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Mediating Cannabis Withdrawal Symptoms via Endocannabinoid Modulation

Discussion in 'Cannabis addiction' started by Shampoo, Feb 10, 2011.

  1. Shampoo

    Shampoo entity of sorts Staff Member

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    Mediating Cannabis/Cannabinoid Withdrawal Symptoms via Endocannabinoid Modulation
    A theory and case study


    Cannabis/Cannabinoid withdrawal is a notable syndrome in frequent, heavy users of Cannabis or synthetic Cannabinoid receptor agonists (Lichtman, 2002). Investigating the functional consequences of the effects of withdrawal has been a significant focus of research over the past decade (Budney et al., 2004; Haughey, 2008). A better understanding of these mechanisms may allow for therapeutic treatment, as outlined within this discussion and caste-study. Withdrawal symptoms precipitated from the cessation of Cannabis or Cannabinoid consumption are largely mediated by upregulation and sensitization of CBRs (in particular, the presynaptic CB1R) (Aceto, 1995). Modulation of the eCB system may prove a viable mechanism for mediating the physiological and psychological effects of this receptor regulation/sensitization. Several routes towards eCB modulation are outlined and the efficacy of their in vivo effects remain in question. A single case-study suggests that the symptoms of cessation-induced withdrawal may be abolished by eCB modulation, though further study is required to generalize the data to a broad population.​


    Abbreviations
    2-AG - 2-Arachidonoylglycerol
    AEA - Anandamide (N-arachidonoylethanolamine)
    BBB- Blood Brain Barrier
    CBR - Cannabinoid Receptor
    CB1R - Cannabinoid Receptor 1
    eCB - Endocannabinoid
    FAAH - Fatty Acid Amide Hydrolase
    MAGL - Monoacylglycerol Lipase
    NAPE - N-arachidonoyl phosphatidylethanolamine


    Theory: Increasing basal levels of eCBs

    One route to increasing basal levels of eCBs (AEA, 2-AG..etc.) is inhibiting their uptake and degradation, while another is supplementing the necessary precursors required for their synthesis and release. A number of approaches in both of these directions may be effective; a cursory review of which are provided here.

    The primary eCB, AEA, is largely degraded in vivo by FAAH, a process which results in the production of ethanolamine and arachidonic acid (Di Marzo, 2008). Inhibitors of FAAH will lead to increased levels of AEA at the synapse, resulting in increased occupancy of presynaptic CB1Rs (Williams & Kirkham, 1999; Hwang, 2009). One known inhibitor of FAAH is AM-404 (N-(4-hydroxyphenyl)arachidonoylethanolamide), an active metabolite of paracematol (acetaminophen) which readily crosses the BBB (Kumpulainen, 2007). N-oleoylethanolamine and N-linoleoylethanolamine are also inhibitors of FAAH, both of which are found in chocolate. In other words, supplementation with paracematol and chocolate may both increase basal concentrations of AEA. Additionally, chocolate contains AEA itself, which has been shown to readily cross the BBB. Finally, Biochanin A, an isoflavanone, has been shown to be an effective peripheral inhibitor of FAAH (Thors et al., 2010) and is readily found in a number of dietary sources, including red clover, soy beans and peanuts. Peripheral inhibition of FAAH may help to mediate some physiological symptoms of Cannabis/Cannabinoid withdrawal, including gastric discomfort and increased nociceptive sensitivity.

    In regards to the other major CB1R agonist eCB, 2-AG, much of the above applies, as FAAH is responsible for at least some component of 2-AG metabolism. The remaining metabolism of 2-AG is mediated by MAGL (by some reports, this may be the primary metabolic enzyme involved in 2-AG degradation) (Di Marzo, 2008). Though inhibitors of MAGL are not nearly as readily available as FAAH inhibitors, JZL184 has been shown to elevate 2-AG levels in vivo (Long et al., 2008), but for the time being this remains a research tool, not for human consumption. Elevating 2-AG levels may be best accomplished via FAAH inhibitors as described above.

    It should be noted that, unlike most neurotransmitters, eCBs are synthesized on-demand, so simply inhibiting their degradation will not necessarily have the desired effect. There are a number of means of increasing the synthesis of eCBs, namely exercise* (Sparling, 2003; Dietrich, 2004). A number of studies have shown that prolonged physical exertion results in the increase synthesis and release of the eCBs AEA and 2-AG. In combination with an FAAH inhibitor, exercise may produce prolonged increases in the synaptic concentrations of these eCBs.

    Additionally, supplementing one's diet with the precursors and co-enzymes necessary for the synthesis of these eCBs may prove to be an additionally effective means for increasing eCB levels. Some notable supplements in this regard are arachidonic acid, glycerol, and NAPE. Arachidonic acid is an omega-6 fatty acid and may be found in a number of OTC supplements, as well as naturally occurring in a number of ingestible animal products, including meat, eggs, and some dairy. Glycerol is a sugar-substitute and may be found from many culinary sources. NAPE is also found as a supplement and despite some purported psychoactivity (debatable), is not controlled or scheduled in any manner. Acetyl-CoA is the only readily bioavailable coenzyme in the synthesis of eCBs, and may be supplemented in the diet by pantothenic acid (vitamin B5).

    In conclusion, one might find themselves fit to inhibit the development of certain forms of Cannabis/Cannabinoid withdrawal by a combination of precursor/coenzyme supplementation, degradation inhibition and exercise-induced eCB synthesis. A diet with supplements of arachidonic acid, glycerol, chocolate, and/or NAPE, as well as pantothenic acid, in addition to regular exercise and the use of FAAH inhibitors such as paracemtol/AM-404 (or, again, chocolate) should suffice to account for these factors.

    *Note -- Exercise also has been shown to increase endogenous production of endogenous opioids. Considering the relationship between Cannabinoid withdrawals and opioid receptor activation/regulation, this may be another mechanism by which exercise may inhibit the expression of certain forms of cannabinoid withdrawal.


    In practice: A case-study
    Resources

    Aceto, M. "Cannabinoid Precipitated Withdrawal by the Selective Cannabinoid Receptor Antagonist, SR 141716A." European Journal of Pharmacology 282.1-3 (1995): R1-R2.

    Budney, Alan J., Hughes, J.R., Moore, B.A., & Vandrey, R. (2004, November). Review of the Validity and Significance of Cannabis Withdrawal Syndrome. American Journal of Psychiatry, 161, 1967-1977.

    Di Marzo, V. "Endocannabinoids: Synthesis and Degradation." Rev Physiol Biochem Pharmacol 160 (2008): 1-24.

    Dietrich, A. "Endocannabinoids and Exercise." British Journal of Sports Medicine 38.5 (2004): 536-41.

    Haughey, Heather M., Erin Marshall, Joseph P. Schacht, Ashleigh Louis, and Kent E. Hutchison. "Marijuana Withdrawal and Craving: Influence of the Cannabinoid Receptor 1 () and Fatty Acid Amide Hydrolase () Genes." Addiction 103.10 (2008): 1678-686.

    Hwang, Jeannie, Crista Adamson, David Butler, David R. Janero, Alexandros Makriyannis, and Ben A. Bahr. "Enhancement of Endocannabinoid Signaling by Fatty Acid Amide Hydrolase Inhibition: A Neuroprotective Therapeutic Modality." Life Sciences (2009).

    Kumpulainen, E., H. Kokki, T. Halonen, M. Heikkinen, J. Savolainen, and M. Laisalmi. "Paracetamol (Acetaminophen) Penetrates Readily Into the Cerebrospinal Fluid of Children After Intravenous Administration." Pediatrics 119.4 (2007): 766-71.

    Lichtman, A. H., and B. R. Martin. "Marijuana Withdrawal Syndrome in the Animal Model." J Clin Pharmacol 42 (2002): 20S-7S.

    Sparling, P. B., A. Giuffrida, D. Piomelli, L. Rosskopf, and A. Dietrich. "Exercise Activates the Endocannabinoid System." NeuroReport 14.17 (2003): 2209-211.

    Thors, L., J. J. Burston, B. J. Alter, M. K. McKinney, B. F. Cravatt, Robert A. Ross, R. G. Pertwee, R. W. Gereau 4th, J. L. Wiley, and C. J. Fowler. "Biochanin A, a Naturally Occurring Inhibitor of Fatty Acid Amide Hydrolase." Br J Pharmacol 160.3 (2010): 549-60.

    Williams, Claire M., and T. C. Kirkham. "Anandamide Induces Overeating: Mediation by Central Cannabinoid (CB1) Receptors." Psychopharmacology 143.3 (1999): 315-17.
     
    Last edited: Feb 11, 2011
  2. iheartbonsai

    iheartbonsai

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    This is a great post!

    I think this information will be very useful for someone experiencing withdrawal symptoms.


    Do you think JZL184 inhibition factor is actually irreversible?

    If so, do you think would that mean that after application one would experience more CB activity than others if cannabinoids are applied?

    Could it be that the lab rats will be somewhat stoned for the rest of their lives? Never sober again from just one application?

    Very interesting indeed.

    Again thanks for the high quality post!

    Definitely got me thinking :thumbsup:



     
    Last edited: Feb 13, 2011
  3. Shampoo

    Shampoo entity of sorts Staff Member

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    Yes, but to understand the implication of that you must understand the nature of protein/enzyme turnover in human biology. JZL184 irreversibly inhibits MAGL, but the specific MAGL that you have at this moment is undergoing regular synthesis and degradation, down and up-regulation. The body is far from static.

    Possibly, but only for the active life of the compound.

    No.

    As an example, paracemetol (acetaminophen) is an irreversible COX inhibitor-- does a single dose of paracemetol have permanent NSAID effects?

    From the discussion of Long et al., 2009:
     
    Last edited: Feb 13, 2011
  4. iheartbonsai

    iheartbonsai

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    Thanks for clearing that up! I don’t know chemistry that well but I'm learning.

    Just saw the reputation comment thanks for the tip and neutral status.

    Like with chemistry; still have some learning to do! So I really do appreciate your understanding. Constructive feedback is always welcomed.
     
    Last edited: Feb 15, 2011
  5. nate81

    nate81 Titanium Member

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    I loved this Shampoo. Alfrendo will use this knowledge himself. He had read but forgotten that endogenous cannabinoids were released with exercise. Just so people are aware, "prolonged exercise" that releases cannabinoids typically means an hour of exercise at 70-80% of your maximum heart rate. A bit of dark chocolate right before and right after exercise will catch those eCB's nicely.
     
  6. FreeBliss

    FreeBliss Silver Member

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    definatly give your self the precursors. please god dont give any ideas for cb reuptake inhibitors. someone would love to patent a new crazy drug.

    animide or whatever i thinks converted from omega 3's. sorry i just seen u say omega 6 was the one. i will have to look that up. hemp seed oil contains them all 3,6,and9.
     
    Last edited: Mar 6, 2011
  7. Shampoo

    Shampoo entity of sorts Staff Member

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    Right. Did you get a chance to read the thread before replying?
    The eCB system does necessarily not work this way. There is serious debate as to the existence of an eCB transport protein. eCBs are synthesized on-demand, and are a retrograde neurotransmitter (i.e. they are released by the post-synaptic neuron and act on the presynaptic neuron). eCBs are then degraded by FAAH (post-synaptically) or MAGL (presynaptically) (also, included in the first post..). FAAH inhibition is the route to inhibiting enzymatic degradation. MAGL inhibition is another possibility (see... the first post). As for the concept of a "crazy drug," the eCB system is a major target of pharmaceutical development, and a number of enzyme inhibitors are currently being investigated for pharmaceutical effects; there does not appear to be much psychoactivity involved (i.e. an FAAH or MAGL inhibitor does not get you "high").
     
    Last edited: Jul 6, 2011
  8. NeuroChi

    NeuroChi is not his mind Staff Member

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    To clarify slightly further: "on-demand" refers to their synthesis and release only when it is appropriate for the post-synaptic neuron to do. This occurs when the pre-synaptic neuron is releasing higher than baseline levels of Glutamate and accumulation of Calcium occurs in the post synaptic neuron. It is possible that the reason that FAAH or MAGL inhibitors do not have psychoactive effect is that they would only increase eCB levels where eCB's are present, which surely isn't in every neuron throughout the entire brain (at a given time). Administering exogenous cannabinoids systemically results in a wholesome distribution of cannabinoids at every* synapse, hijakcing the system in such a way that would theoretically be impossible with eCB inhibitors.
     
  9. bufalantan

    bufalantan

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    Sorry shampoo, but how is it mediating Cannabinoid withdrawal via Endocannabinoid Modulation , if a cannabinoid like am-404 was used?


    Some would suggest co administration of alpha lipoic acid with Omega 3, at 1:2 ratio, first thing in the morning and the same for bed time with the addition of l-tryptophan (5ht, 5htp, etc).

    Example: 100 mg Lipoic acid, 200 mg Omega 3 (falxseed oil) first thing in the morning (maybe again in the after noon if needed) and with l-tryptophan before bed. Loads of Chocolates in between, bananas, and some thing with vitamins and fibers per your gastric condition. Hydrate and get something to focus on for like 4 days.

    The above was for am-404 free withdrawl. If OTC drugs are an option, the same people that suggested the above would recommend notroopics for a week.

    Non addictive personalities, benzos might be the fastest solution, but of course with an Rx from a professional etc.​
     
    Last edited: Feb 28, 2013