Dextromethorphan and Parkinson’s Disease

(Like everything else on this site and regardless of the language used, this is not to be taken as medical advice. Take the information to your own doctor for advice. Also, be aware that DXM should not be taken with MAOIs, SSRIs, or similar drugs. Do your homework.)

So, what happens to a drug that:

Is so old that no patent potential exists;
Has been abused for decades at doses 100X what might be needed for PD and has done relatively little harm;
Has been shown in published studies to be neuroprotective, to block excitotoxicity, to prevent the neuroinflammatory response of microglial activation, to ease the dyskinesia brought on by levadopa, and more;
Costs only pennies per day and needs no prescription;
And seems to not only ease chronic problems such as neurodegeneration but to also offer major relief of acute symptoms, as well?

Seemingly, the answer is to ignore it completely other than to try to whip up a little hysteria about it so that it can be banned if it starts cutting into profits.

I am speaking of that old bugaboo from our childhoods, the drink of addicts and winos, the road to ruin – cough syrup.

In reality, I am talking about dextromethorphan, an NMDA antagonist that is the active ingredient in the most common OTC cold medications in the US. And, from observations of my own one-rat trial, that seems to be an amazingly effective adjunct to my PD medications.

I have, over the last two weeks, noted the following improvements:

My “ON” times have gone from two hours to four or more;
When I do go “OFF”, the climb back ON is half as difficult as it was;
OFF used to mean freezing almost 100% of the time but now is seemingly 25% at most. I can move slowly and carefully where I could not before;
Dyskinesias and the sore muscles that go with them have seen a similar reduction;
My sleep has improved and my skin has too.
My lower legs are stronger and gait problems are down 75%.
Brain fog is 25% of what it was.

I began with a total daily dose of just 15 mg or one teaspoon of cough syrup. I divided that into four to coincide with my prescription medications. So, the net of all this was that four times each day I was consuming one-quarter teaspoon of cough syrup containing approximately 4 mg of DXM. When one considers that the suggested dosing for cough suppression is 30 mg repeated at six to eight hour intervals (or a daily maximum of 120 mg) my 15 mg seems rather paltry!

I am now in the process of determining the optimal dose for my particular metabolism. There is a wide range of sensitivity in the population as a result of differing rates of processing with as much as ten percent of people being “slow metabolizers.”I seem to belong to that group and my experience should provide some assistance to any who might choose to follow.

DXM is a bi-phasic drug that has an effect at a low dose that is diametrically opposed to the effect of a slightly higher dose. So, dosage is critical. The rate of metabolism for a normal system processes a single dose in about four hours while a “slow” system may require four days. Under these conditions, the only way to determine an effective dose is trial and error. After about three days of the amounts noted, I began to experience rapidly worsening symptoms. Concluding that I was taking too much for my system to handle, I quit for two days and things did, indeed, improve.

I am, at this point, going to paste in a part of an email from yesterday to a friend that will provide more detail:

<<Begin quote>>
I began anew yesterday and took a quarter tsp of DXM in the morning and have done so again this morning. (A moment to clarify. Cough syrup is standardized at 15 mg per tsp and the suggested dose for cough is 30 mg every six hours with a max of 120 mg per 24 hrs. I am taking a single 4 mg dose each morning at present. One-thirtieth of the label max. Even if my metabolism is slow (which I suspect that it is) that leaves a good safety margin.) I am going to start talking in terms of “mg” rather than “tsp” so remember that one tsp equals 15 mg.

So, having taken 4 mg yesterday morning, I had a pretty good day. No particularly bad periods until evening and they were better than a couple of weeks ago. In fact, I am going to invent a unit of measurement for my overall condition. I will call it the Misery Index and define it at 100 two weeks ago and ten yesterday. At 100 I was taking large amounts of medication on a two hour schedule and getting poor results. I was regularly going Off at the end of the two hour window with Freezing. It was common for it to require two hours or more to get back On so I would “lose” an entire cycle. This was typically the state of affairs in the afternoon. Mornings were better and evenings worse. It was not unusual to be forced to crawl to bed at least once a week. Similarly, it was not unusual to go Off with Freezing in public as morning turned into afternoon. On one occasin I was forced to crawl out of my bank. Loss of bladder control via urge incontinence happened as much as twice a week. Sleep was around four hours nightly with early awakening disrupting my med schedule. It was common to find myself cutting my day short to “rush” home as I felt the first signs of approaching Off. In short, I was a sad puppy and that state is an MI of 100.

Yesterday, however, was an entirely different matter. No true Off until 10:00 PM. Medications on a 3 to 4 hour cycle. No other problems. I even did some yard work. That’s an MI of 10.

Sorry to go on so, but as I did it I realized that it was an opportunity to bring some order to the mess and was writing it for me as much as for anyone.

I slept well (7 hours), awakened at 6:00 AM and was On in 45 minutes (was 1 to 2 hours). BP = 136/87. Took 4 mg DXM with a 10/100 sinemet plus a 50/200 sinemet CR plus 8 mg requip. It is now 9:30 AM and still fully On.

<<<End quote>>>

As I write this, I continue to enjoy great improvement that has taken place in less than a fortnight. I am going forward on the assumption that as I finetune my regimen that even more improvements will be noted. I will record them here.

In the meantime, I will review the existing literature and elaborate as appropriate.

Mov Disord. 1998 May;13(3):414-7.

A trial of dextromethorphan in parkinsonian patients with motor response complications.

Verhagen Metman L, Blanchet PJ, van den Munckhof P, Del Dotto P, Natté R, Chase TN.

Experimental Therapeutics Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1406, USA.

The effects of the NMDA antagonist dextromethorphan (DM) on levodopa-associated dyskinesias and motor fluctuations were studied in patients with advanced Parkinson’s disease. During initial open-label dose escalation, 6 of 18 patients reported a beneficial effect at their individually determined optimal DM dose (range, 60-120 mg/day). The 12 remaining patients either experienced reversible side effects, particularly mild drowsiness, or decreased levodopa efficacy, and were therefore excluded from the study. The six responders entered the double-blind, placebo-controlled, crossover study with two 2-week arms separated by 1 week wash-out. On the last day of each arm, motor ratings were performed every 20 minutes for 8 consecutive hours. In addition, motor complications and Activities of Daily Living (ADL) were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) and patient diaries. With DM, dyskinesias improved by 25% according to physician’s ratings and by 40% according to UPDRS interviews, without compromising the anti-Parkinson effect of levodopa. Motor fluctuations and ADL scores also improved significantly. Although the narrow therapeutic index of DM limits its clinical usefulness, these findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate levodopa-associated motor complications.

PMID: 9613730 [PubMed - indexed for MEDLINE]

Neurology. 1998 Jul;51(1):203-6.

Dextromethorphan improves levodopa-induced dyskinesias in Parkinson’s disease.

Verhagen Metman L, Del Dotto P, Natté R, van den Munckhof P, Chase TN.

Experimental Therapeutics Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892-1406, USA.

OBJECTIVE: This study assessed the effects of the N-methyl-D-aspartate (NMDA) antagonist dextromethorphan (DM) on levodopa-induced dyskinesias in Parkinson’s disease (PD). BACKGROUND: Recent experimental evidence suggests that increased synaptic efficacy of NMDA receptors expressed on basal ganglia neurons may play a role in the pathophysiology of levodopa-induced motor response complications. METHODS: DM was given to six PD patients with motor fluctuations in a double-blind, placebo-controlled, cross-over study. At the end of each 3-week study arm, patients received several brief i.v. levodopa infusions while parkinsonian symptoms and dyskinesias were frequently scored. Levodopa dose-response curves for antiparkinsonian and dyskinetic effects were then compared for each study arm. RESULTS: With DM, average and maximum dyskinesia scores improved by >50%, without compromising the antiparkinsonian response magnitude or duration of levodopa, although in some subjects the levodopa threshold dose was slightly higher with DM than with placebo. CONCLUSIONS: These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptors can ameliorate levodopa-associated dyskinesias.

PMID: 9674803 [PubMed - indexed for MEDLINE]

Amino Acids. 1998;14(1-3):75-82.

Blockade of glutamatergic transmission as treatment for dyskinesias and motor fluctuations in Parkinson’s disease.

Verhagen Metman L, Del Dotto P, Blanchet PJ, van den Munckhof P, Chase TN.

National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

In animal models of Parkinson’s disease (PD), glutamate antagonists diminish levodopa (LD)-associated motor fluctuations and dyskinesias. We sought to investigate if these preclinical observations can be extended to the human disease, by evaluating the effects of three non-competitive NMDA antagonists (dextrorphan, dextromethorphan and amantadine) on the motor response to LD in patients with advanced PD. In four separate trials, adjuvant therapy with these drugs reduced LD-induced dyskinesias and motor fluctuations. These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate LD associated motor response complications.

PMID: 9871445 [PubMed - indexed for MEDLINE]

These three reports of different aspects of the same work from 1998 indicate that there are, indeed, little known beneficial effects to be explored. This next report is much more recent and indicates that major positive effects are present at a low dose and that negative effects come into play at a slightly larger one. In other words, dosage is critical. Because our metabolisms differ this becomes very important and prevents standard doses. Trial and error is the only way. Too much will send one Off as serotonin production takes over, Too little will have no effect.

Indian J Exp Biol. 2007 Aug;45(8):712-9.

Effects of dextromethorphan on dopamine dependent behaviours in rats.

Gaikwad RV, Gaonkar RK, Jadhav SA, Thorat VM, Jadhav JH, Balsara JJ.

Department of Pharmacology, Krishna Institute of Medical Sciences, Karad 415 110, India.

Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.

PMID: 17877148 [PubMed - indexed for MEDLINE]

Update 11/11/09:

My improvements continue to hold but it does require paying close attention to dose and time. The company that gets this into a stable time-release formis going to make a bundle. I seem to be able to rely on a five and one-half hour period from first meds and 4 mg DXM at 6:00 AM. That includes a 30 to 60 min coming On period and ends with a 15 onset of Off as the system is cleared. This is without taking additional meds.

If I do continue with meds on my usual schedule, the DXM benefit from the single morning dose seems to last about 32 hours in my case. Remember that I seem to be a “slow” guy.

I still am vulnerable to going Off in the evening. I attribute that to being stubborn about taking additional meds to cover that period, but I am guarding against dyskinesia which lurks at the margins for me. I will deal with this in its own time.

I am adding silymarin back into my regimen due to the load on my liver in metabolizing the DXM. No problems other than suspicious bloating which I had before anyway. Presently, I am abstaining from other supplements to allow things to stabilize.