the canabinoid Matrix need to look at this!

[DrGreen]

this was posted on here years ago, i saved the text and the post was briefly looked at then slung into storage, i think it needs to be seen again so i am reposting it as it must have been 4 years since it had a post, and new commers deser4ve to see this too,

i take no credit for this i have read and read it and did alot off this topic i find myself quoting it to numerous people stil
hoep ya enjoy it as much as i did

Decoding/Understanding the neural matrix: The Endocannabinoid system

Decoding/Understanding the neural matrix: The Endocannabinoid system, Pain, mental health and addiction Pharmacology & Neurotransmitters action in the CNS.

Bree Stegman, RN, September 2008


The endocannabinoid system (ECS) is a neural network which tone regulates mood and natural painkillers.
Cannabis has many complex actions as a neurotransmitter; it is synthesized on demand and is a master regulator of the nervous system. It has receptor and non receptor pathways such as enzyme inhibition and competition. Cannabis effects include receptor antagonist and agonist actions of serotonin (5HT), dopamine (DA), norepinephrine (NE), glutamate, gamma-aminobutyrilc acid (GABA) and acetylcholine (Ach) (Guy,
Whittle & Robson, 2004, p.106), CB1 cannabis receptors are some of the most common receptors in the body involved in crosstalk between receptors in the brain including nonopiod emotional perception of pain, the SIA in the amygdala (Hohman & Suplita, 2006), PAG (Guy et al, 2004, p.239), the area of conditioned fear (Bearman, 2008), RVM, p.276 and vanilloid VR1 receptors (Schlicker & Kathman, 2001). It is my aim to provide teaching to members of the medical field and humanity as mental health consumers for an approach to understanding cannabis research and its medical effects.
GABA/CB1/GPCR

Cannabinoids THC and CBN, CBD ( and the brain's own marijuana (endocannabinoids such as Anadamide and 2AG) bind to an exceptionally abundant receptor in our nervous system named CB1 that is classified as a g protein coupled receptor (GPCR). Another less numerous G coupled receptor includes inhibitory GABA, such as the medication Gabapentin or Lyrica or narcotic benzodiazepines like Ativan or Diazepam use in shutting down electric pain, epileptic and mood signals. CB1 receptors are coupled in nerve terminals with GABA. CB1 receptors are also located presynaptically to inhibit neurotransmitter release in the hippocampus (Schlicker & Kathman, 2001). CBD is a cannabinoid that has very weak affinity for central nervous system (CNS) CB1 receptors so some call it an antagonist or inverse agonist and usually is about 40% of cannabinoids. CBD is shown to activate serotonin receptors (Gardener, 2007). CBD is shown to have anti-anxiety, anti-seizure, anti-inflammatory, anti-cancer and sedative effects (Gardener, 2007) (Rodriguez et al., 2006). Cannabinoids CBC and CBG are not known to have effects at CB1.

Cannabis hijacks GABA GPCR's common pathways of Gi/Go, or Gs. These G's re like secondary neurotransmitters. Gi/Go is the major inhibitory and anti-anxiety route that cannabis influence on nerve transmission usually follows because its receptors far outnumber Gs (Glass & Felder, 1997), but can use the stimulatory Gs path in chronic use (Rubino et al., 2000). This marks the difference in effect on acute versus chronic users. The body is a balancing act tending to down regulate or up regulate eventually what is tipping the scales.

For example with SSRI's such as Prozac increases serotonin by preventing serotonin being uptake at the postsynapse, circulating the serotonin message longer. Serotonin increases CNS cell growth, however desensitizes the amount of receptors available for use (American Scientist, 2000) (Personal research). This means that strong or prolonged cannabis use may eventually provide a weak blockade at the CB1 receptor. Cannabis imitates many drugs of current pharmacy and also has this effect at 5-HT1 serotonin receptors. However most users of cannabis don't want to hear that cannabis works like pharma, albeit in a less harmful manner. This should be looked on as positive because the harsh side effects of SSRI's demonstrate that cannabis works more specifically yet multitudinal and in the same way. This also throws out the window that a synthetic agonist or antagonist has an opposite or like effect of cannabis as it both stimulates the endocannabinoids system.

All the major natural classical cannabinoids studied so far (THC, CBD, CBN) are shown to be partial agonists (Bonhaus et al., 1998), meaning it has both door opening and closing results on a neuron using primarily Gi/Go or sometimes THC to Gs to modulate adenylate cyclase (to primarily decrease or sometimes increase this enzyme) for energy to shut down or stimulate a nerve. This explains the main action of cannabis, however many g-proteins used are not bound to adenylate cyclase or nonnarcotic GABAb (Howlett, 1995).

GPCR's decrease calcium channels and increase potassium channels to increase nerve shutdown, and decreases cAMP energy (Piomelli, 2003). However potassium channels can also be decreased directly by CB1. CB1 receptors are said to work as retrograde signaling to then continue to pass on the original message post synaptically as GABAa is blocked presynaptically (Piomelli, 2003). This means that although a study may prove that a neurotransmitter is blocked by cannabis it does not tell the whole story of how messages can be alternatively passed. Another study shows that GABAb is stimulated in the hippocampus by CB1 receptor activation, and that neither action is due to opiod manipulation which is coupled to g-proteins as well, but rather calcium channel shutdown (Hoffman & Lupica, 2000). GABA eventually increases serotonin and dopamine neurotransmitters.

As well terpenes, the essential oil on the surface of plant cannabis has a medical effect that acts as SSRI: increases norepinephrine, increase dopamine and GABA, aids the activity of cannabinoids (Guy, p.166). Has anti-anxiety anti depressant effects in studies (p.172, 177-178, 237 253). CBC THC and CBD are proven as anti-depressant and anxiety chemicals. The use of the endocannabinoids Anadamide as a THC substitute in studies are unreliable, 2AG an endocannabinoid and synthetics that are active at CB1 are standard (Wiley, 1999).
Got it Backwards?

The message travels backwards across the synapse in a feedback loop as the receiving nerve effects the transmitting cells. This mode of signaling is reverse from the traditional model and is now called: depolarization induced suppression of inhibition (DSI) (Nicoll & Alger, 2004), as a method of nerve communication. This is the reverse of the standard thinking that neurotransmitters are released pre across the synapse to send messages to the post receptor, and reflect the difficulty of interpreting research studies in isolation and are easily open to manipulation of data given the presented material in this literature review.

So even though cannabis is a major inhibitory action on excitatory neuroreceptors presynaptically such as glutamate, serotonin, acetylcholine, noradrenalin release, a balancing act can occur as blanket inhibition is blocked as well (Piomelli, 2003). THC is also proven to stimulate adenylate cyclase energy using this Gs protein stimulatory route (Baywitch et al. 1996), and therefore can stimulate neurotransmission release. Therefore cannabis contains substances that are agonist and antagonist in its effects (a partial agonist). Thus balancing overstimulation and over inhibition in the brain (Grotenherman, 2006). Damaged neuroreceptors malfunction and over or under produce neurotransmitters. The area generally studied is in the hippocampus and cerebellum with GABa and glutamate with retrograde signaling (Guy et al, 2004, p.112), (Schlicker & Kathmann, 2001).

(See glossary and compare a picture of the endocannabinoids system with the picture of neurotransmission).

Anti-anxiety drugs such as Valium/Diazepam or Ativan/Lorazepam act by inhibitory GABA a, the narcotic versus GABAb the cannabis route but are partial synthetic substitutes (Wiley, 1999). Synthetics are modeled after THC and active at CB1, however natural cannabis contain other cannbinoids that bind and have effects as well.

Natural cannabis is not an alkaloid because it contains no nitrogen chain, such as other medical herbs, nicotine, caffeine or narcotics, herbs such as valerian or morphine known for anti-anxiety properties has GABA effects. Anti-anxiety effects are attributed to blockading FAAH (Piomelli, 2003) and adenylate cyclase (Hohman, & Suplita, 2006) which both break down endocannabinoids 2AG and Anadamide (Hohman & Suplita, 2006). Anadamide was isolated as a lipid and not as a peptide/protein like morphine and its enkephalins (Piomelli, 2003). Because it is a fat, it can readily be absorbed and be effective in areas of the brain's enzymes. It is a partial agonist at the CB1 receptor and vannilloid VR1 capsaicin or pain receptor (Guy et al, 2004, p.108, 127). Cannabis is non narcotic and had less in common with opiates than coffee, but has several neurotransmitter effects.

Studies that lament increases in dopamine transmitter and blocked serotonin receptors represent skewed science, in which the majority neurotransmitters are blocked pre and then selectively stimulated pre retroactively through the post nerve using CB1 receptors, such as in the case of dopamine (Bearman, 2006). Anadamide is created in response to stress or the presence of an overabundant dopamine supply for this purpose to create neurotransmitter balance (Fride, 2002). Also to increase needed transmitters or to utilize existing transmitters as an alternate signaling mechanism. The increase in dopamine with cannabis is not made by dopamine cells as with drugs of abuse (Chapter 2). This can actually kick start our own malfunctioning endocannbinoid system by increasing Anadamide, leaving a lasting but imperceptible effect of well being.
CB1 Blockers/Dopamine/Schizophrenia

CB1 antagonist medications are a similar model of the ECS and antipsychotics that are dopamine receptor blockers and represent one half of the ying and yang of cannabis as a partial agonist. Different cannabinoids have different effects as well as individuals have different genetics or physical attributes including transmitters. Antagonists drugs that block CB1 such as Rimombant have shown to provoke anxiety and depression (Viveros, Marco & File, 2006). Pure THC therapeutics such as Marinol and acute, naïve, exposure to cannabis and some high THC cannabis genetic strains can provoke anxiety and pain with Gs proteins, stimulation of adenylate cyclase, and overall CB1 and Anadamide antagonism by THC as suspect..

Although blockers can be therapeutic in addictions, cannabis itself has this effect through its down and up regulation properties, as dopamine is blocked in the striatum and retina, yet released in the nucleus accumbens (Guy, Whittle & Robson, 2004, p.106). Excitatory glutamate inhibition by cannabis is said to be the reason that dopamine is released by GABA into the ventral tegmental area to then inhibit dopamine which then releases acetylcholine in the prefrontal cortex (Guy, Whittle & Robson, 2004, p.107). Chronic exposure to THC desensitizes CB1 receptors (Romero et al., 1998). As chronic exposure to SSRI drugs down regulate HT3 serotonin receptors.

CBD releases endocannabinoids 2AG. CBD is a cannabinoid that is nonpsychoactive yet is still sedating and increases dopamine, mediates THC and anxiety, kills cancer, is neuroprotective, and is anti-inflammatory, anticonvulsant, an SSRI and NE uptake inhibitor (Guy et al, 2004,p.90-92)). It can also attach to VR1 receptors and is anti-psychotic (p.168).
Dopamine

Narcan cannot block the effects of THC and does not affect narcotic mu or delta, rather cannabis is a k opiod agonist and some effects can be blocked with kappa antagonists, and is not by muscarinic or alpha2 adrenergic stimulant pathways (Howlett, 1995). As described earlier opiod receptors are coupled with g-proteins. However in morphine withdrawal opiod receptors are down regulated, but with cannabis they are unregulated (Cichewicz et al., 2001) making an argument for cannabis therapeutics as withdrawal management or harm reduction of opiates yet still modulate analgesia.

CB1 receptors are absent in the nerve terminals in dopaminergic fibers in the ventral tegemental area that projects to the nucleus accumbens which is the traditional model of the reward pathway in addiction (Cheer, 2004)(Schilcker & Kathmann, 2001), although dopamine is increased in these areas, and GABA is the alternate dopamine stimulating mechanism that cannabis follows. THC and addiction claims are controversial. Other studies such as Abood and Martin criticize rat dopamine findings that are “confined to "one strain of rat" and its application "to human abuse is tentative at best." (Abood and Martin, 1992) This conclusion is also reported by the Office of Technology Assessment, which attributes the finding to an in-bred quality specific to Lewis Rats. (US Congress OTA, 1993)” (Gettman, 1997). The same author notes that withdrawal is related to NE in the locus coeruleus and not to dopamine, and that THC dependence is less than nicotine or alcohol. Alcohol and tobacco are associated with depression and brain atrophy, cannabis is not unless used as a coping mechanism (Green & Ritter, 2000).

The question to be asked is, what if we have a dopamine deficient system that increases susceptibility of addiction, or an endocannabinoids deficient system that fails to maintain this tone, to produce Anadamide, to increase or decrease dopamine levels? One CB1 genetic mutation is associated with schizophrenia (Guy et al., 2004, p.92), and these areas are shown to be damaged with nicotine, alcohol or opiate use. Cannabis is known for its neuroprotection via glutamate toxicity blocking (unique) and neuroregenetive properties (of the receptor CB1 as does SSRI drugs to serotonin receptors).

Dopamine is another inhibitory neurotransmitter. Dopamine is needed as the pharmaceutical Wilburton is a dopamine agonist and antidepressant used for smoking cessation. Dopamine is a part of the constituents of the neurotransmitter norepinephrine needed for antidepressants and is common in combination SSRI drugs. Dopamine neurons often refire with an added serotonin. Herbal supplements such as L-Tyrosine or smoking nicotine increase dopamine and norepinephrine and are not closely linked with schizophrenia. Psychiatry is now evolving to discourage nicotine as it interferes with some pharmaceutical antipsychotics. However dopamine blockers also can suppress serotonin as dopamine receptors refire serotonin when saturated.

However a very small percentage of people with mental illnesses are at risk of psychosis with cannabis use but the exception proves the rule and many types are treated by cannabis. CBD, a nonpsychoactive cannabinoid is shown to be anti-anxiety and antipsychotic in its effects (Grotenherman, 2006) (Guy et al, 2004, p.184, p237), which can mitigate pure THC preps.

Withdrawal or short acute symptoms can be managed safely, and is shorter and more gradual than accepted coffee or nicotine, and generally require no medication as treatment. Its low toxicity presents a novel therapeutic and safe profile of side effects (American Medical Assn, position paper, 2008).
ACH

Acetylcholine is a target of atypical antipsychotics and ant-spasmodic drugs and anti-cholinergic effects in the central nervous system. Release of this neurotransmitter at the peripheral level blocks to help control spasms. Acetylcholine is needed for Anadamide release which is potentiated by THC using gi/go proteins. Ach is blocked by cannabis in copious areas of the brain such as hippocampus postsynaptically (Schlicker & Kathman, 2001) but is also released in the prefrontal cortex and hippocampus (Guy, Whittle & Robson, 2004, p.106).

For more understanding of neurotransmitters and where they are generally blocked or released in specific brain areas and parts of the nerve cell, see upcoming graph “Cannabis and neurotransmitters in the CNS”.

Special Thanks to research partner John Berfelo & Bryan Krumm RN, John Gettman.
References:

American Scientist. (July/August 2000 ). Depression and the birth and death of brain cells. Retrieved from http://newbraincell/index.html

Baywitch et al. (1996). Department of Neurobiology. The Journal of Biological Chemistry, 271(17), p.9902-9905. University of Jerusalem , Israel . Retrieved September 8 th , 2008 from http://www.druglibrary.org/crl/receptors/agonists/.pdf

Bearman, D. (2006). PTSD and Cannabis: A Clinician Ponders Mechanism of Action. Journal of the California Cannabis Research Medical Group. Retrieved January 11, 2008 from www.davidbearmanmd.com/docs/ptsdccrmg.htm

Bonhaus e al. (1998). Dual Activation and inhibition of adenyl cyclase by cannabinoid receptor agonists: evidence for agonist specific tracking of intracellular responses. Journal of pharmacology and experimental therapeutics, 287(3). Department of molecular pharmacology, Roche Bioscience pharmaceuticals. Retrieved September 8 th 2008 from http://www.druglibrary.org/PharmacolExpTher.pdf

Cheer, J. F., Wassum, K. M., Heien, M.L., Phillips, P. E., Wrightman, R. M. May 2004. Cannabinoids enhance "subsecond" dopamine release in the nucleus accumbens of awake rats. The journal of neuroscience 24(28), 4393-4400. http://www.jneurosci.org/cgi/content/full/24/18/4393

Cichewicz, D. L, Haller, V.L, Welch, S.P. 2001. Changes in Opiod and cannabinoid receptor protein following a short-term combination therapy thc-9 and morphine. Department of Pharmacology and Toxicology, Virginia Commonwealth University . The Journal of Pharmacology and Experimental Therapeutics, 297(121-127). Retrieved from the Beckley Foundation website http://www.beckleyfoundation.org/librarycontents.html

Where many studies concur with the current research.

Fride, E. 2002. Endo cannabinoids in the central nervous system, an overview.
Retrieved from http://www.beckleyfoundation.org/bib..._E_11181_1.pdf

Gardener, F. (2007). Molecule of the year: Cannabidiol. Retrieved from http://74.125.95.132/search?q=cache:...r12222007.html

Gettman, July 1997. Update about the dependence liability of marijuana. Retrieved from http://www.drugscience.org/Petition/UPDJUL97.html

Glass, M. & Felder, C. C. (1997). Concurrent stimulation of cannabinoid cb1 and dopamine D2 receptors augment s cAMP accumulation in striatial neurons; evidence for a gs linkage to the CB1 receptor. The Journal of Neuroscience, 17(14), p.5327-5333. National Institute of Mental Health, Bethsada Maryland . Retrieved September 8 th , 2008 from http://www.druglibrary.org/.pdf

Green, B E., Ritter, C. March 2000. Marijuana use and depression. Journal of Health and social behavior, 41, 40-49. Retrieved from http://www.beckleyfoundation.org/bib...Green_2000.pdf

Grotenherman. 2006. Endocannabinoids and the endocannabinoid system: Mini-review. Cannabinoids 1(1), p10-14). Retrieved Jan 2008 from http://209.85.173.104/search?q=cache...ed.org/english

Guy, G.W, whittle, B.A., & Robson, P.J. (2004). The Medicinal Uses of Cannabis and Cannabinoids. GW Pharmaceuticals and Oxford University . UK , Pharmaceutical Press.
Many studies in this book concur with others cited here.

Hoffman, A.F. & Lupica, C.R. (2000). Mechanisms of cannabinoid inhibition of GABAa synaptic transmission in the hippocampus. Cellular Neurobiology Branch, NIDA, Baltimore , Maryland . Retrieved September 8 th , 2008 from http://www.jneurosci.org/cgi/content/full/20/7/2470

Hohman, A.G. & Suplita, R.L. (2006). Endocannabinoid mechanism of pain Modulation. Department of Psychology, University of Georgia , Athens .

Howlett, A. C. (1995). Pharmacology of Cannabinoid receptors. Journal of Pharmacology and Toxicology, 35, 607- 634. Department of Pharmacological and Physiological Science. St. Louis University School of Medicine. Retrieved September 8 th 2008 from www.druglibrary.org/crl

Nicoll, R. A. & Alger, B. N. (2004). The Brain's own Marijuana. Scientific American, January. Retrieved January 27 th 2008 from www.cannabis.net/endocannabinoids.html

Piomelli, R. (2003). The Molecular Logic of Endocannabinoid Signalling. Nature Reviews, 11(4), p.873-884, Deparment of Pharmacology, University of California .

Rodriguez, E. M., Millán-Aldaco , D. , Palomero-Rivero, M., Mechoulam, R. & Drucker-Colín , R. August 2006. Cannabidiol, a constituent of cannabis sativa modulates sleep in rats. Febs letters, 580(18), 4337-4345. Retrieved from http://www.sciencedirect.com/science?_ob=Article

Romero et al. (1998). Time course of the cannabinoid receptor in downregulation in the adult rat brain caused by repeated exposure to THC-9. Synapse 30, p.298-308 retrieved September 8 th 2008 from http://www.druglibrary.org/pdf

Many studies in the drug library reinforce other studies cited here.

Rubino, T., Vigano, D., Massi, P., Spinello, M., Zagato, E., Giagnoni, G., Parolaro, D. 2000. Chronic THC9 treatment increases cAMP levels and cAMP dependant protein kinase activity in some rat brain regions. Neuropharmacology, 39, 1331-1336. Retrieved from http://www.beckleyfoundation.org/.pdf

Schlicker, E & Kathmann, M. 2001. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends in Pharmalogical Science 22(11).

Viveros, M. P., Marco, E. M. & File, S. E. Endocannabinoid system and stress and anxiety responses. Department of Physiology & Biology, University of Madrid , Spain .

Wiley, J.L. 1999. Cannabis: Discrimination of Internal Bliss? Virginia Commonwealth University . Department of Pharmacology and Toxicology. Pharmacology, Biochemistry and Behavior, 64(2), 257-260..

Chapter 2: cannabinoids and animal Physiology. Retrieved from http://www.druglibrary.org/schaffer/...m/iom2.htm#ch2

Peace John Berfelo

[Goodbuddy]

Deffo worth a read through the links.

Moving to the medical section where it will be more appreciated

[Skunk Brother]

A good 6months+ worth of reading there, I hope people use it. Great re-post.

[DrGreen]

uyeah me too i use it every day fior like 2 years when explaining to people about medical benefits this topic has helped me alot, its bloody deep!! but damn its soo good ive a few more things to share soon thats your going to love!! look out for the posts