of which about 2-3 mg are lost daily through kidneys, bowel, and sweat glands. The biologic half-life of zinc in the body is about 9 months, so it can take months or years for changes in dietary habits to substantially change zinc status, unless the intake is very high for short periods.

Red meat is a particularly rich source of zinc. Vegetarians may have a harder time getting an adequate amount from the diet. The prevalence of zinc deficiency may be as high as 40% worldwide.

When referring to zinc dosage, it is best to refer to "elemental zinc". Different types of zinc preparations (e.g. zinc gluconate or zinc sulphate) have different amounts of elemental zinc. For example, 100 mg of zinc gluconate contains about 14 mg of elemental zinc. 110 mg of zinc sulphate contains about 25 mg of elemental zinc.

Here are references to articles written by a Vancouver eating disorders specialist between 1994 and 2006, advising supplementation of 14 mg elemental zinc daily (corresponding to 100 mg zinc gluconate daily) for 2 months in all anorexic patients:
http://www.ncbi.nlm.nih.gov/pubmed/17272939
http://www.ncbi.nlm.nih.gov/pubmed/11930982
http://www.ncbi.nlm.nih.gov/pubmed/8199605

Here's a 1987 article from a pediatrics journal, showing improvement in depression and anxiety following 50 mg/d elemental zinc supplementation in anorexic adolescents:
http://www.ncbi.nlm.nih.gov/pubmed/3312133

In this 1990 open study, anorexic patients were treated with 45-90 mg elemental zinc daily, most of whom had significant improvement in their eating disorder symptoms over 2 years of follow-up.
http://www.ncbi.nlm.nih.gov/pubmed/2291418

Here's a 1992 case report of substantial improvement in severe anorexia following zinc supplementation:
http://www.ncbi.nlm.nih.gov/pubmed/1526438

Zinc depletion may lead to an abnormal sense of taste (hypogeusia or dysgeusia). This sensory abnormality improves with zinc supplementation. Here's a reference:
http://www.ncbi.nlm.nih.gov/pubmed/8835055

Here's a randomized , controlled 2009 Turkish study showing that 10 weeks of 15 mg/day zinc supplementation led to improvement in ADHD symptoms in children. However, a close look at the study shows a bizarre lack of statistical analysis comparing the supplemented group directly with the placebo group. When you look at the data from the article, both groups improved to a modest degree on most measures, with perhaps a little bit more improvement in the zinc group. The analysis here was insufficient, I'm surprised a journal would accept this.
http://www.ncbi.nlm.nih.gov/pubmed/19133873

Here's a 2004 reference to a study showing that 6 weeks of 15 mg elemental zinc daily as an adjunct to stimulant therapy improved ADHD symptoms in children, compared to stimulant therapy plus placebo. In this case, there was a valid statistical analysis:
http://www.ncbi.nlm.nih.gov/pubmed/15070418

Here's a 2009 study showing that zinc supplementation improves the response to antidepressants in treatment-resistant depression. The dose they used was 25 mg elemental zinc daily, over 12 weeks.
http://www.ncbi.nlm.nih.gov/pubmed/19278731

Here's an excellent 2008 review article about zinc deficiency, and about the potential role of zinc supplementation in a wide variety of diseases (e.g. infections ranging from the common cold, to TB, to warts; arthritis; diarrhea; mouth ulcers). The review shows that zinc may have benefit for some of these conditions, but the evidence is a bit inconsistent:
http://www.ncbi.nlm.nih.gov/pubmed/18221847

Here is a warning about zinc toxicity:

http://www.ncbi.nlm.nih.gov/pubmed/12368702 {hematological toxicity from taking 50-300 mg zinc daily for 6-7 months. The toxicity was thought to be due to zinc-induced copper malabsorption leading to sideroblastic anemia}

Here is a nice website from NIH summarizing the role of zinc in the diet, in the body, some of the research about health effects, and about toxicity. It sticks to a recommended daily intake of 10-15 mg elemental zinc for adults, or about 5 mg for young children. It states that the maximum tolerable daily intake levels are about 5-10 mg for young children, 20-30 mg for adolescents, and 40 mg daily for adults:
http://ods.od.nih.gov/FactSheets/Zinc.asp

Here is a reference to another excellent review of zinc requirements, benefits, and risks. It makes more cautious recommendations about zinc supplementation, advising no more than 20 mg/day of zinc intake in adults. In order to prevent copper deficiency, it also advises that that the ratio between zinc intake and copper intake does not exceed 10.
http://www.ncbi.nlm.nih.gov/pubmed/16632171

So, were I to make a recommendation about a zinc supplementation trial, I would advise sticking to amounts under 20 mg (elemental) per day for adults, and to ensure that you are getting 2 mg of copper per day with that.

Prazosin and other treatments for PTSD-related nightmares

Nightmares are a common symptom of post-traumatic stress disorder (PTSD).

Various psychotherapeutic approaches can help people to deal with nightmares, both to be more psychologically prepared for them, and to be able to let them pass with a smaller amount of distress. Techniques include simply keeping a written record of the nightmares, with or without doing some cognitive therapy exercises based on this record; practicing relaxation techniques; exposure therapy during the daytime (by evoking the imagery of the nightmares, possibly "rescripting" the sequence of events); or by planning for a "rescripting" of the nightmare during the nightmare itself. Here is a reference to a review article about psychotherapy for nightmares: http://www.ncbi.nlm.nih.gov/pubmed/18853707

Sedative drugs can change dreaming activity, but often times these medications are problematic: tolerance or oversedation may develop, or sometimes the nightmares continue despite other types of sleep improvement.

Prazosin is a cardiovascular drug which blocks alpha-receptors, and is commonly used to treat high blood pressure. Alpha receptors are stimulated by adrenaline, which causes constriction of blood vessels, therefore increased blood pressure. In the brain, increased stimulation of alpha-receptors may be one of the mechanisms driving PTSD-related sleep disturbances such as nightmares. Prazosin has been shown to help reduce PTSD-related nightmares. Here are a few references:

http://www.ncbi.nlm.nih.gov/pubmed/18447662 {a good review article}

http://www.ncbi.nlm.nih.gov/pubmed/17069768 {a 2007 randomized, controlled, crossover study published in Biological Psychiatry, showing pronounced reduction in PTSD-related nightmares with 10-15 mg bedtime doses of prazosin}

http://www.ncbi.nlm.nih.gov/pubmed/12562588 {a 2003 randomized study published in The American Journal of Psychiatry showing substantial benefit in PTSD-related sleep symptoms with prazosin at an average of 10 mg/d}

There is the suggestion in these studies that prazosin, if dosed in the daytime as well, could help treat other PTSD symptoms.

Prazosin has been used for over 35 years in the treatment of hypertension. Interestingly, it is also one of the treatments of choice in the medical management of severe scorpion stings. It may also be a promising option in the treatment of alcoholism (reference: http://www.ncbi.nlm.nih.gov/pubmed/18945226).

Prazosin is well-tolerated by the majority of people taking it. It appears to have minimal psychiatric side-effects. Sedation does not seem to be common. If the dose is too high, too soon, it can cause excessive postural blood pressure drops, with dizziness and a risk of fainting (syncope). It may cause nasal congestion or headache. Priapism (a medically dangerous sexual side-effect) is possible but very rare.

Melatonin: benefits and risks

Melatonin is a hormone synthesized in the pineal gland, and is thought to be important in the regulation of circadian (day-night) rhythms.

It has been used to treat insomnia and sleep-phase abnormalities.

The most interesting study I found regarding long-term use of melatonin was published in JAMA in 2008: http://www.ncbi.nlm.nih.gov/pubmed/18544724
In this prospective, blinded study, elderly patients with dementia were given 2.5 mg melatonin near bedtime, over an average of 15 months of follow-up. Patients in another group were exposed to bright light during the day (approximately 1000 Lux indoors, from 10:00 AM to 6:00 PM). A third group received both melatonin at night and bright light in the day. Placebo groups received no melatonin, or were exposed to typical indoor office lighting, of about 300 Lux.* Interestingly, caregivers were not able to tell whether their site had the ordinary lighting or the bright light (the increased light intensity was measurable with a meter, but was not noticeable subjectively).

The results showed that melatonin consistently improved sleep, particularly helping reduce the time required to fall asleep, and increasing total sleep time.

However, the group receiving melatonin alone showed worsening mood (less positive affect & more negative affect).

The group exposed to bright light in the day, plus melatonin at night, did not show worsened mood.

The authors conclude that bright light in the day helps with mood, cognition, and function in elderly dementia patients. Melatonin alone helps with sleep but has a negative impact on mood. Bright light plus melatonin had a positive impact on all the symptoms studied.

Based on this study, I would encourage anyone using melatonin at night to ensure that they get plenty of bright light during the daytime. It also suggests that any study looking at melatonin treatments should also consider daytime bright light exposure as an important variable which could affect response to melatonin.


Here's a reference to a study showing that 2 mg of sustained-release melatonin improves sleep:
http://www.ncbi.nlm.nih.gov/pubmed/18036082

In this study, children with intellectual disabilities experienced relief of their insomnia (including reduced time to fall asleep, reduced time awake, and increased total sleep time) with 5 mg melatonin supplementation over a 4-week period:
http://www.ncbi.nlm.nih.gov/pubmed/18261024

Here's a study showing improved sleep, with no adverse effects, due to melatonin administration to autistic children:
http://www.ncbi.nlm.nih.gov/pubmed/18182647

Here's a study showing improved sleep in children with epilepsy who were treated with adjunctive melatonin (6-9 mg). There were no significant side-effects:
http://www.ncbi.nlm.nih.gov/pubmed/15794175

High-dose melatonin (1 mg/kg body weight) has been used experimentally to treat intractable epilepsy, but more research is needed to evaluate effectiveness & safety. Here is one reference:

http://www.neurology-asia.org/articles/20043_114.pdf

This study showed improved sleep in adolescents with ADHD, when they were given 5 mg melatonin over a 30-day trial. However there was no improvement in ADHD symptoms:
http://www.ncbi.nlm.nih.gov/pubmed/16670647

Melatonin has been associated with autoimmune conditions. Here is a case report associating melatonin use with autoimmune liver disease:
http://www.ncbi.nlm.nih.gov/pubmed/9412927

Here is an article about melatonin possibly exacerbating rheumatoid arthritis (various reports show increased melatonin levels in rheumatoid arthritis patients):
http://www.ncbi.nlm.nih.gov/pubmed/19069959

Yet, in various other reports, melatonin has been shown in animals to protect the liver from various forms of artificially-induced toxicity. (e.g. http://www.ncbi.nlm.nih.gov/pubmed/15386534)


In conclusion, melatonin appears to be have a reasonable safety profile, and is a potentially effective treatment for insomnia, particularly "initial insomnia" in which there is difficulty falling asleep at the beginning of the night. Typical doses of melatonin range from about 2 mg - 6 mg.

The one main concern about adverse effects concerns possible exacerbation of autoimmune diseases such as rheumatoid arthritis, although the evidence is not clear on this point. Other types of toxicity, while possible, appear to be rare. Melatonin may even protect cells from a variety of different types of harm. But it is important to recognize the possibility that there could be other unknown adverse effects over long periods of time.

As with any treatment, we have to balance risks against benefits: insomnia itself clearly has a variety of negative long-term health effects (ranging from increased risk of physical and psychiatric illness, to increased risk of accidents). Other treatments for insomnia have their own risk/benefit profiles.

Cognitive-behavioural therapies for insomnia are clearly the safest and most beneficial, and should be optimized before any other medical therapy. But it appears to me that melatonin ought to have a place in the medical treatment of insomnia, alongside other established therapies.

*here are some measures of light intensity in different settings, to help give you some reference points to compare:

50 Lux -- family living room

100 Lux -- very dark overcast day

300-500 Lux -- recommended office lighting

400 Lux -- sunrise or sunset on a clear day

1000 Lux -- overcast day

10 000 Lux -- clear day (not direct sun)

100 000 Lux -- direct sun

Increasing Anxiety in Recent Decades

Another question from a visitor:

Shifts towards higher anxiety and neuroticism: Twenge** has noted an increase in anxiety and neuroticism in recent decades. Is this the failure of psychiatry/psychology?

Here's the reference:
http://www.ncbi.nlm.nih.gov/pubmed/11138751

This is a good and important article by Twenge, showing that anxiety and neuroticism (the tendency to experience negative emotion) have increased substantially in the past 5 decades, such that, for example, normal children in the 90's had similar scores on anxiety tests as child psychiatric patients from the 50's. The author finds that economic factors are not associated with this change, but that decreased social connectedness, and an increased sense of environmental danger or threat, are associated.

Here's a related comment:

Baumeister* suggests that purpose, values, sense of efficacy, and self-worth are needed for a meaningful life. Religions and spiritual belief-systems have long provided meaning and more. Nietzsche has supposedly said: "He who has a why to live for can bear almost any how". How do you think one can live a meaningful life? *Baumeister, R. F., & Vohs, K. D. (2002). The pursuit of meaningfulness in life. In C. R. Snyder& S. J. Lopez (Eds.), Handbook of positive psychology (pp. 608-618). Oxford: OxfordUniversity Press.

I have always felt that a strong sense of belonging, safety, meaningfulness, and community is necessary for mental health. Modern culture supports independence. Perhaps modernity also encourages the solitary pursuit of wealth, educational success, etc., in an increasingly competitive and busy culture. People are less likely to join community organizations or visit friends. People are more likely to remain single or live alone for longer periods of their lifetime (in their 20's and beyond). There are more activities that can absorb time and attention while alone (e.g. video games, recreational drugs). Even music--an aspect of life that was previously associated strongly with social connection--has become a medium in which a person can disappear alone, disconnected from the social milieu, thanks to portable music players. A cost of sexual or relationship freedom, particularly in the internet age, can be a tendency for people to have brief, less committed relationships, in the quest for variety, or in the quest for an "ideal mate." Intellectual freedom and advanced knowledge, while possibly allowing for heightened meaningfulness and enlightenment, may also shatter previous bastions of meaningfulness (such as religious dogmas), and may finally cause one to confront the absurdity and seeming empty arbitrariness of the universe. Owen Barfield, in his book Saving the Appearances, described modernity as a "shattering of idols", leaving a spiritual emptiness which science cannot fill.

I guess this is a failure of psychiatry/psychology. Not because the therapies don't work, but because the issue is one of public health and culture. I think this type of evidence emphasizes the importance of encouraging social connectedness and community involvement--to whatever degree is possible--as essentials in a therapeutic prescription for treating anxiety or depression.

In this regard, I encourage involvement in volunteering, community organizations, churches, sports teams, activity clubs, etc. It may be necessary to change one's personal culture in order to change anxiety or depression. You must be wary about being swept up in the prevailing culture, and must instead make active choices about what is healthy and meaningful for you.

*As an addendum here, I have to say that research data of this type may be biased by a variety of factors which differ between one time period and another, including use of language, cultural acceptance of symptoms, etc. Therefore, the children in the 50's may have had lower anxiety scores because they were less familiar with the language associated with anxiety symptoms, were less likely to admit such symptoms on a questionnaire, were more likely to deal with the underlying cause of such symptoms in a different way, etc. We now realize many terrible problems which were going on in the 50's (such as abuse), but which people did not talk about as openly back then. A questionnaire on these issues done at that time might have underestimated the degree of such problems.

**Here's another article, showing increasing life satisfaction over the past decades:
http://www.ncbi.nlm.nih.gov/pubmed/19227700

Intuition in Psychiatric Practice

Another question from a visitor:

Evidence-Based Medicine: Do you find that intuition has its place in practice of clinical psychiatry? Despite years of positive experience with a certain technique or medicine, would you decide against it if the only study done on it finds it harmful or useless? If not, how do you go about qualifying your sense of intuition and personal experience?

Good question. I think the crucial point here is "what constitutes evidence?"

Years of positive personal experience with something is itself a strong type of evidence. A negative study is another type of evidence. In all logical assessments of treatments, we must weigh the positive evidence against the negative.

If there was such a strong negative study, particularly if it was done with scientific and statistical rigour, it should lead to a critical re-appraisal of one's own practice, to examine reasons why one's own experience was so different from what another study shows. We should always be prepared to change our ways if strong evidence challenges the status quo.

I don't think "intuition" need be placed in opposition to "logic" or "evidence." I like to think that healthy intuition is a way to incorporate logic and evidence in a way which is flexible and open-minded, and which allows room for creativity.

In clinical practice, a manifestation of "intuition" may at times be a product of a great deal of experience or mastery in something (with the acquisition of "formal operations" in one's area of specialty, in a Piagetian sense), such that pattern recognition and responses can happen very quickly. We can see this in chess players, musicians, auto mechanics...any type of acquired expertise. Things appear to happen effortlessly, seemingly without a thought--certainly without the laborious calculations or stilted rumination which a beginner might apply to the task. These "formal operations" though, represent a great efficiency of weighing evidence and decision-making, not an absence of reason. Those who reject formal evidence in favour of their supposed "intuition" are in a different camp. This would be like the chess player or musician who does not pay attention to his or her weaknesses of technique, or like the auto mechanic who doesn't bother to check the oil. I consider this practice to be inefficient and potentially quite dangerous. There are studies which show that "intuitive" diagnostic impressions in psychiatry are often inaccurate (I'll have to find some references); yet I return to my claim that intuition can be a manifestation of our ability to process information quickly, efficiently, even subconsciously, and often with a natural grace and ease which can be a joy of life to practice or witness.

But intuition cannot be used recklessly or with disregard for other types of evidence.

Conversely, over-reliance on non-intuitive evidence can also be stilted and inefficient. The musician who has note-perfect technique, without grace, is uninteresting. A physician who goes through a symptom checklist meticulously, but fails to attend to alarming non-verbal cues, may entirely miss the underlying problem--a problem which is not detectable by a checklist, because checklist data may not be valid or relevant in cases where process is not attended to.