'Antidotes' for OD situations.

[MaDMAn_Project]

Most drugs have significant adrenoceptor agonist properties, making available high affinity andrenoceptor antagonists for use in people who are already in a crisis state is potentially fatal.

 

[MagickalKat777]

yeah but you seem to report a lot of incidents where drugs didn't work for you that clearly have for others. either you are different (very possible) or you're talking nonsense, who knows really?:D

xanax for me made speed feel like mdma in terms of euphoric relaxation and loved upness. i would imagine that benzo's work well for other stim abuse comedown situations (they are great for coming down from coke). zoplicone was a godsend for me after a methylone binge, same after using mdma and amt, also it was great for coming down from mdpv.

all in all benzo's/zdrugs are essential if you have overdone hard stimulants

Well the only thing that gets me through cannabinoid induced panic is food and time. I have a number of friends that are the same way.

Xanax was great for stim come downs. I've found Valium to even be superior to Xanax for this purpose - and no rebound anxiety.

My reactions to a number of drugs probably has to do with dose. I tend to take higher doses of things than most people - a lot of drugs that people find unpleasant - they're taking less than a quarter of what I am taking. When I party, I party hard.

The irony of the situation is that it only takes a single medium sized hit of med grade cannabis to put me in full-blown panic mode but I can suck down 2g of methylone in a night and just have an uncomfortable speediness going on which some good old JD or Valium knocks right out.

 

[fryingsquirrel]

IDK about an overdose situation, but seraquel will stop a meth high in it's tracks.

 

[Hammilton]

To block a stimulant (cocaine, meth) you can't just antagonize the receptor the drug is binding to. I don't know a ton about how transporters work, but I don't believe they can be antagonized in the same fashion as GPCRs. I do know that there has been some work on DAT ligands that bind to a site adjacent and nonidentical to the site occupied by DA. The thought is that you get a drug that can bind and still allow dopamine to be transported you can mostly block the effect of the antagonist (DARIs can be thought of as DAT antagonists in that they prevent the transport of the natural ligand).

 

[SugarTorch]

Removing drugs from their known receptors

Hi,
I think that pharmaceutical companies would indeed develop & manufacture antidotes for common drugs of abuse if it were possible to do so for substances like methamphetamine and cocaine. The exact mechanism of how cocaine increases dopamine isn't known; and as Madman said, there is significant adrenal stimulation and thus epinephrine, norepinephrine etc going to alpha and beta receptors all over your body with stimulant use. So for stimulant toxicity you just treat the effects that are most likely to kill you, i.e., try to reverse hypertension and fast heart rate with alpha-and beta-blocking drugs like clonidine and metoprolol. Similarly, with drugs whose synergy or OD causes "serotonin syndrome," it's not known how to displace those substances from the receptors where they inhibit serotonin reuptake. The drugs with the highest incidence of OD mortality are opiates, acetaminophen and then benzos/cocaine, and known antidotes exist for all those except coke. The way that naloxone prevents death from opiate OD is this: the degree of removal of the drug from the mu receptor is directly proportional to the naloxone dose. So one only has to get enough naloxone to reverse respiratory depression, in most cases, because it's apnea that's going to kill you. Opiates aren't really cardiotoxic and they don't have toxic metabolites. Benzos rarely kill people except when combined with other CNS depressants (which they usually are). So the treatment is usually "supportive" (i.e. a ventilator) because reversing benzos means no ability to treat seizures, as someone said previously. In my experience, Ativan and Haldol effectively reduce severe discomfort from meth or cocaine OD, and antihypertensives help mitigate the extreme sympathomimetic stimulation. (however Haldol does lower seizure threshold.) Anyone remember Thorazine for bad LSD trips? Who knows if that works. Lots of fluids helps renal excretion of most drugs. Also, keeping your body temp down is important for serotonin syndrome and stimulant OD. Oh BTW, naloxone also reverses DXM OD, if anyone's interested.
If anyone out there's taking tricyclic antidepressants, those are some of the most cardiotoxic drugs on the market, and there's no antidote. So experiment conservatively.

 

[23536]

(don't remember who said this; no source given either)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1474217/?tool=pubmed

And yeah, I don't like weed for precisely this reason.

Are full agonists more anxiogenic than weed? Should be if that hypothesis is correct.

 

[Hammilton]

The drugs with the highest incidence of OD mortality are opiates, acetaminophen and then benzos/cocaine, and known antidotes exist for all those except coke

There's not exactly an "antidote" for APAP poisoning... NAC is certainly useful, but it can't hardly be called an antidote for our purposes here. The question isn't how you can limit damage done to your body, it's how to stop the drug's effect entirely, blocking it form accessing the receptor. That's not what NAC does at all. It helps your body replenish glutathione, in turn allowing more NAPQI to be conjugated with glutathione and limiting NAPQI's ability to damage the liver.

So the treatment is usually "supportive" (i.e. a ventilator) because reversing benzos means no ability to treat seizures, as someone said previously.

That's not true, though. If there's a benzo OD flumazenil will certainly be used. It's nonsense to say that just because you administered flumazenil you can't treat seizures. There are dozens of other non-Benzo drugs that are still capable and effective AEDs. There are the obvious non-GABAergic sodium channel-ergic )) drugs which are effective, but most GABAergics will still be perfectly effective- barbiturates are the most obvious, of course, and can be used very carefully.

There's a barbiturate antagonist even, called bemegride, though I don't know much about it.

The exact mechanism of how cocaine increases dopamine isn't known

Of course it is. It's an inhibitor of the dopamine transporter, causing dopamine to pool in the synapse.

 

[Hyperthesis]

Are full agonists more anxiogenic than weed?

Definitely!!!

 

[SugarTorch]

Definition of an Antidote?

So Hammilton, what you really are looking for are receptor antagonists to the used substance? And if a treatment or therapy isn't a receptor antagonist, it's not a true antidote? I found this article:

Nature Neuroscience 11, 780 - 789 (2008)
Published online: 22 June 2008 | doi:10.1038/nn.2146

The binding sites for cocaine and dopamine in the dopamine transporter overlap
Thijs Beuming1, Julie Kniazeff2, Marianne L Bergmann2, Lei Shi1,3, Luis Gracia1, Klaudia Raniszewska2, Amy Hauck Newman4, Jonathan A Javitch5, Harel Weinstein1,3, Ulrik Gether2 & Claus J Loland2

This article proposes a model of where, on the DAT, the cocaine receptor lies and says that it "overlaps" with the binding sites for amphetamine and dopamine... which means that there may not be a cocaine-specific receptor, thus no cocaine-specific antagonist, see?
I agree it would be neat and tidy to be able to displace any drug from all its receptors, or specific receptors, when the effects were unwanted or harmful. However, I am arguing that complete antagonism of opiates and benzos with naloxone and flumazenil in many OD situations is undesirable and unwise because of precipitation of withdrawal, which can be more life-threatening than the OD. Abrupt withdrawal of benzos with flumazenil can cause seizures. Yes, you can treat seizures with phenobarb, dilantin and even magnesium, but for status seizures (probably combined with vomiting, since you gave them all that narcan too) the fastest most effective treatment is IV lorazepam or diazepam, and you want to have that available to you. Further, most ODs are polypharm ODs, so when you antagonize one substance, the effects of the others will still be present, and the person treating you might not know all that stuff you took. What if you give narcan to a "known" IV drug user who did heroin/cocaine speedballs? The cocaine toxicity is potentiated because you removed the CNS-depressant effects of the opiate. Or give flumazenil to the Valium OD who also drank a lot of ETOH... you still have a really drunk, sick person who is now puking & seizing...
What I'm saying is that it may be safer to treat the (most lethal) effects of the drug and speed up the metabolism/excretion of it as well, if possible. Antagonists are not benign. We are talking about harm reduction here, right?

 

[23536]

I thought Hammilton was talking about an allosteric ligand which would block cocaine from binding but not interfere with the uptake of dopamine.

And if a treatment or therapy isn't a receptor antagonist, it's not a true antidote?

there are antidotes that aren't receptor antagonists. Protamine sulfate is a heparin antidote because it binds to heparin itself (heparin is such a cool molecule: the most electronegative biological molecule known).

This article proposes a model of where, on the DAT, the cocaine receptor lies and says that it "overlaps" with the binding sites for amphetamine and dopamine... which means that there may not be a cocaine-specific receptor, thus no cocaine-specific antagonist

"overlap" implies that cocaine gets in the way of dopamine, inhibiting its uptake

 

[Hammilton]

So Hammilton, what you really are looking for are receptor antagonists to the used substance? And if a treatment or therapy isn't a receptor antagonist, it's not a true antidote? I found this article:

I'm not looking for anything, the OP asked about antidotes that can completely reverse the OD. Supportive treatment is hardly an antidote. If that were the case you might as well describe a surgeon as the antidote for brain tumors.

This article proposes a model of where, on the DAT, the cocaine receptor lies and says that it "overlaps" with the binding sites for amphetamine and dopamine... which means that there may not be a cocaine-specific receptor, thus no cocaine-specific antagonist

You obviously haven't read much about this issue and don't understand it very fully. For one, when you say "receptor" are you referring to the binding site or an actual specific receptor? I don't know that you can even really consider DAT a receptor...

Anyway, you don't understand the implications of that article at all. That article indicates that there very well may be a cocaine-specific antagonist. It means that part of the cocaine's binding site is distinct from that of DAT. That means we can probably find a ligand that can bind in such a way that it overlaps cocaine's binding site but does not block access to the DA site, thus allowing the transporter to continue transporting DA.

I'd have to find that giant cocaine analogues paper- I'm pretty sure they found DAT ligands with high affinity but very low efficacy at increasing extracellular DA concentrations which is exactly what you'd want for a "cocaine antagonist."

You must understand, though, that cocaine is very different than most of the other drugs we're talking about. It's not binding to a GPCR or LGIC, but a transporter. It's completely different.

Or give flumazenil to the Valium OD who also drank a lot of ETOH... you still have a really drunk, sick person who is now puking & seizing...
What I'm saying is that it may be safer to treat the (most lethal) effects of the drug and speed up the metabolism/excretion of it as well, if possible. Antagonists are not benign. We are talking about harm reduction here, right?

You're talking about harm reduction from the harm a drug that blocks a recreational drug? The antidote itself is harm reduction.

I'm trying to see how effective flumazenil is at blocking ethanol intoxication, but the bit on it causing a Valium / Ethanol OD to start seizing while remaining drunk is silly. For one, flumazenil doesn't ordinarily cause seizures in people who are not physically dependent on a benzo. Ethanol itself blocks seizures.

The scenarios you're presenting become more and more outlandish.

Besides, this isn't OD or BDD, most of the material in this thread already doesn't really belong here- there's nothing advanced about it. The discussion of what drugs can block a recreational drug at the receptor level, and/or how new "antidote" drugs for previously non-antidotable compounds (like cocaine) certainly makes much more sense for a discussion here.

 

[negrogesic]

A well staffed war-chest of vials and autoinjectors, and an LVN girlfriend who at least vaguely knows what you are up to..........

 

[SugarTorch]

Antidotes

A well staffed war-chest of vials and autoinjectors, and an LVN girlfriend who at least vaguely knows what you are up to..........

What is your opinion of the clinical usefulness of naloxone? Flumazenil? Ever have disastrous results with either?

 

[atara]

We know that benzos are fairly effective at helping with a psychedelic overdose, and as far as I'm aware they can also be used for stim overdoses.
How come we don't have full antagonists widely available for these drugs?

Opioid overdose is kind of simple: you block the mu-opioid receptor and the patient starts breathing again.

Psychedelic pharmacology is complex. DMT affects around thirteen different receptors, as well as the serotonin transporter. MDMA releases all sorts of monoamines. AMT does everything MDMA does plus binding to a whole lot of serotonin receptors.

Benzodiazepines are the AK-47 of overdose situations. They work for all of these weird drugs we keep inventing, and then some.

The exception is muscimol and other GABA-A agonist deliriants -- an overdose on these should absolutely not be treated with benzodiazepines, as they will likely make it worse! I don't know how muscimol overdoses are treated. Probably by calling the coroner. There are direct GABA antagonists, but arriving at an appropriate dosage is likely impossible.

 

[fluxy]

i've found zyprexa (atypical antipsychotic) stops any psychedelic experience dead in its tracks with no side effects other that sedation. Benzos just seem to take the edge off. I imagine it would work for stimulants to because it is an antagonist at many dopamine receptors too.

Illhave to make some injectable olanzapine for emergencies. I know naloxone works for DXM (amazingly so, the ambos gave it to me once and i was instanbtly straight until it wore off.)

Onew question though, if you go to sleep after taking the olanzapine, are you still tripping in your induced sleep? Ever since that happened to me ive been wary. i hope someone else doesnt make the same mistake, so this is what happened.

It goes like this,

1) you know your defenitely concious, and have no idea how you got to the place you find yourself in. (in my case a black void, surrounded by some rings so i couldnt move)

2) You cant seem to wake up because of the usually high dose of whatever you took to knock you out of your bad trip

3) there seems to be no way out of this place, no doors.

4) You start drawing some pretty terrible conclusions from this that are much scarier than a bad trip i assure you. If you were a religious person, you would be convinced you were in hell and dead.

 

[max_]

Usually when ODing you don't get specific treatment, instead you get symptomatic treatment. That being treating the symptoms and trying to get you as much back to normal as they can.
You can use, i.e, diazepam to treat stimulant overdose. You won't kick out the stimulants, but your heart will survive. In the case of psychedelics, such as phens, shrooms, lsd, you could use antipsychotic(haldol)+benzos(diazepam). And again, you won't be fighting the real problem, but only the nasty effects. (anxiety, increased heart rate, seizures).
Most of contemporary medical treatments for diseases are the same as these.. You don't get an "anti-flu" medication.. You only get anti-cough, anti-sleepiness, anti-congestive. This is simply because they just don't know how to do it. They don't have an anti-flu med, and they don't have an anti-coke med. Is that simple..

 

[max_]

Opioid overdose is kind of simple: you block the mu-opioid receptor and the patient starts breathing again.

Psychedelic pharmacology is complex. DMT affects around thirteen different receptors, as well as the serotonin transporter. MDMA releases all sorts of monoamines. AMT does everything MDMA does plus binding to a whole lot of serotonin receptors.

Benzodiazepines are the AK-47 of overdose situations. They work for all of these weird drugs we keep inventing, and then some.

The exception is muscimol and other GABA-A agonist deliriants -- an overdose on these should absolutely not be treated with benzodiazepines, as they will likely make it worse! I don't know how muscimol overdoses are treated. Probably by calling the coroner. There are direct GABA antagonists, but arriving at an appropriate dosage is likely impossible.

Hi! About muscimol, I used a lot of amanitas few years ago and i asked a doctor (friend) what should i do if i OD.. Since I always carry my "security benzo" with me, and that just wouldn't work there.. He told me that muscimol (and other amanita muscaria alkaloids) being anticholinergics, what should be used in case of an OD are cholinergics.
Although, wikipedia reads:

There is no antidote, and supportive care is the mainstay of further treatment for intoxication. Patients can develop symptoms similar to anticholinergic or cholinergic poisoning; however, the use of atropine or physostigmine as an antidote is not recommended as muscimol and ibotenic acid do not produce a true anticholinergic syndrome nor do they have activity at muscarinic receptors.[78] If a patient is delirious or agitated, this can usually be treated by reassurance and, if necessary, physical restraints. Additionally, benzodiazepine such as diazepam or lorazepam can be used to control combativeness, agitation, muscular overactivity, and seizures.[46] However, small doses of benzodiazepines should be used as they may worsen the respiratory depressant effects of muscimol.[79] Recurrent vomiting is rare but if present may lead to fluid and electrolyte imbalances; intravenous rehydration or electrolyte replacement may be required.[52][80] Serious cases may develop loss of consciousness or coma, and may necessitate intubation and artificial ventilation.[47][81] Hemodialysis can remove the toxins, although this intervention is generally considered unnecessary.[61] With modern medical treatment the prognosis is typically good following supportive treatment.[57][61]

So I guess you're pretty much fucked if you OD on this thing,,

 

[chaos_destroy]

Onew question though, if you go to sleep after taking the olanzapine, are you still tripping in your induced sleep?

No in my experience it completely stops the trip dead in its tracks. So if you have a small enough dose of zyprexa to not knock you out (2-4mg) you can stay awake but your not tripping anymore at all. So if you sleep you sleep heavily and quite well.

 

[Hyperthesis]

@max:

First and foremost is muscimol a GABA-agonist and not (anti)cholinergic. I would strongly discourage benzos as antidote. Muscimol binds competitive to GABA itself, IIRC, and I can't remember any viable and safe (!) competitive GABA-antagonist. There is pentetrazole, but I don't consider this safe. Professional assistance in case of application is mandatory!

The other Amanita-alkaloids are a different story though, ibotenic acid being mainly a glutamate-receptor agonist, muscarine finally being cholinergic. But the latter occurs usually only in traces and muscarinergic syndrome as cause for Amanita muscaria-poisoning is a common misconception IMHO. After all, the poisoning may look cholinergic, but from a pharmacological point of view it isn't.

GABA- and glutamate-agonism are the main causes for serious Amanita-poisonings. Up to 1 hour after ingestion is gastric lavage still helpful, up to 4 hours is active charcoal recommended. No specific antidote is commonly known resp. clinically used. Pharmaceutically induced vomiting is not recommended and counterproductive. As explained above are (anti)cholinergics not recommended, too. I found benzodiazepines occasionally referenced to treat the delirant agitation upon heavy poisoning, but my personal feeling is that this could worsen the GABAergic activity resp. synergize in a disadvantegeous way with the muscimol.

I think if medical care is available you're not this easily 'fucked'. Fatalities are exceptionally rare. Without medical intervention again, well...

 

[Deleted member 170540]

^ Muscarine is a cholinergic, not an anticholinergic. (just to be a smart-ass...)