• N&PD Moderators: Skorpio | thegreenhand

  • Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

What is the recreational mechanism of brivaracetam?

?

...

Bluelighter
Joined
Dec 29, 2010
Messages
485
Brivaracetam is a new anti-epileptic drug that has been placed on schedule V in the US. As such, it is the first illegal racetam. According to the DEA's scheduling action:

Human studies have
reported that healthy individuals may
experience euphoria, sedation, and a
drunken-like feeling following BRV
administration... In a human
abuse potential study, the oral abuse
potential, safety, tolerability, and
pharmacokinetics of BRV (50 mg, 200
mg, and 1000 mg) were compared to 1.5
and 3.0 mg of the schedule IV CNS
depressant alprazolam (ALP) and
placebo. When surveyed, for all doses of
BRV, there was an increase of drug
likability, feeling of a high, and taking
the drug again in comparison to
placebo. The HHS mentioned that
individuals who took BRV had fewer
sedative, euphoric, stimulant, dizziness,
and overall negative subjective effects
compared to ALP.
Click to expand...

https://www.gpo.gov/fdsys/pkg/FR-2016-05-12/pdf/2016-11245.pdf
Page 3

My question is why does this happen. It seems to be just a more potent levetiracetam analogue, and its purported mechanism is a little confusing to me:

BRV
selectively binds with high affinity to
synaptic vesicle protein 2A (SV2A). It
produces reverse inhibition caused by
negative modulators of gamma
aminobutyric acid (GABA) and glycine
and inhibits sodium (Na+) channels.
These sites appear to underlie
pharmacological activity of BRV.
Click to expand...

What is meant by "reverse inhibition" here?
 
synaptic vesicle protein 2A (SV2A

is ( please excuse the italics I don't know how to turn it off...) is what the prescription anticonvulsant levetiracetam works on...) inhibits works on, inhibits presynaptic calcium channels. It has been shown that deletion of the gene for these proteins causes intractible seizures in rats that cause instant death...

Another example of the DEA's retardation and sheer fucking stupidity in scheduling substances as controlled substances. They should go back and control Keppra not.

Just like they controlled Vimpat...

Now they need to go back and control Tegretol and Trileptal
 
Reversing inhibition of GABA, means it has an agonizing effect. It may not be an agonist itself, but it increases the activity of GABA through reversing inhibition. This agonist like action is apparently enough like a benzo to cause redosing in humans.
 
shugenja said:
Reversing inhibition of GABA, means it has an agonizing effect. It may not be an agonist itself, but it increases the activity of GABA through reversing inhibition. This agonist like action is apparently enough like a benzo to cause redosing in humans.
Click to expand...

Is there an endogenous GABA inhibitor?
 
They call one DBI (diazepam binding ing\hibitor) You can read it in the study Do the intrinsic actions of benzodiazepine receptor antagonists imply the existence of an endogenous ligand for benzodiazepine receptors?

by SE File and SE PILe from this book:

https://www.amazon.com/Gabaergic-Tr...eywords=gabaergic+trasmission+and+and+anxiety

Niacinamide is also believed to be an endogenous ligand that can inhibit ccertain drugs, if that is an intended effec
 
Kainate and glutamate inhibit GABA via presynaptic GRIK 1 receptors. These are the target/main sites of action for the anticonvulsant drug topiramate (Topamax), which increase the amount of GABA via GRIK 1 inhibition.
 
It occurs to me that increasing GABA does not neatly equate to abuse potential. Examples: topiramate, vigabatrin, tiagabine.
 
That is true. Only drugs affecting GABAergic terminals that are coupled with dopaminergic activity have abuse potential. Valproic acid is also a GAT inhibitor, like tiagabine, and lacks abuse potential.

Topiramate is also an AMPA antagonist and produces dissociative effects similar to the perampanel (fycompa) yet it lacks abuse potential.
 
... said:
It occurs to me that increasing GABA does not neatly equate to abuse potential. Examples: topiramate, vigabatrin, tiagabine.
Click to expand...


True, reduction of GABA Transaminase also increases circulating GABA.

Lemon Balm inhibits GABA Transaminase, although I have yet to see the Lemon Balm Tea junkies lining up for a fix. lol

NOTE: Lemon Balm is a very useful herb during Benzodiazepine taper/withdrawal
 
Oh I don#'t know about that sugenja, they just havent had it in the correct tea. Although even sans C.sinensis its great stuff, can drink it by the jug full in the heat of summer, 'tis very refreshing.

And try it in a good delicately flavoured white tea sometime, with a bit of honey if you like it sweetened.You won't be sorry.
 
I'd like to try a properly selective, potent GABA-T inhibitor though. If you look on erowid theres quite a lot of reports of tiagabine use actually. SOME of them went nasty, but these seemed like quite large overdoses. I cant help but wonder if they have something in common 'flavor' wise with orthosteric agonists at GABAa like muscimol. Vigabatrin is definitely a drug to shun however, as its pretty severely ocularly toxic, and around high 40s to 50% of users of the drug develop a reduction in visual field and acuity.

GABAcR mediated?
 
Tiagabine exhibits all of those so called nasty effects via GABA T inhibition and subsequent indirect GABA A and GABA B activation, other unapproved GABA T inhibitors share similar side effect profiles, which is why they never make it to market.

They are all have psychotomimetic and manic side effects, typical of GABA A and GABA B activation, at supra thereapeutic dosages
 
theGirlWithBlueHair said:
That is true. Only drugs affecting GABAergic terminals that are coupled with dopaminergic activity have abuse potential. Valproic acid is also a GAT inhibitor, like tiagabine, and lacks abuse potential.

Topiramate is also an AMPA antagonist and produces dissociative effects similar to the perampanel (fycompa) yet it lacks abuse potential.
Click to expand...

Does this also explain the relative difference in opioids' tendencies to produce euphoria? The most euphoric and abusable opioids being the ones agonizing MOR coupled with dopaminergic activity (especially in the reward circuit)?
So are the coupled receptors by definition slightly differently shaped because of conformation changing from coupling? Or are they also different polymorphs to begin with.. (mutated)
 
All MOR produce euphoria by acting on GABAergic interneurons, rather than dopamine activity directly. And they all produce this effect upon activation. What benzodiazepines do is typical of their activity at the alpha-1 BZD site, which is known as a site of high drug addiction activity and this is why:

https://www.drugabuse.gov/news-even...nderlies-benzodiazepines-addictive-properties

However, all mu opioid receptors are coupled to this activity in the VTA, just as all the alpha-1 BZD subunit GABA A receptors are. The coupled receptors are coupled this way to begin with.

It is not to say these GABAergics don't have abuse potential!! They most definitely do! They just don't produce that strong, euphoric rush. Read up on GAT inhibitors. They are well known for producing z-drug, and muscimol, type pshycotomimetic - yet GHB, baclofen-type manicness - in high dosages.

And topiramate is dissociative as and hallucinogenic as all hell. It's GABA A PAM effects and GRIK 1 antagonism just cause intense amnesia and alzeheimer's-like effects. And valproate just isn't worth the risk to find ut.
 
Then, the euphoria potential of an opioid depends on its efficacy at MOR but without affecting the attenuating KOR? Can you predict the euphoric potential of an opioid knowing its efficacy on MOR and KOR?

I'm not trying to find the most potent opioid or something like that, but this is being discussed in a fentanyl topic here in NSP (someone claimed potency is related to euphoria), and understanding this would be elucidating..

(Thanks for the explanation on interneurons, by the way - very insightful.. I do hope they can design benzos that are effective while avoiding alpha1.... but I thought I remember a1 being responsible for hypnotic effects and a2 for anxiolysis while a5 is associated with dependency... so that is confusing, you mention the z-drugs - I thought they were selective for a1 so you would expect them to have relatively very high abuse potential and also euphoria??)
 
The KOR would affect its efficacy at the MOR, by antagonizing it. But remember oxycodone, which many people really like, which is mainly a kappa opioid antagonists, but many of them are powerful delta opioid antagonists, whose effects are somewhat unclear...

And then they can have significant affinity for sigma receptors as well, which can contribute to euphoria.

No you can never predict its euphoric/abuse liability knowing its dissociative constant/EC/IC 50 at the receptors.

Take oxycodone for example, which is kappa opioid preferring over mu.

lol, it wouldn't matter if you were trying to find the most potent opioid, would it?
 
Sorry not "most potent", meant "most euphoric"...
Just meant to say this is not a simple-minded attempt to get highest as f possible.. :)
As a reason to hijack this thread, that would have seemed more terrible than the more relevant reason I mentioned.

If KOR agonism counters euphoria produced by MOR, wouldn't KOR antagonism be consistent with potentiation of euphoria? That KOR is preferred over MOR wouldn't really matter for that very reason?

I appreciate that prediction is very difficult because of the many complicating factors, but it would be a little different if very selective agents were used (also in conjuction) to map which mechanisms are additive and which are attenuating?

Anyway, knowing more about what contributes is already helpful - also it is clearer if MOR is the major contributor... and I wonder how drugs like diamorphine and fentanyl fit this picture.

Back to GABAergics and racetams then I guess?
 
You must log in or register to reply here.
Top