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The Questions SWIM want's answered about THC and Marijuana

Discussion in 'Cannabis & Health' started by Roads, May 10, 2010.

  1. Roads

    Roads

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    SWIM searched around the forum for something similar to this, or a thread that might answer some of these questions, but he couldn't really find anything. Bare with him friends! # IX is the one I really want to find the answer to!

    A few important links:
    http://www.crackwalker.ca/420/serotonin.html

    http://www.sciencedaily.com/releases/2007/10/071023183937.htm



    I. Modern research (see links) suggests THC in low doses may stimulate serotonin production and can actually block the reuptake of serotonin, similar to the way SSRIs work. However, high doses of THC apparently caused serotonin levels to plummet to below normal levels.
    a. Does the decrease in serotonin explain THCs anti-nausea properties?
    b. Does THC perhaps modulate Substance P as well? (neurotransmitter indicated in nausea and pain)
    c. If not through serotonin, how does marijuana facilitate its mood boost?
    d. Does this massive drop in serotonin correspond to the marked increase in anxiety and paranoia?

    II. Could long term exposure to high doses of THC cause 5-HT receptor up-regulation from the sustained net decrease of serotonin? Does this manifest a long term alteration to mood and emotion?

    III. Could we then assume that the primary mechanism of marijuana's euphoria and mood lift to be primarily related to dopamine and/or norepinephrine release?

    IV. What about THCs supposed modest modulation of Mu1 opioid receptors?
    a. Is there a dopamine release similar to that caused by opiates triggered due to this?
    b. Can we assume that this modulation is similar in nature to anandamide binding to CB1 and producing endorphins during severe pain and/or stress?
    c. Can we explain THC's observable potention of the effects/euphoria from various opiates by its actions involving the Mu1 receptor?

    V. Increases in dopamine and norepinephrine don't explain the motivation-killing effect marijuana has on many people, how do we explain this?
    a. Conversely, how do we explain the acute mania or hypomania some individuals experience on marijuana?
    b. What exactly is THC doing to norepinephrine?
    c. possible overall dopamine reduction?

    VI. Does THC do anything to acetylcholine? Glutamate? Histamine? GABA?
    a. How do we explain THCs effect on memory (acetylcholine involvement?)
    b. How does THC produce its profound sedative/depressant effects? (is GABA involved?)
    c. Glutamate plays a role in the chemical processes triggered by CB1 activation, and could explain why mood stabilizers and anti-convulsants that effect sodium channels and regulate the excitatory capability of glutamate can sometimes be observed to blunt the effects of certain drugs, marijuana included.

    VII. How do we explain high doses of marijuana, especially high quality marijuana with a high THC to CBD ratio, sometimes causing moderate auditory and visual hallucinations?
    a. Possible mild indirect 5-HT2a agonist activity?
    b. Mild Kappa Opioid receptor activity perhaps? (salvia divinorum is a kappa opioid partial agonist, and a D2 partial agonist, but has no affinity for 5-HT2a which is the primary target of basically all other hallucinogens, yet it still produces similar effects to classic tryptamines. Ibogaine is also a kappa opioid agonist and induces hallucinations as well)
    c. Dopamine receptor agonism related? Partly explains psychedelic aspects of salvia and ibogaine.
    1. Dopamine receptor antagonism caused by anti-psychotics are sometimes observed to reduce the subjective positive effects of THC.
    2. Marijuana is rumored to increase risk for developing schizophrenia and general psychosis. The dopamine hypothesis of schizophrenia implicates dopaminergic dysfunction as the cause of psychosis, paranoia, delusions and hallucinations.
    2a. Is long term alteration of dopamine function via THC responsible for the supposed increased risk stoners have to psychosis/schizo disorders?
    2b. Could alterations to dopamine function be related to the intense paranoia sometimes experienced with pot?



    VIII. Due to high doses of THC having adverse effects on serotonin, should the frequent use of high doses of marijuana, especially crippy with a high THC percentage, be discouraged in patients taking anti-depressants that exert their effects on serotonin?
    a. In comparison, would low, sub-recreational, therapeutic doses of THC constitute a possible adjunct in major depression therapy or as an anti-depressant in and of its self?

    IX. CB1 agonism causes CB1 receptor down-regulation. As it is possible to up-regulate other brain receptors with certain chemicals (E.G. NMDA antagonists like DXM and Ketamine decrease tolerance to stimulants like Amphetamine via up-regulation), are there any chemicals that could stimulate the up-regulation of CB1 receptor sites?
     
  2. fatal

    fatal

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    question IX:
    anandamide causes CB1 receptor upregulation.
    Karaliota et al. 2008

    it has also been shown that thc can lower acetylcholine. CB1 receptor agonists have been shown to inhibit binding at the muscarinic acetylcholine receptor in the human brain.(Bordayo et al 1999) this receptor is involved in memory and autonomic function. through this activity they effectively lower the amount of acetlycholine your brain is receiving and therefore how much you are using. through this it can cause symptoms of lowered acetylcholine also. this may have to do with the memory phenomena associated with thc. it could also play a primary function in potheadedness by causeing dismotivation lowered/dulled reaction to stimulii and as above poor memory functions. this effect has some similarity in mechanism to alzheimers because they both work as the result of inhibition of the acetylcholine systems in the brain.

    :joint:
     
    Last edited: May 16, 2010
  3. Roads

    Roads

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    An excellent response. SWIM thanks ye.

    SWIMs question now is, if Anandamide causes CB1 up-regulation, how then may he alter his diet and or lifestyle to stimulate an aggregate increase natural anandamide levels? Exercise perhaps?

    Could that then help explain why exercise helps reduce marijuana tolerance, partly through increases in anandamide brought on through physical exertion?
     
  4. fatal

    fatal

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    Piomelli Deitrich 2004

    After 40 minutes of excercise runners had 80% more anandamides in their blood than normal. So yes the more active you are the higher you will get when you smoke weed.

    also you can alter your diet to increase your levels of anandamide. chocolate, cocoa beans, and sea urchin roe(eggs) all contain anadamide and related compounds in varying amounts. the fatty acid amide hydrolase (FAAH) enzyme is responsible for breaking down anadamide in the body into arachidonic acid and ethanolamine which are inactive compoounds. so if you were to lower your levels of FAAH then you are going to have more anandamide in your system. there are several drugs which are effective in FAAH inhibition, URB597 is one example. they are freely available and quite legal. getting ahold of some would probably be easy. one study(Jayamanne et al 2005) which put URB597 against HU210 in rat studies actually concluded that while it produced the same effects in the rats pain reactions the URB597 rats were unaffected by motor impairment which the HU210 rat subjects were. therefore it is possible that not only is FAAH regulation without serious health side effects of its own but that it may even be a better way to get high healthwise than cannabinoids themselves.

    :joint:
     
  5. Roads

    Roads

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    Very good info; gratzie amico mio!

    This alone is motivating SWIM to increase his level of exercise in his day to day life. SWIM is going to start doing more cardio (running around his neighborhood few nights a week) and doing some light weight lifting as well to see if he can increase his marijuana highs via more natural anandamide production.

    SWIM would put forth the theory that cardiovascular exercise, jogging in particular, will probably produce the highest levels of anandamide and beta endorphine vs. a session of equal time length of targeted weight lifting - due mostly to the sustained high physical stress level on multiple muscle systems, the liver (breaking down fat), the circulatory system and respiratory system; as opposed to the intermittent physical stress felt by singular targeted muscle groups at a time with weight lifting.

    SWIM is also very interested in FAAH inhibitors you mentioned as well; certainly the internet is the only place to find them, but where exactly would one look into a substance like the "URB597" you mentioned?

    SWIM has also recently read about how THC and the other cannabinoids are mainly metabolized through the liver's CYP450 enzymes known as CYP2C9, CYP2C19, and CYP3A4 respectively. Inhibition of any of these enzymes could prolong the marijuana high greatly:
    - Any CYP450 inhibitors out there?
    -SWIM has heard some anti-depressants which greatly inhibit the production of some major cyp450 enzymes... would these effect the high?
    - Any major inducers of those enzymes to stay away from?

    Furthermore, theoretically, administering a drug, or multiple drugs to the system that are broken down as substrates of those enzymes (which includes MANY psychoactive drugs and non-psychoactives) could interfere with the breakdown of THC/other cannabinoids and prolong their effects by creating what would essentially amount to a sort of "catalysis queu" where there aren't enough of the particular enzyme to break everything down at the normal rate.
    - Administering increasing numbers of substrates could theoretically cause the body to modify and increase base production of those enzymes to meet the bodies catalysis needs; potentially allowing the plan to backfire.

    SWIM will report back on this topic after a week or so of exercising and will determine if there are any subjective differences in his marijuana high.
     
    Last edited by a moderator: Sep 12, 2010
  6. fatal

    fatal

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    to acquire URB597 i would venture to say you do it the same way you get any chemical for research. it may be expensive, but for experimental purposes it is compelling. im confident if you spent a half hour or so trying to find it you would. i am considering picking up a small amount of it to do some research into this topic on the scientific side. ill post some more in the way of scientific discourse in this thread tommorrow. too little time to go into a dissertation about liver enzymes. duty calls.
    :hoover:
    :joint:

    [​IMG]
     
    Last edited: Jun 15, 2010
  7. fatal

    fatal

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    ok then your new question poses an interesting idea. can you overwhelm the body's cyp450 enzymes as a system? you mentioned using a high level of substrates to do this. well here is a (somewhat complete) list of substrates of the various CYP450 enzymes;


    1A2;
    amitriptyline
    clomipramine
    imipramine
    fluvoxamine
    duloxetine
    mirtazapine
    chlorpromazine
    fluphenazine
    haloperidol
    perphenazine
    clozapine
    olanzapine
    ziprasidone
    ropinirole
    ALL methylxanthines

    2B6;
    selegiline
    bupropion
    methadone

    2C19;
    amitriptyline
    clomipramine
    imipramine
    diazepam
    phenytoin
    phenobarbital
    citalopram
    escitalopram
    fluoxetine
    sertraline
    venlafaxine
    PPIs

    2D6;

    tranylcypromine
    meclobemide
    amitriptyline
    clomipramine
    desipramine
    doxepin
    imipramine
    nortriptyline
    citalopram
    fluoxetine
    escitalopram
    paroxetine
    nefazodone
    trazodone
    duloxetine
    venlafaxine
    chlorpromazine
    fluphenazine
    haloperidol
    thioridazine
    perphenazine
    aripiprazole
    clozapine
    quetiapine
    risperidone
    metoprolol
    most beta blockers
    codeine
    hydrocodone
    dextromethorphan
    tramadol
    tamoxifen
    ondansetron

    3A4;

    amitriptyline
    clomipramine
    doxepin
    imipramine
    buspirone
    citalopram
    escitalopram
    paroxetine
    sertraline
    mirtazapine
    nefazodone
    trazodone
    venlafaxine
    chlorpromazine
    haloperidol
    perphenazine
    pimozide
    aripiprazole
    clozapine
    quetiapine
    risperidone
    ziprasidone
    triazolo-benzodiazepines
    zaleplon
    zolpidem
    zopiclone
    carbamazepine
    valproic acid
    buprenorphine
    codeine
    fentanyl
    hydrocodone
    meperidine
    methadone
    tramadol
    statins(exceptions pravastatin and rosuvastatin)
    antiarrhythmics
    CCBs
    beta blockers
    macrolide
    azithromycin

    fatal added 28 Minutes and 17 Seconds later...

    but what about the cyp450 inhibitors you ask? wouldnt they be more useful? wellindeed they most certainly would. why inhibition of those enzymes would just about totally shut down the digestion of marijuana and marijuana related particles by your body assuming you were the one taking them. but what about a list of those chemicals too? alright then if you insist, CYP450 inhibitors;

    1A2;

    amitriptyline
    imipramine
    fluvoxamine
    duloxetine
    ciprofloxacin
    norfloxacin
    ofloxacin
    cimetidine

    2B6;
    fluvoxamine
    clopidogrel
    ticlopidine

    2C19;
    amitriptyline
    imipramine
    fluoxetine
    fluvoxamine
    paroxetine
    PPIs (lansoprazole is the most potent in vitro inhibitor of 2C19)
    ketoconazole

    2D6;

    All TCAs
    fluoxetine
    paroxetine
    bupropion
    sertraline
    duloxetine
    fluvoxamine
    citalopram
    chlorpromazine
    fluphenazine
    haloperidol
    perphenazine
    thioridazine
    aripiprazole
    clozapine
    risperidone
    methadone
    valproic acid
    *quinidine*
    ritonavir
    cimetidine
    diphenhydramine
    Vistaril
    metoclopramide


    3A4;

    nefazodone
    norfluoxetine
    fluoxetine
    fluvoxamine
    haloperidol
    pimozide
    ciprofloxacin
    norfloxacin
    keto- and itraazole
    diltiazem
    verapamil
    cimetidine
    protease inhibitors
    NNRTIs

    fatal added 11 Minutes and 17 Seconds later...

    how about those nasty CYP inducers? CYP inducing chemicals are an every day part of your diet! oh no! how can you avoid these horriffic pot ruining chemicals in your everyday life? dont eat your vegetables! and you can just absolutely forget about charbroiled hamburgers! no my friend youll be living the life of a pothead now. CYP inducers;

    1A2;

    modafinil
    cruciferous vegetables
    charbroiled foods

    2B6;

    phenobarbital
    cyclophosphamide

    2C19;

    carbamazepine
    valproic acid
    phenobarbital
    phenytoin
    rifampin

    2D6;

    No Inducers!

    3A4;

    carbamazepine
    oxcarbazepine
    topiramate >200mg
    phenobarbital
    phenytoin
    rifampin
    ritonavir
    efavirenz
    St. John's Wort
    modafinil

    thats all for now. more later.


    :joint:
     
    Last edited: Jun 17, 2010
  8. Roads

    Roads

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    Good post SWIFatal. A few specifics I must address.

    Firstly, I've seen quite a bit of confusion and conflicting information on the metabolism of Clonazepam (Klonopin). Clonazepam is simply the chlorinated form of Nitrazepam. Every source I've found says that these nitro-benzos are both metabolized by 3a4, and thus should be subject to potentiation via White Grapefruit Juice inhibition of cyp 3a4. But many anecdotal sources throughout the internet's drug forums say that the aforesaid 3a4 inhibition doesn't apply to clonazapam but only to the triazolo-benzos. And to further compound the confusion, there are almost an equal amount of anecdotal reports that it does in fact work, and SWIM has personally felt 1.5mg of clonazepam potentiated so heavily after drinking half a bottle of white grape fruit juice that he felt drunk and had much difficult maintaining balance.

    SWIM is very confused, as many enzyme lists like SWIFatal's do not include Clonazepam as a 3a4 substrate, yet SWIM is certain 3a4 is the one breaking down Clonazepam as he has seen other websites list it as being a 3a4 substrate in addition to the other nitro-benzos. Clonazepam is however listed in the wikipedia article as a substrate of 3A4. SWIM is sure K-pin goes via 3A4 but would like to get this cleared up with more research if possible.

    Now, most importantly, THC is degraded via 3a4, 2c9 and 2c19, therefore inhibition of all of those enzymes should theoretically increase THC serum levels for more prolonged periods.

    SWIM has discovered that polyunsaturated fats, particularly EPA and DHA (fish oil, fatty acids) inhibit 2c9 and 2c19 in lower doses, and 1A2, 2E1 and 3A4 at higher doses. The abstract in the link confirms.

    http://www.sciencedirect.com/scienc...serid=10&md5=36395dc5c6fffe57087d472373d9b281

    Now, white grapefruit juice inhibition of 3A4 appears to be mostly intestinal and not hepatic. So potentiation of opiates, benzos and other drugs would be primarily mediated through intestinal blockade of 3A4. SWIM is going to guess that the EPA and DHA inhibition of 2C9, 2C19, 3A4 are at least partially hepatic and partially intestinal. Furthermore, 3A4 enzymes have also been found in concentrations in parts of the brain; inhibition there could further potentiate marijuana and other psychoactives.
     
  9. fatal

    fatal

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    the list may not necessarily be complete

    :joint:

    (<
     
  10. fatal

    fatal

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    I am sure that reducing the levels of the enzymes mentioned in any of those three areas(hepatic intestinal or cerebral) would help. i am guessing here but most likely intestinal enzyme levels would have less to do with it if you were smoking the thc. likely the smoked products would not find their way to the intestinal tract as often as if they were eaten. how do we blockade 3A4 enzyme from the brain and what if any would be the negative side effects of such drastic measures? more research may reveal the answer. guess its time to get started.



    :joint:

    (<
     
  11. Sir_Bongalot

    Sir_Bongalot

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    I have to say that a lot of the opinion expressed in this thread (especially towards the beggining) relating to THC is conjecture and not proven or even generally accepted to be true.

    This thread started on the premise that marijuana in low doses increases serotonin. This was all from one highly limited study in rats. And from this huge conclusions are drawn. I had already read this study before and its only a small study, at best a curosity which needs larger study and replication but it is not proof of anything, it should be treated as conjecture, not taken to form complex and deep conclusion about how THC effects the brain.

    Definately people are reading too much into things and seeing things that aren't there.
     
  12. fatal

    fatal

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    if you dont have anything to contribute to the thread that is productive please keep it to yourself. let me point out a couple thing. this thread is the most comprehensive science realted posting in this(cannabis) forum. you do not have any evidence for your claims which are, to summarize, that we should not be taken seriously and that some study about rats which proved something about serotonin which was at the beggining of the thread, and has tertiary relevance to the rest of it, somehow proves that all of the science we have uncovered to post here is "conjecture and not proven or even generally accepted"? maybe if you read through the thread you would learn something about marijuana's chemistry and the way it works in the body. if you have evidence which suggests opposite of something that has been posted i would be happy to read it and see what you are talking about. you may notice that there are sources for the things we are talking about. science sources. lab coats, shiny glass vials, rats, the whole shebang.

    :joint:

    :joint:
     
    Last edited: Sep 29, 2010
  13. fatal

    fatal

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    Does anyone have any idea if receptor up regulation would havean effect on withdrawal symptomology? This might be a question to start a new thread on actualy. I thought of it while reading through this thread though so... What do you think? If it can decrease tolerance would it also help to get rid of withdrawal symptoms?


    This thread doesnt have that much to do with cannabis health risks really. $.02


    :joint:
     
  14. corvardus

    corvardus Gold Member

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    Whilst I can't answer the question directly I'll forward you to

    FAAH−/− Mice Display Differential Tolerance, Dependence, and Cannabinoid Receptor Adaptation After Δ9-Tetrahydrocannabinol and Anandamide Administration; Neuropsychopharmacology 35, 1775-1787

    Would seem to suggest that treatment of andanamide in FAAH knockout mice reduced the CB1 downregulation in mice with consequent reduced dependant liability (withdrawls). With a direct administration of rimonabant (a CB1 antagonist) reduced the magnitude of withdrawl than those mice on THC.

    It would seem to suggest, therefore, that upregulation of CB1 receptors will, indeed, decrease tolerance and the withdrawal symptoms associated with it.

    The cannabis forums are currently undergoing somewhat of a renewal as posts are being moved to more appropriate sub-forum. The cannabis health risk tag was simply a tool to help the moderators do their work and will probably get deleted once the process is complete.
     
  15. fatal

    fatal

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    How interesting. Will have to do some further research in this area. Thanks for the info. ;)

    :joint: