Polypharmacy

Bilz0r...As you say the best pharmacological treatment is etiological, but the mechanisms for such gene/transduction altering drugs are murky and will not be understood completely for quite a while. That being said, what about combining four theoretical compounds in a once a day pill for massively comorbid psych patients.

Partial dopamine agonist or uptake inhibitor
Partial opioid agonist/uptake inhibitor
Partial CB agonist/uptake inhibitor
Partial serotonin agonist/uptake inhibitor

Sure the tertiary pill wouldn't get at the genetic and transcriptural basis of neural activity, but I bet the combined effects of nudging each one of the neurotransmitter systems could be an effective moderator.

this will never happen.

DA uptake inhibitor + CB1 agonist = paranoia

from anecdotal experience,
mixing amphetamines and THC can induce a bit of paranoia, aswell as increased heart rates etc.

Got that heart rate thing right...

Um, although I agree with you about opioids, especailly in panic disorders, why the others?

Because the pharmaceutical companies will realize an option for massively screwed neural systems at this point is to try tweaking each of their NT systems. If you don't cosmetically treat the NT systems you have to start digging into the effectors/2nd messenger systems and even gene therapy.

Mitogen, amphetamine is used to produce hyperdopaminergic states and model psychosis, but partial DA agonists like arpiprazole are effective treatments for most symptoms of schizophrenia with little side effects. THC is a very sticky molecule which affects a wide variety of receptors directly and indirectly, and therefore would not be a good model for a partial CB agonist.

Well I don't think we should start talking about aripiprazole just yet. Sure there is some potential for mixed dopamine agonist/antagonists like stepholidine, and drugs like aripiprazole, but I've heard of quite a few clinicians reporting massive psychosis on aripiprazole treatment...

THC effects a lot of receptors directly? At reasonable concentrations? Such as?

Is it safe though to start just mixing drugs together. I thought that the risk of serious side effects such seizures is a dangerous possibility when taking drug cocktails. I am not sure of the exact mechanism of why people experience seizures. I heard of a kid who had one on they way to school. He had combined ritalin with effexor.

Any stimulant has the potential to decrease the seizure threshold. A seizure is uncontrolled brain-wide (or at least grand-scale) firing of the neurons. Any drug which increases the liklihood of neurons firing has the chance of precipitating a seizure. at least that's my layman understanding

THC affects CB1, CB2, TRPV1 and 2 receptors directly. It affects retrograde signalling for other NT systems. It also indirectly affects 5HT DA opioid and NE systems indirectly.

Is it safe to start mixing drugs together? That depends, but what do u think adderall is? A mixture of two salts. Many psych patients are on a cocktail of drugs.
Velocide, I didn't say it would be a stimulant?

I don't think most of the ideal drugs have even been invented yet. I mean where else can you go in terms of drugs, besides combining them? I mean you can target the intracellular effectors or 2nd messengers (and maybe the glial environment), but other than that you are left with human gene therapy/genetic engineering, someone the public is definitely not comfortable with at this point.

i see where you're coming from but polypharmacy is evil

hmm,
if one could actually manage to tweak all the previously mentioned NT systems in an appropriate fashion, such as can be attempted with occasional success in monopharmaceutical regimes, then yes, this potentially would be a pancaea.

[/me gets up to do another PBS wash]

but... the number of variables involved in altering signalling and network integration with just one drug is staggering.
add another and you start getting into areas which are simply not in the least predictable (especially in a psych setting.)

combine FOUR different drugs and your patient will almost certainly end up considerably more retarded than they originally were.

Adderal is just one drug in which the pharmacist has gotton mixxy-wixxy with the salts. My pal was in a psychiatric ward and has since disappeared into different detached friendship circles. He was given rispiridol, effexor, and zopiclone pills. But that is not going to do a seizure (well it might do) because there are not enough stimulants in the cocktail. He did describe one time though where he was on 150mg effexor and 4mg rispiridol. He had been smoking tobacco like a chimney and after he smoked a bong of marijuana he sat in a chair and described what translated as a massive psychosis.

Combining four or more drugs isn't necessarily dangerous or unnecessary...in fact, it could be quite helpful. Many people take multiple drugs for heart disease; maybe blood pressure med, cholestoral (statin) med, aspirin therapy, and now even Plavix (possibly some or all or maybe even more...don't know enough about it). Someone could have thyroid problems and take a fifth drug for that. Then they could be bipolar and get an SSRI + mood stabilizer. They may have anxiety still and take an occasional benzo and the SSRI could cause insomnia in which case they may be prescribed Ambien. Then, they have chronic back pain and are on a Duragesic or OxyContin plus Diluadid for breakthrough pain. Now, that's a person with a lot of problems, but they could be on up to 11 meds (10 Rx's). I sure there are people on even more medications. The AIDS cocktail is normally a combination of 3 drugs.

I am bipolar with chronic insomnia and still have occasional anxiety (normally during periods of excessive stress). I take 60 mg/day Cybambalta ("real" SSNRI; unlike Effexor it have more of an even effect on both serotonin and norepinephrine whereas Effexor mainly acts on serotonin), 150 mg Lamictal (newer anti-convulsant used as a mood stabilizer; first (and only one of two, I think) FDA-approved med for bipolar since Lithium), 1-2 mg ProSom (estazolam = benzo for insomnia), 2 mg Klonopin (clonazepam = benzo for anxiety, and 2 mg Ativan (lorazepam = benzo for panic attacks).

What you have to what for is drug interactions and side effects...one person could take only 2 drugs and have SEVERE complications, as serious as death, while another could take 10 or 15 and have no problems, in fact, they could "cure" (or significantly reduce) symptoms of whatever ailments they suffer from.

Edited typo.

"THC effects TRPV1 and 2 receptors directly" Got any references for that?

Yeah, mixing drugs in necessarily dangerous, but the more you mix, the bigger the risk it is going to be... I like Rothmans idea of a magic shotgun... You don't want to single out a receptor, because 1 receptor will always effect lots of systems... what you want to effect are pharmacologically modifiable systems that are only mutually inclusive only to a small extent; like a ven diagram, all the drugs overlapping on the one system.

In the non-cross over systems, because the alteraction on a single system might only be 10%, there aren't major side effects, but when all the seperate 10%s cross over, you totally effect the important system.

It is true that because someone is mixing drugs this does not automatically signal for danger. It is a good general rule of thumb though. It is like why does Pfizer bother only getting specifically one diastereomer in the production of sertraline. The same can be said about GSK with paxil. Obviously it would be easier and save alot of hassle to just give a mixture of isomers. The reason why not is safety. I bet the seizure threshold is significantly reduced. If you were to measure LD50's in mice I reckon (although I dont know) that the pure enantiomer would have a far more acceptable therapeutic index.

Just for the record, I'm not recommending this hypothetical drug- I'm just saying I could see Big Pharma releasing a polypharmaceutical drug in the future.

Bilz0r, its late and but heres a ref from pubmed which "supports an emerging role for TRP channels as ionotropic cannabinoid receptors."

"Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1."
Nature. 2004 Jan 15;427(6971):260-5. Epub 2004 Jan 07.
PMID: 14712238
Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D.

Department of Cellular and Molecular Pharmacology University of California, San Francisco, California 94143-2140, USA.

here's another one:
Delta 9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism.

Zygmunt PM, Andersson DA, Hogestatt ED.

Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University Hospital, SE-221 85 Lund, Sweden.
J Neurosci. 2002 Jun 1;22(11):4720-7.
PMID: 12040079

in a psychiatric setting, i mean

we are talking about a psychiatric clinical setting here though right?
surely, some drugs will have predictable pharmacodynamic interactions with others. for example, benzos are relatively innocuous with other drugs so long as other CNS depressants are not co-administered.

wheny you start messing around with diffuse modulatory systems, interactions between multiple will build up quickly

Yeah, I thought you were those papers (or this one)...

I'll quote from Zygmunt et al., 2002 "However, our experiments with VR1 gene knock-out mice clearly show that the molecular target for THC is distinct from the VR1. The vanilloid receptor-like (VRL-1)"

It's not direct man.