![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 17 of 17. This is the beginning of the thread.
Posted by PeterMartin on May 20, 2021, at 12:10:50
Linkadge (or anyone else w/ scientific knowledge):
I'm taking a relatively new medicine called Rybelsus (aka Semaglutide/Ozempic) for weight loss. It's a GLP-1 (glucose like protein) receptor agonist. This class of medication is relatively new (post-2010). Per some research it seems like there are GLP-1 receptors in the brain and the medication does cross the BBB.
I'm also taking methylphenidate and Marplan. I found this study that shows GLP-1 receptors can alter the way dopamine works in regards to Cocaine (stimulant).
I'm curious if based on this paper you think Semaglutide may change the way Methylphenidate works in the brain? Could it potentially make it more effective/less addictive?
Basically I'm hoping someone can read this and see if there may be a beneficial interaction between Ritalin & GLP-1 agonists like the one I'm taking. Thanks!!
https://www.sciencedirect.com/science/article/abs/pii/S0031938416312215
Highlights
Cocaine-evoked increases in dopamine signaling are greater in the NAc shell vs core.
Central GLP-1R activation suppresses phasic dopamine signaling in the NAc core.
GLP-1R effects are not due to alterations in dopamine reuptake.====
Abstract
Drugs of abuse increase the frequency and magnitude of brief (13 s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse.
Posted by linkadge on May 20, 2021, at 17:20:37
In reply to Attn: Linkadge(?) Can you elaborate on this study?, posted by PeterMartin on May 20, 2021, at 12:10:50
Let me read it over. I'll get back to you.
Linkadge
Posted by linkadge on May 20, 2021, at 17:42:00
In reply to Attn: Linkadge(?) Can you elaborate on this study?, posted by PeterMartin on May 20, 2021, at 12:10:50
So reading over the study, it seems that GLP-1 agonism *decreases* the release of dopamine in the nucleus accumbens that results from cocaine administration.
I.e. cocaine increases dopamine release in the nucleus accumbens and GLP-1 agonists (i.e. potentially Semaglutide) would reduce this.
As to whether it decreases the (possible) addictive effects of ritalin is unclear (but would seem logical). Ritalin also activates the reward system, but to a lesser extent than cocaine. The study suggested that the decrease was not due to effects on dopamine transporter binding (i.e. it is not directly counteracting the drug's effect). I would be interested to find out if GLP-1 agonists decrease dopamine release in other brain regions. If so, it may mean an overall decrease in the efficacy of ritalin (i.e. requiring a higher dose). However, I wouldn't necessarily assume that this would happen. Ritalin's actions are complex. Although dopamine plays a role in it's effects, it may have additional effects that go beyond increasing dopamine. Also, I wouldn't assume that Semaglutide is decreases overall dopamine function (unless a study indicated this).
If the decrease in dopamine release from Semaglutide was selective to the nucleus accumbens, then I would think that it could counteract some of the addictive potential of ritalin. That being said, some studies link ADHD to reward deficits (which ritalin may help counteract).
This being said, I wouldn't read into it too much. What happens on paper doesn't always directly translate to what occurs in real life. I would go based on your response to the medications. For example:
Do you notice any less ups / downs when taking ritalin?
Do you notice any loss of efficacy?
Linkadge
Posted by PeterMartin on May 20, 2021, at 21:53:50
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by linkadge on May 20, 2021, at 17:42:00
Thank you so much for looking that over and summarizing it in a way I could understand.
I've actually -just- started retaking Ritalin this week after a year off of it. So I don't have the best baseline to say if the effect has changed. Semaglutide is something I started taking 3 months ago so this is my first time taking Ritalin w/ it. I can't say I've noticed a difference so far.
I appreciate your reply very much.
Posted by Lamdage22 on May 21, 2021, at 2:21:18
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by PeterMartin on May 20, 2021, at 21:53:50
Are you losing weight?
Posted by undopaminergic on May 21, 2021, at 3:19:24
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by linkadge on May 20, 2021, at 17:42:00
>
> As to whether it decreases the (possible) addictive effects of ritalin is unclear (but would seem logical). Ritalin also activates the reward system, but to a lesser extent than cocaine.
>I'm not sure about that (lesser extent than cocaine). I think the difference may be attributed to the route of administration. Ie. cocaine is rarely taken orally. Injected methylphenidate has pretty much indistinguishable effects from cocaine, and the main difference is the shorter half-life of cocaine, meaning it's possible to re-dose it more freqently than methylphenidate and still get a high.
Cocaine is also a serotonin reuptake inhibitor, which means it would be expected to decrease dopamine release through increased agonism at serotonin 5-HT2C receptors.
> Ritalin's actions are complex.
Not as complex as those of cocaine.
> [Ritalin] may have additional effects that go beyond increasing dopamine.
Yes, it is also a noradrenaline reuptake inhibitor, like cocaine.
Does it also bind to other receptors/sites?
-undopaminergic
Posted by Petermartin on May 21, 2021, at 3:19:58
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by Lamdage22 on May 21, 2021, at 2:21:18
> Are you losing weight?
Absolutely. Very happy w this so far. Appetite is much reduced, and when I do eat I *feel* full 2/3 to 3/4 of the way through meals I'd chow down on before (like a 12oz steak and fries).
3/12/2021 - 232.1 (started on 3mg titrating dose)
5/20/2021 - 213.8 (this morning /2nd month on 7mg)So almost 20lbs. I really want to get under 200 then I'll be completely stoked. An almost year run of Topamax had me down to 204 in 2016 but gained it all back on Nardil/etc since then. 232 is the heaviest I've ever been and it was still creeping up every few months.
I'm pretty sure it'll be submitted to FDA for weight loss approval by the end of the year. Should be a game changer for many.
Posted by undopaminergic on May 21, 2021, at 3:28:31
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by Petermartin on May 21, 2021, at 3:19:58
The most effective appetite suppressant I've even tried was buprenorphine. But I took methylphenidate at the same time, and I'm pretty sure the combination is stronger.
-undopaminergic
Posted by Lamdage22 on May 21, 2021, at 3:58:31
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by Petermartin on May 21, 2021, at 3:19:58
Awesome. It sounds beneficial. And I surmise you eat healthier foods, too. Neuroleptics definitely cause me to not just eat high calorie foods, but also low nutrient foods.
> Absolutely. Very happy w this so far. Appetite is much reduced, and when I do eat I *feel* full 2/3 to 3/4 of the way through meals I'd chow down on before (like a 12oz steak and fries).
>
> 3/12/2021 - 232.1 (started on 3mg titrating dose)
> 5/20/2021 - 213.8 (this morning /2nd month on 7mg)
>
> So almost 20lbs. I really want to get under 200 then I'll be completely stoked. An almost year run of Topamax had me down to 204 in 2016 but gained it all back on Nardil/etc since then. 232 is the heaviest I've ever been and it was still creeping up every few months.
>
> I'm pretty sure it'll be submitted to FDA for weight loss approval by the end of the year. Should be a game changer for many.
Posted by rjlockhart37 on May 21, 2021, at 17:48:50
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by Lamdage22 on May 21, 2021, at 3:58:31
dextroamphetamine made me lose weight and keep it off, when i was on it, food was like a chore to do, i didnt want to eat...i lost weight, and i took it over a period of 12 hours, so full appitiete suppression and i lost....i got skinny that's all i can ssy. It was dexedrine spansules, 2 in morning 2 in afternoon, 12 hour coverage
Posted by Lamdage22 on May 21, 2021, at 21:38:07
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by Petermartin on May 21, 2021, at 3:19:58
They will make a few dollars with that if it turns out that way and proves to be effective for most people.
> I'm pretty sure it'll be submitted to FDA for weight loss approval by the end of the year. Should be a game changer for many.
Posted by linkadge on May 22, 2021, at 8:34:09
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by undopaminergic on May 21, 2021, at 3:19:24
I suppose it is a matter of dose, but the reason I say this is .....
At a similar of DAT inhibition, cocaine causes more dopamine release than ritalin. Some of this effect can be blocked by 5-ht1b receptor antagonists. When you add serotonin reuptake inhibition to ritalin, you get a greater degree of dopamine release, via stimulation of 5-ht1b receptors in the NAC. Cocaine is a triple reuptake inhibitor whereas ritalin does not have any effects on the serotonin transporter.
Also in studies on addiction related genes (i.e. intermediate early genes / cfos), you notice a much more significant activation with cocaine than ritalin. Interestingly, adding a serotonin reuptake inhibitor to ritalin produces a more 'cocaine like' profile in terms of activation of addiction pathways.
That being said, if you took a dose of ritalin that produced higher DAT inhibition, the effects could be more similar.
Linkadge
Posted by NKP on May 23, 2021, at 5:11:18
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study? » undopaminergic, posted by linkadge on May 22, 2021, at 8:34:09
> I suppose it is a matter of dose, but the reason I say this is .....
>
> At a similar of DAT inhibition, cocaine causes more dopamine release than ritalin. Some of this effect can be blocked by 5-ht1b receptor antagonists. When you add serotonin reuptake inhibition to ritalin, you get a greater degree of dopamine release, via stimulation of 5-ht1b receptors in the NAC. Cocaine is a triple reuptake inhibitor whereas ritalin does not have any effects on the serotonin transporter.
>
> Also in studies on addiction related genes (i.e. intermediate early genes / cfos), you notice a much more significant activation with cocaine than ritalin. Interestingly, adding a serotonin reuptake inhibitor to ritalin produces a more 'cocaine like' profile in terms of activation of addiction pathways.
>
> That being said, if you took a dose of ritalin that produced higher DAT inhibition, the effects could be more similar.
>
> Linkadge
>
>Does that mean that taking methylphenidate while on an SSRI might be more addictive than taking methylphenidate when not on an SSRI?
Posted by linkadge on May 23, 2021, at 12:33:35
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by NKP on May 23, 2021, at 5:11:18
In theory, yes this could be true.
I have not had a problem with taking them together. I have kept doses low, and have no compulsion to increase the dose. I've also come off of both fairly quickly without major issues.
Also, as I don't snort or inject either, so the rate of DAT occupancy is likely more gradual.However, I can't compare to cocaine, as I have never taken this.
Everybody's different however. Some people abuse benzodiazapines, but I never really saw why (they never gave me a buzz or anything).
Linkadge
Posted by undopaminergic on May 23, 2021, at 13:59:03
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study? » NKP, posted by linkadge on May 23, 2021, at 12:33:35
>
> I have not had a problem with taking them together. I have kept doses low, and have no compulsion to increase the dose. I've also come off of both fairly quickly without major issues.
>I sometimes had sleepiness/lethargy upon discontinuation of cocaine-like stimulants, lasting a day or two, but nothing like the prolonged aftermath of phenylethylamine (ampehtamine-like) abuse.
> Also, as I don't snort or inject either, so the rate of DAT occupancy is likely more gradual.
>I experimented with intranasal ethylphenidate [EPH] (very similar to methylphenidate [MPH]), but found it was too hard on the nose, and any improved high (I don't remember) was certainly not enough to be worth even occasional use through this route. Perhaps I had the free base of EPH, or a salt other than the HCl? Alternatively, EPH is more offensive to the nasal mucosa than MPH.
> Everybody's different however. Some people abuse benzodiazapines, but I never really saw why (they never gave me a buzz or anything).
>That is my experience too with benzos. I'm thinking that those people using them heavily and chronically are self-medicating for anxiety and/or other consequences of excessive stimulatory (such as from glutamate) neurotransmission. Then again, back when I did have anxiety, benzos didn't help. They worked for insomnia, but the quality of the sleep they induced was next to worthless.
-undopaminergic
Posted by sigismund on May 23, 2021, at 17:25:49
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by undopaminergic on May 23, 2021, at 13:59:03
>self-medicating for anxiety
Or fear.
Posted by linkadge on May 25, 2021, at 17:43:16
In reply to Re: Attn: Linkadge(?) Can you elaborate on this study?, posted by undopaminergic on May 23, 2021, at 13:59:03
I don't know too much about ethylphenidate (i.e. if it has any effects on the serotonin transporter). I never had any compulsion to increase the dose of methylphenidate. In fact, I am prescribed 20mg, but rarely go above 5mg.
For me, it does seem to have a normalizing effect on my thinking / attention as well as making me more interested in work / achieving goals.
Linkadge
This is the end of the thread.
Psycho-Babble Medication | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.