momatik
Well-Known Member
Another member here on FC introduced me to the idea of decreasing tolerance through supplementing ones diet with omega-3-6-9.
I was reading up further on the subject and found this. Valuable info for sure.
http://www.drugs-forum.com/forum/showthread.php?t=154610
To summarize, the idea is that one can supplement ones diet to decrease withdrawal symptoms. This would also make your "break" more efficient.
I was reading up further on the subject and found this. Valuable info for sure.
http://www.drugs-forum.com/forum/showthread.php?t=154610
To summarize, the idea is that one can supplement ones diet to decrease withdrawal symptoms. This would also make your "break" more efficient.
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
Quote:
Subject data
Age: 23
Weight: 145lb
Height: 5' 7"
BMI: 22.7
Current supplements/medication: GliSODin (100mg, daily in weekly on/off cycles), Alpha-GPC (250mg, daily), Omega 3-6-9 (600mg, daily), multivitamin (3-4x/week), Melatonin (500g, 3-4x/week), Phenibut (1-2x/week)*, Zolpidem tartate (5mg, 1-2x/week)*
Additional notes: Subject is well-educated (B.S., M.S., PhD Candidacy), actively monitors a vegetarian diet, in excellent physical condition (average resting heart-rate [HRrest] is 54 BPM) and of relatively healthy mental status (diagnosed major depressive disorder, no incidence of significant clinical depression in 6mo.).
*Phenibut & Zolpidem use were temporarily discontinued 3 weeks prior to trial initiation with no significant withdrawal or side-effects.
Subject Cannabis/Cannabinoid use history: The subject was a regular consumer of Cannabis from age 16-23, ingesting ~500-1,000mg of high-quality (18%+ THC) Cannabis daily from age 19-23 with intermittent 5-6 day cessation periods occurring 1-3x/year. Previous use was regular but not daily (~4-5x/week). Over the past 18 months, the subject has intermittently experimented with synthetic cannabinoid agonists (orally, transdermally and through vaporization [rarely]) not limited to but including CP-47,497/55,940, HU-210, JWH-007/015/018/019/073/081/133/200/210/250, WIN 55,212-2. The subject has not previously noted significant side-effects from regular usage, though suffers withdrawal symptoms upon cessation which include an increase in HRrest and blood-pressure, increased irritability and generalized anxiety, difficulty in initiating and maintaining proper sleep, poor mood and motivation, increased sensitivity to painful stimuli, gastric discomfort with decreased frequency of bowl movements, severely decreased appetite and increased incidence of both conscious and unconscious (sleeping) bruxism.
Study: The subject ceased all Cannabis/Cannabinoid consumption without tapering from the above average doses (500-1,000mg/day, Cannabis). Immediately the subject began supplementing with 3-4oz 78% chocolate spread intermittently throughout the day, 50mg Safflower-oil NAPE 1x/day in the morning, along with additional 5mg pantothenic acid, 1200mg Omega 3-6-9 complex. The subject also began using a mild glycerol extract in place of sucrose in his morning coffee. With each meal, the subject ingests 500mg paracematol. In addition to the subject's regular exercise regimen (90min cardiovascular oriented cycling 3x/week, 60min strength training 2x/week), a 60min cardiovascular exercise (running) was incorporated into the subject's routine on the 2 previously-designated "off-days."
After 10 days, the subject reported absolutely no withdrawal symptoms. Appetite was maintained at standard levels, no anxiety/irritability was reported, sleep patterns noted as regular (100-110min REM/night, as monitored by EEG), no incidence of bruxism, sensitivity to painful stimuli, or change in frequency of bowel movements. A mild increase in HRrest (?+5-7BPM for days 1-6 post-cessation, +/-0BPM thereafter) was noted with no change in mean blood-pressure.
On day 10, the subject ceased consumption of NAPE-isolate and reduced paracematol to 1x/day with no notable change in effect. On day 15 the subject ceased consumption of additional Omega 3-6-9 complex, glycerol, paracematol and pantothenic acid supplementation with no notable change in effect. On day 17 the subject resumed normal exercise routine by returning to two "off-days" with no notable effect. The study ended on day 30 with the subject reporting normal behavior, no notable side-effects from withdrawal, no notable cravings to re-administer Cannabis/Cannabinoids even when probed with multiple cues (the presence of smoke, the aroma of fresh Cannabis, and the tactile handling of glassware used for Cannabis consumption). A follow-up study on day 60 reports no change. Compliance with cessation was monitored by self-report.
Conclusions: The above study suggests that a chemical and physical supplementation diet may act to prevent the development of Cannabis/Cannabinoid-mediated withdrawal symptoms in some subjects. Further study is required to generalize to a larger population. The individual contributions of each element are debatable, and future studies with isolated or combined supplementation are required to further define the effects of the regimen on abolishing Cannabis/Cannabinoid-mediated withdrawal.
Resources
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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).
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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.
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