Ecopipam and Dr. Ondo.

Can anyone spot the flaw in his reasoning? See last 6 paragraphs after his name in center. As far as I can tell Ecopipam’s closest cousin is cannabis, but that’s neither here nor there

New Study Will Test Treatment for Augmentation

The RLS Foundation Research Grant Program has awarded $37,000 to William G. Ondo, MD, of Houston Methodist Neurological Institute, to explore a potential treatment for augmentation. The study “Treatment of RLS Augmentation with Ecopipam, a D1 Specific Antagonist” will evaluate the drug ecopipam in reversing the symptoms of augmentation, a common side effect of dopamine medications taken for RLS. Dr. Ondo is director of the RLS Quality Care Center at Houston Methodist, and a member of the RLS Foundation Scientific and Medical Advisory Board.

“Dr. Ondo’s proposal presents an exciting opportunity to investigate a new approach to treat RLS augmentation,” says RLS Foundation Executive Director Karla Dzienkowski, RN, BSN. “As the only organization with a dedicated RLS research grant program, it is our hope that research like Dr. Ondo’s will lead to new and better treatments and one day, a cure for patients living with RLS.”

William Ondo, MD

Summary:“Treatment of RLS Augmentation with Ecopipam, a D1 Specific Antagonist”

Dopamine and dopamine agonists (medicines that mimic dopamine) can dramatically treat RLS and periodic limb movements in sleep (PLMS). However, chronic use often results in augmentation, a condition manifested by earlier onset and intensification of the original RLS symptoms. Understanding and eliminating augmentation is arguably the greatest practical problem in RLS management.

The mechanisms by which dopaminergics actually treat RLS are not entirely understood. First, dopamine and dopamine agonists react with at least five different dopamine receptors, which can do very different things depending on their type and location. In fact, in several known systems, the D2/3 types seem to do the exact opposite of the D1 type.

Based on clinical and basic science information, our team and others have speculated that stimulation of dopamine D2/3 receptors in the spinal cord treats RLS symptoms. The main dopaminergic RLS medications (pramipexole, ropinirole, rotigotine and L-dopa) all mostly stimulate D2/3 receptors, but also stimulate D1 receptors to a lesser degree, especially L-dopa.

We previously developed an animal model of RLS in mice and rats. This model consists of iron deprivation, and destruction of the dopaminergic neurons that descend into the spinal cord, where they interact with both D1 subtype and D2/D3 type receptors. These animals showed markedly increased activity consistent with RLS, although they could not tell us if they had RLS sensations. Importantly, the symptoms improved with the D2/3 drugs to treat RLS, such as pramipexole and ropinirole, but also dramatically worsened with a drug that specifically stimulates D1 receptors. No such drug is available for human use.

In later experiments, we tried to identify underlying mechanisms of augmentation by treating some of these modeled mice chronically with the dopamine agonist pramipexole. The main change over time

was that treatment increased spinal cord affinity (efficiency) of the D1 receptors (which seem to worsen RLS symptoms in the model). There was also a mild reduction in D3 receptor density over time. Therefore, our hypothesis for augmentation is that over time, the ratio of the “bad” D1 receptors to “good” D2/3 receptors increases, thus causing the chaotic condition where the same drug both treats and worsens the condition. In turn, based on this theory, if you could block the stimulation of the D1 receptors and keep the D2/3 stimulation, you could have benefit similar to when the medicine was first started.

Unfortunately, there are very few medicines that specifically block D1 receptors without also blocking D2/3 receptors. In fact, only one such drug has ever been tested in humans: ecopipam (owned by Psyadon Pharmaceuticals), an investigational D1-specific blocker. The drug has been tested in more than 1,000 people with Tourette’s syndrome, obesity, schizophrenia, cocaine dependency, Lesch-Nyhan syndrome, and diabetes mellitus. It is currently undergoing studies in Tourette’s. The safety profile has been good, with sedation the most common side effect (potentially desirable in people who have RLS).

We will be conducting a small, short study of ecopipam in RLS patients currently taking only dopamine agonists – pramipexole (Mirapex), ropinirole (Requip) or rotigotine (Neupro) – who initially had good benefit but now have augmentation. Other RLS drugs will not be allowed in the study. Participants will add either ecopipam or placebo for six weeks to their current dopamine drug. Participants will then “cross over” to the other arm (placebo or ecopipam) for another six weeks, so that everyone will get both ecopipam and placebo at some point in the study. Neither the patient nor the physician will know which group they are in, to avoid bias. Overall, there will be six visits in Houston over about 14 weeks. We will assess a number of RLS and augmentation scales to determine if the medicine helps augmented RLS. Based on the results of this “exploratory” study, funded by the RLS Foundation, other larger studies might follow.

EDIT: Google Ondo and YouTube. It’s an hour long but about 24 minutes in there are brain images of a Parkinson patient, one with RLS and normal. It’s clear that the Parkinson patient has way too much iron compared to control. We have a black hole where there should be at least a little iron. Watch for about another two minutes. Very interesting.

[Joolsg]

I have just sent a reply to Lana about a very similar trial at East Carolina University by Prof. Stefan Clements. He's doing trials on a drug to stop the D1 receptors over reacting. I suspect it's ecopipam.

[Hidden in reply to Joolsg]

Will take a peek at that. Stopping the D1s from overreacting is great in the short term. Beyond great, because it sounds like the D1s are truly what causes augmentation. But in the long run blocking them will only up-regulate them even more than they are already up-regulated from the Prami alone. A double whammy. If Ecopipam is like it's cousin Cannabis it might offer a modicum of relief and buy you some more time on the DAs without substantially worsening the eventual augmentation. So I guess if that's the case then why not. I believe the Ecopipam is a delay tactic and who doesn't want to delay augmentation.

[Hidden in reply to Joolsg]

I found Dr. Clemens' patent application. uspto.report/patent/app/201...

Same thing as Dr. Ondo..... A D1 Antagonist. These two are either dumb as doorknobs or it's all about the $$$. Or if someone can explain to me how antagonizing the "bad" D1s (as Dr. Ondo calls them) will NOT, in the long run, make them ever bigger, I'll retract my statement.

Agonizing the D1s (which is what we really need to do, not antagonize them) will make them smaller, however painful a process as that may be. Painful because you're provoking the bad D1s to release an excitatory signal, that most likely will make your legs go crazy, however briefly and in the short run, but should shrink them (yay) in the long run. No pain, no gain. Remember, the dopamine AGONISTS make our D2 receptors release a calming signal and in the process make them smaller. And as we NOW know (while allegedly unbeknownst to the drug makers), the DAs were not only making the calming D2/D3s smaller, but was also simultaneously up-regulating the "bad" D1s and that is what truly led us to augmentation hell and probably DAWS. So by agonizing the D1s (as opposed to the D1 Antagonist named in the patent) we will shrink them, and who knows, maybe build up our pathetic D2s a little bit in the process, god forbid. The point here, as I see it, is that we really need to get the "bad" D1s back to baseline, as quickly as possible, and end the augmentation and/or withdrawal hell.

The D1 receptors are the most abundant type in the CNS and possibly the rest of the body. Berberine, which I've been taking, is a natural D1 Agonist. I've taken it by itself for months at a time over the years trying to modulate my gut microbiome because supposedly it's a great antimicrobial and mostly inhibits the pathogenic bacteria and not your friendly flora. That's a big supposedly. I never noticed any symptoms related to the taking of it by itself. I might as well have been taking oat bran. Now I've been taking it with a flavonoid to make it more bioavailable. I took it in the afternoon at first and couldn't figure out why my RLS had taken a turn for the worse. Just like I didn't realize about the melatonin. When I take it in the morning I feel wired, in an uncomfortable way, and I pee and poop more, also not in a good way. And the RLS still seems slightly ramped up, even though berberine has a short half life. I guess it's not nice to fool mother nature and yet I feel as though this might be the way to go if you're augmenting on the DAs.

That's what makes Neupro a superior DA in my opinion. It does a little agonizing at the D1 receptor site, in addition to a lot of agonizing at the D2/D3 receptor site. So probably less bang for your buck in the short run, but better in the long run. If I understand the way buprenorphine works, it too agonizes at the D1 receptor site, and for that reason is called a partial agonist. I think it's also "partial" at the opiate receptor sites as well, however, I would have to teach myself about that whole system before I can speak. onlinelibrary.wiley.com/doi...

europepmc.org/article/MED/2...

The important thing to remember is that a D1 antagonist will further up-regulate the "bad" (Dr. Ondo's term) D1s, as it provides short term relief, at best, to those augmenting on DAs. So not worth it in my opinion, but these guys will be retired and sipping pina coladas on some island paradise by the time the world catches on.

[WideBody]

I am so lost, this stuff is so far over my head, I can't see anymore.

When you get it figured out, or at least can point me in the right direction. Low-glutamate diet? Obviously gabapentin and pregabalin, but the method of action is not really understood.

I would really like to understand this stuff, but I am really more concerned with making my RLS go away.

BTW, last night was AMAZING, I had a really long day. I had zero RLS when I went to bed and I slept like a baby, even overslept this morning. Today is gonna be a good day.