Thursday, March 10, 2011

Hodgepodge of Speculative Neurotransmitter Madness - Magnesium!

Ugh. I have a cold. I had been invincible, contracting H1N1 (most probably) with the only symptoms being a headache, missing norovirus gastroenteritis over Christmas, seeing cold after cold take down others while I had a mere sniffle and a bit of a scratchy throat that resolved in a day. Until the oldest went to pre-school and brought home a doozy, with sniffles keeping her awake, then her sister, who loves to suck her thumb and cannot sleep with a stuffy nose, poor pooky doo - which meant 5 nights in a row of horrible broken sleep, and then I succumbed to the virus myself. Today I caved and bought some sudafed (my name is now on a mysterious government registry of potential methamphetamine makers), and since the strongest substance I normally imbibe is tea, I'm feeling a little racey right now. Racey and less sniffly than this morning. Which is perfect, because Pubmed sent a crazy short paper to my inbox the other day, Dextromethorphan as a potential rapid-acting antidepressant.

Let's keep in mind this 3 page ditty was published in Medical Hypothesis, which we might as well rename "Rampant Speculation That Is Pubmed Searchable." Which is great, really. We can call it the bleeding edge of science. But let's not jump to act on these speculations. Let's learn from them about the brain and how it works.

To be more explicit - DO NOT go out and down a bottle of Nyquil (with dextromethorphan as the cough suppressant ingredient) for its hypothesized antidepressant effects. You may notice that another ingredient of Nyquil is acetaminophen (Tylenol) which we were talking about earlier this month and how unpleasant moderate amounts can be. You've been duly warned.

Back to the paper. It begins with the club drug, horse tranquilizer, and childhood anesthetic agent (kids are apparently less bothered by the hallucinations than adults), ketamine. Ketamine sits on the NMDA receptor and keeps glutamate from doing it's dire deed of letting calcium ions through and wreaking havoc on the poor neurons. There are actually a number of studies (1) showing that IV ketamine infusion can nearly instantly relieve a severe depression. Unfortunately, there is usually a relapse within a few weeks, so it is not the most practical of remedies. But its temporary success has led researchers on the hunt for other pharmaceuticals which will act on the NMDA receptor.

Dextromethorphan is an interesting pharmaceutical primarily used as a cough suppressant. However, it has multiple effects, including NMDA receptor antagonsim (like ketamine), a mu opiate receptor agonist (so it is an opiate), and a serotonin receptor blocker, calcium channel blocker, and muscarinic receptor blocker. Most of the activities of this pharmaceutical can have positive mood effects. Therefore it might have some antidepressant effects, similar to ketamine.

What do we know about antidepressant action at the NMDA receptor? Well, one of my favorite minerals, magnesium, can sit on the receptor and block access to glutamate. Several reports (discussed in my blog post here) connect low magnesium levels to depression, and supplementing magnesium can have rapid antidepressant effects, even in treatment resistant depression. Low levels of magnesium in the spinal fluid have been documented in treatment resistant depression. A randomized controlled trial of magnesium chloride vs. tricyclic antidepressant imipramine showed equal antidepressant efficacy in 23 patients with hypomagnesemia, type II diabetes, and depression (2).

Another antagonist of the NMDA receptor is PCP ("angel dust") which can cause immediate rage and depression - unlike ketamine. (I had the action of PCP backwards at first until Peter kindly corrected me - but the paper was a bit confusing on this point. Nor have I seen PCP usage since 2003 - and then only once, so the pharmacology was rusty. Angel dust is not big around these parts. Probably not that big anywhere considering just how unpleasant it is.)

Back in 2003 I was a resident working the emergency room as the psychiatry consultant, finishing up an evaluation, when a new patient was brought into the ED causing quite a rumpus.   The emergency room resident came up to me almost immediately.  "We have someone else for you."

"Why me?  I bet you $20 she's as high as a kite,"  I said.  (Actually I never would have said that.  Residents are fairly universally destitute and would not risk $20.  Probably I just said, "She's as high as a kite.")  An important distinction, actually, as I can't legally send one to the hospital against her will simply for being high (nor would I want to).  Nor does someone who is high enough to significantly affect judgment technically have the capacity to make important treatment decisions such as "Am I willing to be locked up into a drug treatment program" or not.  Nor does a sit down discussion and motivational interviewing about getting treatment do much good when someone is high.  Therefore, when someone is high, my options as a psychiatrist are essentially nil.  We have to wait until the feet are a bit more on the ground.

Well, the tox screen came back positive for all sorts of things, PCP among them, which I think explained quite the level of rumpus-making - we don't get a whole lot of meth in the Northeast except in certain populations - mostly it is alcohol and opiates and cocaine. A few hours passed by and the person was able to go home with some options for treatment should she choose to pursue them.  

Keep in mind, friends, that PCP and large amounts of ketamine or dextromethorphan cause hallucinations. Which doesn't sound like that much fun to me.

The author if the paper calls for trials of dextromethorphan in the treatment of depression (currently there are none.)

Personally, I'm more intrigued by the magnesium angle. Way more paleo. Cheaper. No hallucinations. No addiction that I'm aware of. And most of those on a standard diet imbibe less than the RDA. Magnesium is one of the few supplements I take regularly, because it is hard to get in appropriate amounts without drinking untreated spring water, and it is so vital.

Further reading:

Magnesium and the Brain


  1. Sorry to hear about your cold. Hope you'll feel well enough for dinner on Saturday.

  2. I've had it for a week. Last gasp. Will be better by Saturday!

  3. Dear Dr. Deans,

    Please analyze the Oppositional Defiant Disorder, and suggest modes of treatment.

    Thank you in advance,

    Donald Boland

  4. Pumpkin seeds are a great source of magnesium!

  5. Hi D - there's a bit about oppositional defiant symptoms in the Food Intolerance and ADHD post"

    I have a paper on my nightstand about ODD, however, so it is in the queue.

  6. I keep meaning to look into Magnesium more, specifically what type people should take. When I've glanced at the myriad of supplements I've seen Mg Citrate, Gluconate, Lactate, and others. Also, a mysterious 'chelate'... whatever that is.

  7. Vl - it is confusing. Oxide is cheapest but poorly bioavailable - eventually you will start to top off magnesium stores with it. Citrate more likely to cause diarrhea. Other amino acid chelates are bioavailable but more expensive. Also, probably want to avoid aspartate. Then there are the lotions, and the fizzy drinks. Nephropal had a great post a while back that is still linked (I think) from one of my magnesium posts. Oxide in fizzy tablet is highly bioavailable.

  8. NAture Calm is what I recommend to all my patients. I also tell them Epsom Salts work. There is better absorption transdermally than orally for most Mag compounds. Moreover, if they have a leaky gut it is worse. Remember Phyates bind Mg better than anyother metal!!!! If you use oral Mg supplements I use malate and acetate because they work best in the face of microvilli damage. And if your treating mental illness they likely have a leaky gut too.

  9. BillyE, a patient of Dr Ken Tourgeman, posted at Nephropal that he is using magnesium oil (magnesium chloride) in a spray bottle for 100% absorption.

    Perhaps you let your Vit D3 supplementation dwindle a little and those nasties brought home from pre-school overwhelmed your immune system!!

  10. The only human RCTs of mental-health related magnesium supplementation used the oxide - but even in one of those studies, the researchers mentioned they would use mg citrate if they did another trial.

  11. Aloha!
    Love the fact that I stumbled upon your blog! I'm always jazzed to see conversation around the supplements we can recommend to our Eating Disordered clients with low mood prior to the consideration of meds. I have been suggesting Mg for other reasons so this is delightful to see. I'll be back for more info.
    Mahalo for being here!

  12. I've taken magnesium for 2 weeks and love the energy and regularity that I have with it. However, I've developed an itch! Can a person be allergic to magnesium?

  13. I just discovered your blog by searching "magnesium's affect on neurotransmitters." Will be a regular reader now. Here's the info I'm after: My son, age 9, has ADHD, SPD, Dysgraphia, Gluten-Intolerance. He is having a lot of severe reactions to ADHD meds and anti-depressants. In an effort to find out why he's so resistant to appropriate treatment, we did a Hari Tissue Analysis. It showed all his main mineral ratios were off. When we started supplementation, it made this super-sweet kid very aggressive and violent. I took the supplements away one at a time to find that it was the Cal+Mag+Zinc. Gave just Magnesium and discovered it was the culprit. His Magnesium level tested at 1.8 when it should be 6 though. I have spent hours researching why he would have a negative reaction to Magnesium (and the other supplements, B vitamins give same reaction, L-Tryptophan makes him have extreme panic and fear -- Imipramine caused same reaction). We are trying desperately to figure out why a kid who is low in Magnesium has a bad reaction to it's supplementation (250mg a day). Anyone have any insight? It was also found that he has high levels of mercury in his tissues, which we haven't tackled yet, so I'm wondering if that could be the cause. I am so lost!


  14. Hi Penny,

    You might try posing this question at paleohacks or in the Mark's daily apple forum to see if someone else has had the same experience. Sometimes upregulating serotonin can cause panic and anxiety (common side effect of the first week or so of an SSRI or TCA which exlpains the L-tryptophan and imipramine) but I can't really figure out why magnesium would do it.


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