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!
Magnesium and the Brain