N&PD Moderators: Skorpio
Unsustainable drugs
rakketakke
Bluelighter
"The Abrupt Cessation of Therapeutically Administered Sodium Oxybate (GHB) Does Not Cause Withdrawal Symptoms. Clinical Toxicology. 2003, Vol. 41, No. 2 , Pages 131-135"
And tolerance doesn't build rapidly either then again it's so easy to go overboard nontheless so can't really dub it sustainable.
atara
Bluelighter
I think it's more revealing to look at the granularity at the level of the effect rather than the compound. You get tolerance to some effects very rapidly: respiratory depression first among these, but also euphoria, psychedelia, and sleep-induction[1]. Other effects, such as anorexia, analgesia, sedation, or indeed the focus-promoting effects of stimulants, tend to persist.
Unfortunately anxiolysis seems to be on that list of effects which doesn't stick around for very long, which leads to people taking monumental amounts of benzos just to function -- oh well, I'm sure we'll figure it out someday.
[1]: GHB seems to be the exception to this rule.
ebola?
Bluelight Crew
tweex said:
Yeah...well, I overused amphetamines on the combination and did not really cycle with tons of nootropics like you did. I can see why you haven't acquired tolerance (yet?) using the combination. At once a week dosing (when they really are single doses, not binging!), tolerance takes a really long time to catch up with people.
hammilton said:
This is actually a pretty ingenious idea for a functional homologue of a "'partially' agonistic reuptake inhibitor"
ebola
Hammilton
Bluelighter
Well we know that there are so called cocaine antagonists which bind to a site on the transporter which block cocaine from binding but don't block dopamine. I don't know if these drugs have an inhibitory effect on dopamine's binding, but I do know that they allow dopamine to bind simultaneously. They might actually fit this description already, but I'm not super familiar with them.
This link talks about it some, but it doesn't seem to acknowledge the existence of such compounds, which surprises me a bit, because I was pretty sure I'd read about some. It does mention rimcazole which blocks cocaine from binding to a degree at least.
Molpharm.aspetjournals.org%2Fcontent%2Fearly%2F2007%2F12%2F21%2Fmol.107.044586.1.full.pdf
I believe there's been significantly more work on this than this paper suggests.
I know that drugs like benzatropine bind to DAT without causing hyperactivity or addiction, and a number of more selective DAT ligands have been made based on it. I think many are non-addictive and may act as cocaine antagonists. It would be interesting to see if any of these merely reduce the affinity dopamine has for binding, increasing the extracellular concentration of dopamine at a much reduced rate.
ebola?
Bluelight Crew
So we can say that experiments suggest that a ligand of the sort that you hypothesized would be potentially viable, given that other allosteric modulators at monoamines are known.
...
Hmmm...we might also have an example of a 'sorta releaser', ie fencamfamine, which causes relatively muted monoaminergic release, augmented by activity as a reuptake inhibitor.
ebola0
Lightning-Nl
Bluelighter
Actually, that's exactly what Amphetamine does. It only partially blocks reuptake. Unlike direct inhibitors of transporter proteins (like Methylphenidate, or Cocaine) Amphetamine has no direct effects on the transporters themselves. Instead, it's believed that the way Amphetamine inhibits reuptake is through agonization of TAAR1
This receptor is believed to act as a type of autoreceptor for the monoamines. But, it has the opposite action of an autoreceptor. Instead, agonization of TAAR induces the proteins to actually carry hormones out of the uptake cells instead of carrying them in. I read a study recently that said Methylphenidate complete inhibited the reuptake of Dopamine and Norepinephrine (and to a lesser, insignificant exent - serotonin as well).
But the same study said that Amphetamine, while it does stop the reuptake of Monoamines, it's action on the uptake cells is quite different and instead of completely inhibiting transporter flow, it induces the opposite of uptake. This blocks hormones from being able to enter the cell because everything is moving out, not in. I'll look for the study ASAP.
Also, this sentence baffled me - "increases phosphorylation of the transporters". How can you "increase phosphorylation"? That doesn't even make sense. Something is either phosphorelates (phosphate has formed a complex with the molecule), or it isn't phosphorylated. Something can't be slightly phosphorylated. It either contains a phosphorous atom or it doesn't.
atara
Bluelighter
Ballz Trippington said:
This may be due to the fact that cannabis has a couple of active constituents, obviously CBD and THC, and maybe something else (who knows?).
More of the transport protein is phosphorylated -- there are several transporters on any DAT-expressing cell -- than would be otherwise. It's a population increase.
Lightning-Nl
Bluelighter
Hey guys, how sustainable is the med combo in on right now.
For ADHD - 10-40 milligrams of Amphetamine daily (usually only 30 milligrams. Sometimes 40 - taken throughout the day. Instant release Adderall, not extended)
Sleep latency issues - 10 milligrams Zolpidem daily (to put me to sleep - right before I go to bed)
Sleep sustainability issues and RLS - 30 milligrams of Temazepam daily (to keep me asleep. Treatment for RLS - about 30 minutes to 1 hour before I go to bed)
Panic attacks - 1 milligram of Lorazepam (PRN) for sudden, extreme attacks of anxiety (I usually have to take it once a week. Some weeks I don't need it at all, and some weeks I need it 3 days I a row. There's no set time I take this, it's as needed) I've noticed that since I've started the Temazepam, I haven't needed it at all in the past couple of weeks.
To decrease tolerance to Amphetamine, but it can help with benzo tolerance as well - 60 milligrams of Dextromethorphan daily (to decrease tolerance to the aforementioned drugs, taken the same time as the Temazepam)
Mood stabilizer and for pain associated with daytime RLS - 1200 milligrams of Gabapentin daily (600 milligrams with my morning Adderall dose, 600 milligrams halfway through the day)
Mood stabilizer for Bipolar Disorder - 50 - 100 milligrams of Lamotrigine sporadic trough the day (Lamotrigine works amazing for my mood issues. I REALLY want to be able to take it every day, but it gives me heart palpitations)
To help sleep on the nights when the aforementioned meds aren't doing it for me - 50 - 100 milligrams of Diphenhydramine (I use DPH on the nights I still can't sleep to stop myself from taking more benzo's)
Anyways, how sustainable is this? I imagine the Adderall/Lamotrigine/DXM/Gabapentin is a stable and viable long term med regiment. But I'm incredibly worried about the benzo's. What is everyone's recommendation on this?
ebola?
Bluelight Crew
swamp said:
This is wrong. Amp inhibits reuptake completely insofar as it is active in reversing transport, as a transporter reversed and undergoing efflux cannot take up its usual ligand. TAAR agonism elicits downstream effects only indirectly.
Can you please link the relevant study? This is the first that I've heard of the TAAR exerting such an effect.
...
I don't think that a daily regimen including amps and benzos will be indefinitely sustainable.
ebola
endotropic
Bluelight Crew
A couple of ways you can interpret that which make sense. Individual transporters can be phosphorylated multiple times at separate residues. Or consider that when someone talks about a protein in a physiological setting they're likely considering the entire pool of that protein throughout the entire brain, so something could increase phosphorylation by increasing the % of transporters that are phosphorylated vs. not.
I've heard that TAAR hypothesis, but it's definitely not a confirmed accepted mechanism.
I think using low dose d-amp daily as prescribed is probably fairly sustainable for attention/cognitive purposes no? As far as recreation definitely not though. Tolerance to the therapeutic effects of benzo's is pretty much inevitable though, and hard to reverse once it sets in.
It's also pretty irresponsible to add anxiolytic drugs to when you're already on an anxiogenic stimulant. I don't know your situation but it's usually better to cut out all anxiogenic influences before you start stacking anxiolytics.
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The_red_pill
Ex-Bluelighter
And then of course you have drugs like Ritalin, which rather than building a tolerance to (Tachyphylaxis) you can become sensitised to (Bradyphylaxis?)
People often say that the first time they smoked pot nothing happened, sometimes this happens with opioids too.
I personally (and I think other might agree) gave up pot because the side effects AND the effects were increasing as the years went by.
I could smoke countless bongs of hydro skunk when I was 18, by 23 it would take a quarter of a cone of crappy bush weed to make me uncomfortable stoned.
I think it is a good example of a unsustainable drug but for the opposite reason that you would expect.
http://en.wikipedia.org/wiki/Drug_sensitization#Sensitization
Lightning-Nl
Bluelighter
It actually is a confirmed mechanism. Many studies on the subject are currently cited on the Wikipedia "Amphetamine" article. I'd pull some for you, but my computer died on me today, and I'm still trying to find my files. Just one of those days I guess...
I disagree entirely.
I have ADHD and I have anxiety issues. How else do I treat that!? I've tried ALL other alternatives! Name any drug that's used as an anxiolytic, and I've been on it. Seriously! Doxepin, Mirtazepine, Hydroxazine, Seroquel, Risperdal, Abilify, Buspar!!! Holy fuck!! Even I can't believe it!!! NONE OF THEM HELPED! NONE! ZERO! NILL! I tried EVERY FUCKING ALTERNATIVE! Nothing fucking worked!!!
Also, I wasn't even on Adderall or any stimulant when I was trying all of these!!! All of them made my anxiety 10 times worse. They all had paradoxical effects on me. I would get extremely paranoid and very agitated. Do you have ANY idea what it's like to be SO tied that you can barely stay awake, but be so scared for your life that you have to FORCE yourself to stay awake?! Do you?! DO YOU HAVE ANY IDEA WHAT IT WAS LIKE TRYING TO STAY AWAKE ON 200 FUCKING MILLIGRAMS OF SEROQUEL!?!?!? There is no worse hell.
I DESERVE to be on benzo's. I DESERVE to be on Adderall! Interestingly enough, Adderall has paradoxical effects on me too!! It actuay ELIMINATES a TON of my anxiety, makes me the opposite of agitated and makes it so I can actually function like a human being!! But it doesn't help for sleep. That's why benzo's are TOTALLY APPROPRIATE for this situation.
Please do not make broad statements like that. You don't know everyone's situation and statements like that is what has caused my personal hell for the past 4 years.
The_red_pill
Ex-Bluelighter
And then of course you have drugs like Ritalin, which rather than building a tolerance to (Tachyphylaxis) you can become sensitised to (Bradyphylaxis?)
People often say that the first time they smoked pot nothing happened, sometimes this happens with opioids too.
I personally (and I think other might agree) gave up pot because the side effects AND the effects were increasing as the years went by.
I could smoke countless bongs of hydro skunk when I was 18, by 23 it would take a quarter of a cone of crappy bush weed to make me uncomfortable stoned.
I think it is a good example of a unsustainable drug but for the opposite reason that you would expect.
Not true. I am taking both Prazosin and Clomipramine for anxiety while being treated with Ritalin for ADHD. Interestingly, ritalin is very calming for the most part but tends to boost the anxiety when it is wearing off
endotropic
Bluelight Crew
That's your opinion, and that's fine. You probably could have stopped there though.
I'm glad you've found a regimen that works for you, but maybe you shouldn't post about it if you don't want to hear comments on it.
Lightning-Nl
Bluelighter
Yeah, I should have.
I get emotionally impulsive. Especially when something pisses me off. I usually have good control over it, but not with things that have been traumatic for me. I have Post-Traumatic Stress Disorder that's been induce by the same system that was supposed to help me with PTSD. This evil "doctor" (I put that in quotes because she wasn't a doctor, and she wasn't someone who was helping me).
She told me that I was a drug addict (when I'd only ever tried pot a couple times), told me that all my symptoms weren't real and that it was all in my head, and that I was the one who was wrong and that she was right. At this point, I already knew tons about Pharmacology and she was threatened by that.
She forced me to be on meds on that made things worse. She made me feel worthless and awful and the worst part was, I couldn't change doctors! She told EVERYONE that I was just drug seeking (when I never once asked her for any drug), and told them that she better keep treating me, or else.
I feel in danger anytime I hear anything that would have been remotely like something she would have said. I live in fear of having to go back to a doctor like her ever again.
Rorthron
Bluelighter
I'm surprised no one mentioned DMT. There is no tolerance build up with Ayahuasca. In several DMT churches people are taking Ayahuasca - not daily but on a weekly basis at least - for decades of continuous use. Everyone is hit the same way, no matter how long one has been taking it. What changes is how we consciously adapt to the altered state and are able to function and react. I've been a member of the Santo Daime Church, so I know as a fact that this happens.
DMT is a real sustainable drug.
Lightning-Nl
Bluelighter
I highly doubt that.
I'm not trying to put down a religion, or deny your feelings, however, Serotonin downregulation in response to increased Serotonergic activity would make this a very unsustainable drug, especially in the long term.
Help?!?!
Bluelighter
Actually I found that not to be so. DMT only forms tolerance rapidly but then seems to decline fairly rapidly as well. I vaped DMT daily for a long portion of time and there was never a need to increase the dose really, though I only did it about once everyday.
babylonboy
Bluelighter
I think this is the effect of a psychological phenomenon in which familiarity with a psychoactive sensitises, or, perhaps it is better to say, facilitates recognition of its subjective effects. I'm sure we've all seen (or been) the naive teenage drinker loudly slurring "I'm not drunk, I can't feel anything, I need more", whereas, as a drinker of ten years, I can now distinguish the effect of half a pint of beer or less. Similarly, opioids and stimulants can be subtle in a way initially, one learns the high over time. Sensitisation does occur, of course, but we need to be careful (always!) to remember the role that consciousness plays in the way we experience drugs.