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Serotonin, tryptophan metabolism and the brain-gut-microbiome axis

12/31/2017

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​Something for 2018 ~ Gut instinct is bidirectional
 
Serotonin, tryptophan metabolism and the brain-gut-microbiome axis
Behavioural Brain Research
15 January 2015: Pages 32-48
S.M. O’Mahony, et al
 
The Abstract as Poem
(Or, A Microbiota Ode to the Brain-Gut Axis)
 
The brain-gut axis is
 a bidirectional communication system
 between the central nervous system
 and the gastrointestinal tract.
 
Serotonin functions as a key neurotransmitter
 at both terminals of this network.
 
Accumulating evidence points to a critical role
 for the gut microbiome
 in regulating normal functioning of this axis.
 
In particular,
 it is becoming clear
 that the microbial influence on tryptophan metabolism
 and the serotonergic system
 may be an important node in such regulation.
 
There is also substantial overlap
 between behaviours influenced by the gut microbiota
 and those which rely on intact serotonergic neurotransmission.
 
The developing serotonergic system may be vulnerable
 to differential microbial colonisation patterns
 prior to the emergence of a stable adult-like gut microbiota.
 
At the other extreme of life,
 the decreased diversity and stability of the gut microbiota
 may dictate serotonin-related health problems in the elderly.
 
The mechanisms underpinning this crosstalk
 require further elaboration
 but may be related to the ability of the gut microbiota
 to control host tryptophan metabolism along the kynurenine pathway,
 thereby simultaneously
 reducing the fraction available for serotonin synthesis
 and increasing the production of neuroactive metabolites.
 
The enzymes of this pathway are immune and stress-responsive,
 both systems which buttress the brain-gut axis.
 
In addition,
 there are neural processes in the gastrointestinal tract
 which can be influenced
 by local alterations in serotonin concentrations
 with subsequent relay of signals
 along the scaffolding of the brain-gut axis
 to influence CNS neurotransmission.
 
Therapeutic targeting
 of the gut microbiota
 might be a viable treatment strategy
 for serotonin-related brain-gut axis disorders.
 
Here’s to Buttressed Happy Guts in 2018!
 
*Next Up: 1 February 2018 and a 2020 Update.
 
Posted by Bryan W. Brickner
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Homeostasis: Equinox Serotonin (5HT) Headache Stories

9/20/2014

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PictureHomeostatic Life Light (2014)






The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius

Headache Edition ~ Autumnal Equinox


Equinox and Homeostasis are mid-point extremes and today’s serotonin system science looks at 5-HT (5-hydroxytryptamine) and its role in modulating another extreme, the brain: specifically, headaches. Below are five (brief) science stories from the National Institutes of Health (PubMed). The serotonin brain tales include: pro-cognitive 5-HT4 receptors, mitigating medication overuse, abnormal headache chronicity, (red) wine interference mechanisms, and new cluster headache horizons.

Autumnal Equinox Health Everyone!

1. Serotonin 5-HT4 Receptors ~ Pro-Cognitive Hippocampal Effects
“Activation of serotonin 5-HT4 receptors has pro-cognitive effects on memory performance. … These results indicate that 5-HT4 receptors are not synthesized by cholinergic cells, and thus would be absent from cholinergic terminals. In contrast, several non-cholinergic cell populations within the basal forebrain and its target hippocampal and cortical areas express these receptors and are thus likely to mediate the enhancement of acetylcholine release elicited by 5-HT4 agonists.”
Serotonin 5-HT4 receptors and forebrain cholinergic system: receptor expression in identified cell populations.
Peñas-Cazorla R, Vilaró MT.
Brain Struct Funct. 2014 Sep 3. [Epub ahead of print]
PMID: 25183542 [PubMed - as supplied by publisher]
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2. Serotonin Metabolism ~ Reversing Anxiety and Depression
“Medication overuse headache (MOH) affects between 1% and 2% of the general population but is present in up to 50% of patients seen in headache centers. … We conclude that headache frequency can be reduced to episodic headache in more than 50% of the patients by simple detoxification and information. Approximately half the patients will not have need for prophylactic medication after withdrawal. Pain perception is altered in patients with MOH but can be restored to a baseline pattern, indicating a reversible mechanism in the central sensitization leading to chronic pain. The great comorbidity with depression and anxiety could be a consequence of the altered serotonin metabolism indicating a reversible and potentially treatable condition.”
Medication overuse headache.
Munksgaard SB, Jensen RH.
Headache. 2014 Jul-Aug;54(7):1251-7. doi: 10.1111/head.12408. Epub 2014 Jul 2.
PMID: 24990298 [PubMed - in process]
Related citations

3. Serotonergic Homeostasis ~ Chronic Migraine and Tension-Type Headaches
“The primary aim of this study (TA-CH, Tryptophan Amine in Chronic Headache) was to investigate a possible role of tryptophan (TRP) metabolism in chronic migraine (CM) and chronic tension-type headache (CTTH). … Our results support the hypothesis that TRP metabolism is altered in CM and CTTH patients, leading to a reduction in plasma TRY. As TRY modulates the function of pain matrix serotonergic system, this may affect modulation of incoming nociceptive inputs from the trigeminal endings and posterior horns of the spinal cord. We suggest that these biochemical abnormalities play a role in the chronicity of CM and CTTH.”
Tryptamine levels are low in plasma of chronic migraine and chronic tension-type headache.
D'Andrea G, D'Amico D, Bussone G, Bolner A, Aguggia M, Saracco MG, Galloni E, De Riva V, D'Arrigo A, Colavito D, Leon A, Perini F.
Neurol Sci. 2014 Jul 14. [Epub ahead of print]
PMID: 25016960 [PubMed - as supplied by publisher]
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4. Serotonin Metabolism / Migraines ~ Wine Interference Mechanisms
“Wine, and specifically red wine, is a migraine trigger. Non-migraineurs may have headache attacks with wine ingestion as well. The reasons for that triggering potential are uncertain, but the presence of phenolic flavonoid radicals and the potential for interfering with the central serotonin metabolism are probably the underlying mechanisms of the relationship between wine and headache. Further controlled studies are necessary to enlighten this traditional belief.”
Wine and headache.
Krymchantowski AV, da Cunha Jevoux C.
Headache. 2014 Jun;54(6):967-75. doi: 10.1111/head.12365. Epub 2014 May 6.
PMID: 24801068 [PubMed - in process]
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5. Serotonin Homeostasis ~ New Migraine and Cluster Headache Horizons
“Migraine and cluster headache are primary headache disorders commonly encountered in clinical practice. … This article will highlight several of the new treatments that are currently under investigation including novel delivery mechanisms of already existing medications, calcitonin gene-related peptide (CGRP) receptor antagonists, antibodies to CGRP and its receptor, serotonin receptor agonists, transient receptor potential vanilloid receptor modulators, orexin receptor antagonists, glial cell modulators, and neuromodulation.”
New treatments for headache.
Vollbracht S, Rapoport AM.
Neurol Sci. 2014 May;35 Suppl 1:89-97. doi: 10.1007/s10072-014-1747-z.
PMID: 24867844 [PubMed - in process]
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Serotonin Video: The Truth about Depression BBC Full Documentary 2013
~
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Homeostasis: Publius’ (Ultralow) THC Political Cannabinoid Science

9/5/2014

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PictureThe Cannabis Papers by Publius






The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius

Welcome Homeostasis!
Burning Man Edition

Today’s science roundup looks at four 2014 articles on how the cannabinoid system (CS) modulates our health through homeostasis. The line-up links to CS PubMed articles discussing: hippocampus inhibition and excitation, pain relief from a Chinese herb (thunder God vine), GABA pain dis-inhibition, and brain protection from a single ultralow dose of tetrahydrocannabinol (THC).

The annual Burning Man festival in Black Rock City (NV) was last week; participants test their CS by enduring two Black Rock extremes ~ art and nature ~ which create space for mind and body to catch a glimpse of … spirit.

I. Hippocampus Homeostasis (Inhibition and Excitation) and the CS (Endos)
“Endocannabinoids (eCBs) modulate both excitatory and inhibitory neurotransmission in hippocampus via activation of pre-synaptic cannabinoid receptors. Here, we present a model for cannabinoid mediated short-term depression of excitation (DSE) based on our recently developed model for the equivalent phenomenon of suppressing inhibition (DSI). … Finally, we explore under which conditions the combination of DSI and DSE can temporarily shift the fine balance between excitation and inhibition. This highlights a mechanism by which eCBs might act in a neuro-protective manner during high neural activity.”
Cannabinoid-mediated short-term plasticity in hippocampus.
Zachariou M, Thul R.
J Comput Neurosci. 2014 Aug 16. [Epub ahead of print]
PMID: 25123173 [PubMed - as supplied by publisher]
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II. Homeostasis (Pain Relief) and CS CB2 Signaling
“Celastrol, a major active ingredient of Chinese herb Tripterygium wilfordii Hook. f. (thunder god vine), has exhibited a broad spectrum of pharmacological activities, including anti-inflammation, anti-cancer and immunosuppression. … Taken together, our results demonstrate the analgesia effects of celastrol through CB2 signaling and propose the potential of exploiting celastrol as a novel candidate for pain relief.”
Celastrol attenuates inflammatory and neuropathic pain mediated by cannabinoid receptor type 2.
Yang L, Li Y, Ren J, Zhu C, Fu J, Lin D, Qiu Y.
Int J Mol Sci. 2014 Aug 6;15(8):13637-48. doi: 10.3390/ijms150813637.
PMID: 25101848 [PubMed - in process] Free Article
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III. Homeostasis (GABA Pain Dis-inhibition) and the CS
“At the cellular level, opioids and cannabinoids are hypothesised to activate descending analgesia through an indirect process of 'GABA disinhibition'-suppression of inhibitory GABAergic inputs onto output neurons which constitute the descending analgesic pathway.”
Descending modulation of pain: the GABA disinhibition hypothesis of analgesia.
Lau BK, Vaughan CW.
Curr Opin Neurobiol. 2014 Jul 24;29C:159-164. doi: 10.1016/j.conb.2014.07.010. [Epub ahead of print] Review.
PMID: 25064178 [PubMed - as supplied by publisher]
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IV. Homeostasis (CS CNS Protection) from a Single Ultralow Dose of THC
“In our previous studies, we found that a single ultralow dose of tetrahydrocannabinol (THC; 0.002 mg/kg, three to four orders of magnitude lower than the conventional doses) protects the brain from different insults that cause cognitive deficits. … Our results suggest that an ultralow dose of THC that lacks any psychotrophic activity protects the brain from neuroinflammation-induced cognitive damage and might be used as an effective drug for the treatment of neuroinflammatory conditions, including neurodegenerative diseases.”
Ultralow doses of cannabinoid drugs protect the mouse brain from inflammation-induced cognitive damage.
Fishbein-Kaminietsky M, Gafni M, Sarne Y.
J Neurosci Res. 2014 Jul 16. doi: 10.1002/jnr.23452. [Epub ahead of print]
PMID: 25042014 [PubMed - as supplied by publisher]
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Video: Cannabinoid Profiles - THC, THCA, THCV, CBD, CBG, CBN, CBC & Terpenes    

PictureOnce Upon A Time ...



Posted by Bryan W. Brickner






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Homeostatic Cannabinoid Science ~ Publius’ World Cup Edition

7/6/2014

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PictureThe Cannabis Papers by Publius (2011)






The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius


A World (Cup) of Cannabinoids: Fielders Edition

Today’s science roundup looks at ten articles on how the cannabinoid system (CS) modulates our health and homeostasis; the line-up links to 2014 CS PubMed articles: four directly on homeostasis, two on the circulatory system, two on the central nervous system, and one each on our digestive and respiratory systems.

I. CNS (Pediatric Brain Injury) and the CS
“Paediatric traumatic brain injury (TBI) is a leading cause of death and disability. Previous studies showed neuroprotection after TBI by (endo)cannabinoid mechanisms, suggesting involvement of cannabinoid receptors (CBR). … The results may provide explanation for the neuroprotective properties of cannabinoid ligands and future therapeutic strategies of TBI.”
Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet.
Donat CK, Fischer F, Walter B, Deuther-Conrad W, Brodhun M, Bauer R, Brust P.
Acta Neurobiol Exp (Wars). 2014;74(2):197-210.
PMID: 24993629 [PubMed - in process]
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II. Digestive System (Irritable Bowel Syndrome) and the CS
“The activation of the ATP ion-gated channels, voltage-gated sodium (Nav) and calcium (Cav) channels, as well as the activation of protease-activated receptors (PAR2), transient receptor potential vanilloide-1, serotonin, cannabinoids and cholecystokinin are involved in the genesis of visceral hypersensitivity in IBS.”
Main ion channels and receptors associated with visceral hypersensitivity in irritable bowel syndrome.
de Carvalho Rocha HA, Dantas BP, Rolim TL, Costa BA, de Medeiros AC.
Ann Gastroenterol. 2014;27(3):200-206. Review.
PMID: 24976114 [PubMed - as supplied by publisher] Free PMC Article
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III. Respiratory System (Paraquat and Acute Lung Injury) and the CS
“Paraquat [PQ], a widely used herbicide, is well known to exhibit oxidative stress and lung injury. … The results suggested that activating CB2 receptor exerted protective activity against PQ-induced ALI [Acute Lung Injury], and it potentially contributed to the suppression of the activation of MAPKs and NF- κ B pathways.”
CB2 Receptor Activation Ameliorates the Proinflammatory Activity in Acute Lung Injury Induced by Paraquat.
Liu Z, Wang Y, Zhao H, Zheng Q, Xiao L, Zhao M.
Biomed Res Int. 2014;2014:971750. doi: 10.1155/2014/971750. Epub 2014 May 22.
PMID: 24963491 [PubMed - in process] Free PMC Article
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IV. Homeostasis (Indole Quinuclidine Analogs) and the CS
“Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors.”
Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole quinuclidine analogs.
Franks LN, Ford BM, Madadi NR, Penthala NR, Crooks PA, Prather PL.
Eur J Pharmacol. 2014 Aug 15;737:140-8. doi: 10.1016/j.ejphar.2014.05.007. Epub 2014 May 20.
PMID: 24858620 [PubMed - in process]
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V. Circulatory System (Ischemic Heart Disease) and the CS
“Ischemic heart disease is associated with inflammation, interstitial fibrosis and ventricular dysfunction prior to the development of heart failure. … Therefore, the endocannabinoid-CB2 receptor axis plays a key role in cardioprotection during the initial phase of ischemic cardiomyopathy development.”
The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy.
Duerr GD, Heinemann JC, Suchan G, Kolobara E, Wenzel D, Geisen C, Matthey M, Passe-Tietjen K, Mahmud W, Ghanem A, Tiemann K, Alferink J, Burgdorf S, Buchalla R, Zimmer A, Lutz B, Welz A, Fleischmann BK, Dewald O.
Basic Res Cardiol. 2014 Jul;109(4):425. doi: 10.1007/s00395-014-0425-x. Epub 2014 Jul 1.
PMID: 24980781 [PubMed - in process]
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VI. Homeostasis, Endocannabinoid Deficiencies and the CS
“Subsequent research has confirmed that underlying endocannabinoid deficiencies indeed play a role in migraine, fibromyalgia, irritable bowel syndrome and a growing list of other medical conditions. Clinical experience is bearing this out. Further research and especially, clinical trials will further demonstrate the usefulness of medical cannabis. As legal barriers fall and scientific bias fades this will become more apparent.”
Clinical endocannabinoid deficiency (CECD) revisited: Can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?
Smith SC, Wagner MS.
Neuro Endocrinol Lett. 2014 Jun 30;35(3):198-201. [Epub ahead of print]
PMID: 24977967 [PubMed - as supplied by publisher]
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VII. Homeostasis (Epilepsy, Neuronal Plasticity) and the CS
“Synaptic communication requires constant adjustments of pre- and postsynaptic efficacies. In addition to synaptic long-term plasticity, the presynaptic machinery underlies homeostatic regulations which prevent out of range transmitter release. In this mini-review we will discuss the relevance of selected presynaptic mechanisms to epilepsy including voltage- and ligand-gated ion channels as well as cannabinoid and adenosine receptor signaling.”
Presynaptic mechanisms of neuronal plasticity and their role in epilepsy.
Meier J, Semtner M, Winkelmann A, Wolfart J.
Front Cell Neurosci. 2014 Jun 17;8:164. doi: 10.3389/fncel.2014.00164. eCollection 2014. Review.
PMID: 24987332 [PubMed]
Related citations

VIII. Homeostasis (Turning Agonists into Antagonists) and the CS
“However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists.”
Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB2R selective benzimidazoles reveal unexpected intrinsic properties.
Nimczick M, Pemp D, Darras FH, Chen X, Heilmann J, Decker M.
Bioorg Med Chem. 2014 Jun 13. pii: S0968-0896(14)00454-4. doi: 10.1016/j.bmc.2014.06.008. [Epub ahead of print]
PMID: 24984935 [PubMed - as supplied by publisher]
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IX. Circulatory System (Blood Vessels-Heart) and the CS
“2-Arachidonoylglycerol [2-AG] plays an important role in the regulation of the circulatory system via direct and/or indirect, through their metabolites, effects on blood vessels and/or heart. Accumulating evidence reveals that 2-AG is involved in the pathogenesis of various shocks and atherosclerosis.”
Role of endocannabinoid 2-arachidonoylglycerol in the physiology and pathophysiology of the cardiovascular system.
Karabowicz P, Grzęda E, Baranowska-Kuczko M, Malinowska B.
Postepy Hig Med Dosw (Online). 2014 Jun 12;68(0):814-27.
PMID: 24934539 [PubMed - in process]
Related citations

X. CNS (Brain Mitochondria) and the CS
“Our results show that the use of appropriate controls and quantifications allows detecting mtCB1 receptor with CB1 receptor antibodies, and that, if mitochondrial fractions are enriched and purified, CB1 receptor agonists reliably decrease respiration in brain mitochondria.”
Cannabinoid control of brain bioenergetics: Exploring the subcellular localization of the CB1 receptor.
Hebert-Chatelain E, Reguero L, Puente N, Lutz B, Chaouloff F, Rossignol R, Piazza PV, Benard G, Grandes P, Marsicano G.
Mol Metab. 2014 Apr 2;3(4):495-504. doi: 10.1016/j.molmet.2014.03.007. eCollection 2014 Jul.
PMID: 24944910 [PubMed] Free PMC Article
Related citations

See also: Alzheimer’s, Cancer and Homeostatic Cannabinoid Science

Bonus Video: Homeostasis

Posted by Bryan W. Brickner


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Solstice Serotonin (5HTP) Science Stories

6/20/2014

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PictureLife ~ circa 2014






Serotonin activation was our topic on 19 April 2014; it’s serotonin life sciences today with the precursor 5-HTP (5-hydroxytryptophan) in highlight. 

Below are four (brief) science stories from the National Institutes of Health (PubMed). Shortened titles should suffice to suggest the main themes: Therapeutic 5-HTP, Hot Flash and Breast Cancer Reduction, Irritable Bowels, and Morphine’s Efficacy. The links and quotes are from PubMed (1998-2014).

Healthy Solstice Everyone!
~.~
Therapeutic 5-HTP Has Been Shown … (1998)
“5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. … Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.”
5-Hydroxytryptophan: a clinically-effective serotonin precursor.
Birdsall TC.
Altern Med Rev. 1998 Aug;3(4):271-80. Review.
PMID: 9727088 [PubMed - indexed for MEDLINE] Free Article
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Hot Flash (and Breast Cancer) Reduction: a hypothesis (2005)
“This would be particularly desirable for menopausal women with breast cancer or with risks of breast cancer. This article discusses the background information on hot flashes, SSRIs, tryptophan, and 5HTP, and possible clinical application of 5HTP for menopausal women with breast cancer risk.”
The potential of 5-hydryoxytryptophan for hot flash reduction: a hypothesis.
Curcio JJ, Kim LS, Wollner D, Pockaj BA.
Altern Med Rev. 2005 Sep;10(3):216-21.
PMID: 16164376 [PubMed - indexed for MEDLINE] Free Article
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A Serotonin-mediated Mechanism in Bowels (2014)
“Oral 5-HTP induced alterations in mucosal 5-HT metabolism. In healthy controls, a reinforcement of the intestinal barrier was seen whereas such reaction was absent in IBS [irritable bowel syndrome] patients. This could indicate the presence of a serotonin-mediated mechanism aimed to reinforce intestinal barrier function, which seems to dysfunction in IBS patients.”
Serotonergic reinforcement of intestinal barrier function is impaired in irritable bowel syndrome.
Keszthelyi D, Troost FJ, Jonkers DM, van Eijk HM, Lindsey PJ, Dekker J, Buurman WA, Masclee AA.
Aliment Pharmacol Ther. 2014 Jun 18. doi: 10.1111/apt.12842. [Epub ahead of print]
PMID: 24943480 [PubMed - as supplied by publisher]
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Serotonin and Morphine’s Efficacy (2014)
“Systemic administration of morphine increases 5-HT levels in the spinal cord, and the increase in 5-HT contributes to morphine-induced analgesia in the normal state but attenuates that in neuropathic pain through spinal 5-HT3 receptors. The plasticity of the descending serotonergic system may contribute to the reduced efficacy of systemic morphine in neuropathic pain.”
Peripheral Nerve Injury Reduces Analgesic Effects of Systemic Morphine via Spinal 5-Hydroxytryptamine 3 Receptors.
Kimura M, Obata H, Saito S.
Anesthesiology. 2014 Jun 2. [Epub ahead of print]
PMID: 24887968 [PubMed - as supplied by publisher]
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VIDEO:
5HTP benefit and side effects of 5htp, dosage, anxiety, weight loss, sleep

BONUS VIDEO: Serotonin/Binaural Beats
5-HTP secretion for happiness binaural beats, intensity WARNING

~ Posted by Bryan W. Brickner ~


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Homeostatic Cannabinoid Science ~ Publius’ May Roundup

5/30/2014

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Picture
Astrocyte / Blood-Brain Barrier by Ben Brahim Mohammed

The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius

Here are seven new 2014 findings on how the cannabinoid system (CS) modulates homeostasis and other systems in our bodies: the roundup links to recent PubMed articles on the urinary, neuroendocrine, digestive, central nervous and serotonin systems.

I. Urinary System (Kidney / Diabetes) and CS
“A functionally active endocannabinoid system is present within the kidney. The cannabinoid receptor type 2 (CB2) is expressed by both inflammatory cells and podocytes, and its activation has beneficial effects in experimental diabetic nephropathy. … Thus, CB2 deletion worsens diabetic nephropathy, independent of bone marrow-derived cells.”
Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice.
Barutta F, Grimaldi S, Franco I, Bellini S, Gambino R, Pinach S, Corbelli A, Bruno G, Rastaldi MP, Aveta T, Hirsch E, Di Marzo V, Gruden G.
Kidney Int. 2014 May 14. doi: 10.1038/ki.2014.165. [Epub ahead of print]
PMID: 24827776 [PubMed - as supplied by publisher]
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II. Neuroendocrine System (Skin) and CS
“Recent evidence has shown that the neuroendocrine regulation of human skin biology also extends to keratins, the major structural components of epithelial cells. For example, thyrotropin-releasing hormone, thyrotropin, opioids, prolactin, and cannabinoid receptor 1-ligands profoundly modulate human keratin gene and protein expression in human epidermis and/or hair follicle epithelium in situ.”
Harnessing neuroendocrine controls of keratin expression: A new therapeutic strategy for skin diseases?
Ramot Y, Paus R.
Bioessays. 2014 May 13. doi: 10.1002/bies.201400006. [Epub ahead of print]
PMID: 24823963 [PubMed - as supplied by publisher]
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III. Digestive System and CS
“Palmitoylethanolamide (PEA), a naturally-occurring acylethanolamide chemically related to the endocannabinoid anandamide, interacts with targets that have been identified in peripheral nerves controlling gastrointestinal motility, i.e. cannabinoid (CB1 and CB2 ) receptors, transient receptor potential vanilloid type-1 (TRPV1), and peroxisomal proliferator activated receptor α (PPARα).”
Ultramicronized palmitoylethanolamide normalizes intestinal motility in a murine model of post-inflammatory accelerated transit: involvement of CB1 receptors and TRPV1.
Capasso R, Orlando P, Pagano E, Aveta T, Buono L, Borrelli F, Di Marzo V, Izzo AA.
Br J Pharmacol. 2014 May 12. doi: 10.1111/bph.12759. [Epub ahead of print]
PMID: 24818658 [PubMed - as supplied by publisher]
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IV. Central Nervous System and CS
“G-protein-coupled receptors (GPCRs) constitute an example of proteins that are the key factors in the framework needed to sustain brain and nerve structure and function. The versatility underlying nervous system anatomy takes advantage of a recently discovered feature of GPCRs, the possibility to form heteromers that, placed at specific neuronal subsets and at specific locations (pre-, post-, or peri-synaptic), contribute to attain unique neural functions.”
G-Protein-Coupled Receptor Heteromers as Key Players in the Molecular Architecture of the Central Nervous System.
Brugarolas M, Navarro G, Martínez-Pinilla E, Angelats E, Casadó V, Lanciego JL, Franco R.
CNS Neurosci Ther. 2014 May 9. doi: 10.1111/cns.12277. [Epub ahead of print]
PMID: 24809909 [PubMed - as supplied by publisher]
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V. Serotonin System and the CS
“Serotonin (5-HT) plays pivotal roles in the pathogenesis of post-infectious irritable bowel syndrome (PI-IBS), and luminal 5-HT time-dependently modulates visceral nociception. We found that duodenal biopsies from PI-IBS patients exhibited increased 5-HT and decreased anandamide levels and that decreased anandamide was associated with abdominal pain severity, indicating a link between 5- HT and endocannabinoid signaling pathways in PI-IBS.”
Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats.
Feng CC, Yan XJ, Chen X, Wang EM, Liu Q, Zhang LY, Chen J, Fang JY, Chen SL.
Pain. 2014 May 8. pii: S0304-3959(14)00225-5. doi: 10.1016/j.pain.2014.05.005. [Epub ahead of print]
PMID: 24813296 [PubMed - as supplied by publisher]
Related citations

VI. Central Nervous System (Blood-Brain Barrier) and CS
“Early brain injury (EBI), following subarachnoid hemorrhage (SAH), comprises blood-brain barrier (BBB) disruption and consequent edema formation. … We suggest that CB2R stimulation attenuates neurological outcome and brain edema, by suppressing leukocyte infiltration into the brain through TGF-β1 up-regulation and E-selectin reduction, resulting in protection of the BBB after SAH.”
Cannabinoid type 2 receptor stimulation attenuates brain edema by reducing cerebral leukocyte infiltration following subarachnoid hemorrhage in rats.
Fujii M, Sherchan P, Krafft PR, Rolland WB, Soejima Y, Zhang JH.
J Neurol Sci. 2014 Apr 30. pii: S0022-510X(14)00270-6. doi: 10.1016/j.jns.2014.04.034. [Epub ahead of print]
PMID: 24819918 [PubMed - as supplied by publisher]
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VII. Central Nervous System (Memory) and CS
“The reactivation of a memory can result in its destabilization, necessitating a process of memory reconsolidation to maintain its persistence. Here we show that the destabilization of a contextual fear memory is potentiated by the cannabinoid CB1 receptor agonist Arachidonyl-2-chloroethylamide (ACEA). … These results indicate that memory expression and destabilization, while being independent from one another, are both dependent upon memory reactivation. Moreover, memory destabilization can be enhanced pharmacologically, which may be of therapeutic potential.”
Inhibition and enhancement of contextual fear memory destabilization.
Lee JL, Flavell CR.
Front Behav Neurosci. 2014 Apr 28;8:144. doi: 10.3389/fnbeh.2014.00144. eCollection 2014.
PMID: 24808841 [PubMed] Free PMC Article
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Bonus Video:

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Passing the Alzheimer’s Test and One’s Cannabinoid System ~ An Update

5/29/2014

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Picture
In March we noted the relentless strength of Alzheimer’s disease ~ and it’s still going strong. Good thing so is the science. Here are five more 2014 National Institutes of Health (PubMed) research updates on Alzheimer’s disease and cannabinoids.

The researchers in the third piece below make an interesting point concerning time; seems there haven’t been enough “adequately powered trials” on the safety of cannabinoids in older test subjects. That is harmful and a symptom of our polity.

Talk cannabinoids please … waiting another generation is not acceptable.

I.
Cannabinoid receptor-dependent metabolism of 2-arachidonoylglycerol during aging.
Pascual AC, Gaveglio VL, Giusto NM, Pasquaré SJ.
Exp Gerontol. 2014 Jul;55:134-42. doi: 10.1016/j.exger.2014.04.008. Epub 2014 Apr 24.
PMID: 24768821 [PubMed - in process]
Related citations

II.
Cannabinoids for pain in dementia: the good, the bad, and the ugly.
Ahmed AI, van den Elsen GA, van der Marck MA, Olde Rikkert MG.
J Am Geriatr Soc. 2014 May;62(5):1001-2. doi: 10.1111/jgs.12817. No abstract available.
PMID: 24828945 [PubMed - in process]
Related citations

III.
Efficacy and safety of medical cannabinoids in older subjects: a systematic review.
van den Elsen GA, Ahmed AI, Lammers M, Kramers C, Verkes RJ, van der Marck MA, Rikkert MG.
Ageing Res Rev. 2014 Mar;14:56-64. doi: 10.1016/j.arr.2014.01.007. Epub 2014 Feb 5.
PMID: 24509411 [PubMed - in process]
Related citations

IV.
Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS.
Murataeva N, Straiker A, Mackie K.
Br J Pharmacol. 2014 Mar;171(6):1379-91. doi: 10.1111/bph.12411.
PMID: 24102242 [PubMed - in process]
Related citations

V.
Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer's disease.
González-Naranjo P, Pérez-Macias N, Campillo NE, Pérez C, Arán VJ, Girón R, Sánchez-Robles E, Martín MI, Gómez-Cañas M, García-Arencibia M, Fernández-Ruiz J, Páez JA.
Eur J Med Chem. 2014 Feb 12;73:56-72. doi: 10.1016/j.ejmech.2013.11.026. Epub 2013 Dec 7.
PMID: 24378710 [PubMed - in process]
Related citations

VI.
Video ~ Holistic Alzheimer’s Video: Cannabis Oil and Medical Marijuana

Posted by Bryan W. Brickner

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My Story: 101st Airborne to Medical Cannabis Activist ~ Jim Champion

4/26/2014

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Picture
Picture
Eisenhower with the 502d Parachute Infantry Regiment, 101st Airborne, 5 June 1944.

As a member of the 502nd Infantry, US Army 101st Airborne, my unit was deployed to the kingdom of Jordan in the late 1980s. Soon after, I found myself diagnosed with MS (multiple sclerosis) awaiting a medical discharge instead of starting my second enlistment.

I’ve presently had MS for over 25 years. Each time I went to the doctor with spasms or atrophy that was bending my body into painful and unnatural positions, I’d walk out with a new muscle relaxer or pain pill. By 2003 I found myself taking a cocktail of approximately 59 pills a day which did little for the pain and spasms, and instead turned me into what felt like a sleeping zombie. I’d literally fall asleep in the middle of a conversation! I was a prisoner in my own body.

Later that year I had a muscle spasm that lasted for days. Nothing I did or took would stop it. My cousin came over and convinced me to try cannabis. By the time we finished, my body had stopped twitching and I felt relaxed for the first time in a long time! I was also experiencing another strange sensation: I was hungry! At first, my wife was worried about my smoking on top of all the pills I was taking, but cannabis was providing unparalleled relief from the spasms and atrophy. No spasms or atrophy, no pain! After discussing it with her, we took inventory of my pills and began tapering down the ones I no longer needed thanks to the relief provided by one cannabis cigarette a day! We not only reduced the overall number of pills to just 24 per day, we were able to eliminate some intoxicating medicines all together. By the time we were finished I no longer took Valium, Xanax for tremors, Gabapentin, morphine and Vicodin for breakthrough pain, and several others. Also I reduced the methadone I take every day.

Since that time I have literally been a new man! I used to lay in bed for weeks at a time. I neither had the energy nor desire to ever leave my house. The pills had been making me sicker and weaker. Now I only stay in bed at night and go outside often (when it’s warm outside) and do the things I love – attending Bears, Blackhawks, Bulls, and Cubs games when I choose.

While the Medical Cannabis bill had passed in the Illinois legislature we had all been waiting for the Governor to sign it. My wife saw Governor Quinn at the Lincoln Hotel in Springfield and wanted him to meet me. He had to leave the Lincoln but told her he’d meet me in his office the next morning! He was on time and very nice. He was concerned with what I had to say. I told him about our Medical Cannabis bill and he said he would seriously consider it. When the signing came about I was asked to not only attend but to speak and I received the first pen he signed the bill with. Along with Governor Quinn, Senator William Haine was instrumental in getting Representative Lou Lang’s bill passed and signed. All of us patients who need this medicine are now waiting for the particulars such as dispensary locations, ID registration, and other necessary components of this newly legalized medicine to take effect so we can avail ourselves access.

We now know that this medicine may come in edibles, in vaporizers, tinctures and other ways of dispensing the product that we so seriously need; this personal journey, from Airborne to MS to Activism, has taught me much – mostly, how to think through stress, prepare for contingencies, and deal with life’s obstacle course.

Jim Champion

Edited by William Abens
Posted by bwb 
   
Picture
502nd Inf.
Cannabinoid System Video:
Three Veterans with PTS: Cannabis Therapy 2013   
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Synaptic Serotonin’s Bicycle Day 2014: A (Short) Science Story

4/18/2014

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Picture
Albert Hoffman 1993 (by Philip H. Bailey)

Bicycle Day is the day scientist Albert Hoffman took an intentional dose of lysergic acid diethylamide (LSD) and then rode his bike home.

Hoffman’s intentional dose on 19 April 1943 was actually his second “contact” with LSD. The macro dose day is the memorable bicycle ride home; the unintentional first dose was at a micro level absorbed through his skin (or somehow). Hoffman wasn’t ever very clear on how that happened; he did note a slight modulation from the micro experience … enough to convince him to try the macro.

LSD works because it modulates one’s serotonin system and its plethora of receptors (15 last time I checked). Hoffman was the first to experience the synaptic serotonin effects LSD yields – yet we all modulate our bodies via serotonin … we just do it daily in a micro way (it’s in us).

Below is a four-part science story from the National Institutes of Health (PubMed): it includes a dialogue between our immune and serotonin systems, an early microbiota life tale, a circadian clocks discussion, and talk of bowels (irritable and otherwise) and the brain-gut axis. The links and quotes are from PubMed.

Think of cannabinoids as the wheel’s hub and serotonin as the transmission: for certain, as Albert Hoffman attested, it’s a neurotransmission without equal.

Happy Bicycle Day 2014 Everyone!

~
I. A Dialogue (immune and serotonin systems)
“Neuropsychiatric disorders have long been linked to both immune system activation and alterations in serotonin (5-HT) signaling. In the CNS, the contributions of 5-HT modulate a broad range of targets, most notably, hypothalamic, limbic and cortical circuits linked to the control of mood and mood disorders. In the periphery, many are aware of the production and actions of 5-HT in the gut but are unaware that the molecule and its receptors are also present in the immune system where evidence suggests they contribute to the both innate and adaptive responses. In addition, there is clear evidence that the immune system communicates to the brain via both humoral and neuronal mechanisms, and that CNS 5-HT neurons are a direct or indirect target for these actions.”

A dialogue between the immune system and brain, spoken in the language of serotonin.
Baganz NL, Blakely RD.
ACS Chem Neurosci. 2013 Jan 16;4(1):48-63. doi: 10.1021/cn300186b. Epub 2012 Dec 7. Review.
PMID: 23336044 [PubMed - indexed for MEDLINE] Free PMC Article
Related citations

II. Early Life (immune, endocrine and serotonin systems)
“Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. … Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. … However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. … Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission.”

The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.
Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, Dinan TG, Cryan JF.
Mol Psychiatry. 2013 Jun;18(6):666-73. doi: 10.1038/mp.2012.77. Epub 2012 Jun 12.
PMID: 22688187 [PubMed - indexed for MEDLINE]
Related citations

III. Circadian Clock (chickens and serotonin biosynthesis)
“Serotonin in blood plasma is primarily synthesized in the duodenum [first section of the small intestine], as brain derived serotonin does not cross the blood-brain barrier. Because serotonin in the brain and retina is synthesized under the control of a circadian clock, we sought to determine if a circadian clock in the duodenum regulates serotonin synthesis and release in blood. We examined gene expression in the duodenum of chickens at different times of the day and found that the duodenum rhythmically expresses molecular circadian clock genes and genes controlling serotonin biosynthesis, specifically tryptophan hydroxylase, in a light dark cycle (LD). … Because serotonin in the gut affects duodenal nutrient absorption and gut motility, the control of serotonin production in the duodenum by LD cycles could provide an additional mechanism by which the external environment controls nutrient uptake and digestive function.”

Biological clocks in the duodenum and the diurnal regulation of duodenal and plasma serotonin.
Ebert-Zavos E, Horvat-Gordon M, Taylor A, Bartell PA.
PLoS One. 2013 May 30;8(5):e58477. doi: 10.1371/journal.pone.0058477. Print 2013.
PMID: 23737937 [PubMed - indexed for MEDLINE] Free PMC Article
Related citations

IV. Bowels (irritable and otherwise: brain-gut axis)
“Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract characterized by abdominal discomfort, pain and changes in bowel habits, often associated with psychological/psychiatric disorders. It has been suggested that the development of IBS may be related to the body’s response to stress, which is one of the main factors that can modulate motility and visceral perception through the interaction between brain and gut (brain-gut axis). … Several lines of evidence indicate that 5-HT and its receptor subtypes are likely to have a central role in the pathophysiology of IBS. 5-HT released from enterochromaffin cells regulates sensory, motor and secretory functions of the digestive system through the interaction with different receptor subtypes. It has been suggested that pain signals originate in intrinsic primary afferent neurons and are transmitted by extrinsic primary afferent neurons. Moreover, IBS is associated with abnormal activation of central stress circuits, which results in altered perception during visceral stimulation.”

Serotonin receptors and their role in the pathophysiology and therapy of irritable bowel syndrome.
Stasi C, Bellini M, Bassotti G, Blandizzi C, Milani S.
Tech Coloproctol. 2014 Jan 15. [Epub ahead of print]
PMID: 24425100 [PubMed - as supplied by publisher]
Related citations

Plus ~ Today's Video ~
Serotonin and the Gut Brain Connection
http://www.youtube.com/watch?v=KYT5syDMsTQ

Posted by Bryan W. Brickner

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Indiscernible Cannabinoid System Science ~ Publius’ February 2014 Roundup

2/27/2014

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Picture
The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius 


This roundup links to seven 2014 PubMed articles on cannabinoids modulating other systems in our bodies, such as: the olfactory, endocrine, vanilloid, serotonin, opioid, dopamine, and nervous systems. There’s also a bit of systemic science ~ getting a good night’s sleep.


I. Olfactory System and CS
“Thus, CB1 receptor-dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior.”

The endocannabinoid system controls food intake via olfactory processes.
  Soria-Gómez E, Bellocchio L, Reguero L, Lepousez G, Martin C, Bendahmane M, Ruehle S, Remmers F, Desprez T, Matias I,
  Wiesner T, Cannich A, Nissant A, Wadleigh A, Pape HC, Chiarlone AP, Quarta C, Verrier D, Vincent P, Massa F, Lutz B,
  Guzmán M, Gurden H, Ferreira G, Lledo PM, Grandes P, Marsicano G.
  Nat Neurosci. 2014 Mar;17(3):407-15. doi: 10.1038/nn.3647. Epub 2014 Feb 9.
  PMID: 24509429 [PubMed - in process]

II. Endocrine System (Hypothalamus-pituitary axis) and CS
“Whereas the effect on 3β-HSD was counteracted by SR141716A (Rimonabant) - a selective antagonist of CB1, thus indicating a CB1 dependent modulation - the effect on cyp17 was not, suggesting a possible involvement of receptors other than CB1, probably the type-1 vanilloid receptor (TRPV1), since AEA works as an endocannabinoid and an endovanilloid as well.”

Hypothalamus-pituitary axis: an obligatory target for endocannabinoids to inhibit steroidogenesis in frog testis.
  Chianese R, Ciaramella V, Fasano S, Pierantoni R, Meccariello R.
  Gen Comp Endocrinol. 2014 Feb 21. pii: S0016-6480(14)00053-7. doi: 10.1016/j.ygcen.2014.02.010. [Epub ahead of print]
  PMID: 24566122 [PubMed - as supplied by publisher]

III. Vanilloid System (Schizophrenia) and CS
“Our results indicate that the schizophrenia-like behaviors displayed by SHR [Spontaneously Hypertensive Rats]  are differently altered by cannabinoid and vanilloid drugs when compared to control animals and suggest the endocannabinoid and the vanilloid systems as a potential target for the treatment of schizophrenia.”

Effects of cannabinoid and vanilloid drugs on positive and negative-like symptoms on an animal model of schizophrenia: The SHR strain.
  Almeida V, Peres FF, Levin R, Suiama MA, Calzavara MB, Zuardi AW, Hallak JE, Crippa JA, Abílio VC.
  Schizophr Res. 2014 Feb 17. pii: S0920-9964(14)00062-0. doi: 10.1016/j.schres.2014.01.039. [Epub ahead of print]
  PMID: 24556469 [PubMed - as supplied by publisher]

IV. Serotonin, Opioid, and Dopamine Systems and CS
“In this review we highlight the evidence for the physiological role of such constitutive GPCR [G protein-coupled receptor]   activity (in particular for cannabinoid 1, serotonin 2C and mu-opioid receptors) in the ventral tegmental area and in its output regions like the nucleus accumbens. We also address the behavioral relevance of constitutive GPCR signaling and discuss the repercussions of its abolition in dopamine-related psychiatric diseases.”

The vital role of constitutive GPCR activity in the mesolimbic dopamine system.
  Meye FJ, Ramakers GM, Adan RA.
  Transl Psychiatry. 2014 Feb 11;4:e361. doi: 10.1038/tp.2013.130.
  PMID: 24518399 [PubMed - in process]

V. Sleep, Systems and CS
“Overall, these findings demonstrate that the EC [Endo-Cannabinoid] system actively regulates cortical up-states and important features of NREM sleep such as its duration and low frequency cortical oscillations.”

Endocannabinoid Modulation of Cortical Up-States and NREM Sleep.
  Pava MJ, den Hartog CR, Blanco-Centurion C, Shiromani PJ, Woodward JJ.
  PLoS One. 2014 Feb 10;9(2):e88672. doi: 10.1371/journal.pone.0088672. eCollection 2014.
  PMID: 24520411 [PubMed - in process] Free PMC Article

VI. Central Nervous System and CS
“In the present study, we discovered that 2-AG significantly protects CN neurons in culture against lipopolysaccharide (LPS)-induced inflammatory response.”

Endocannabinoid 2-Arachidonylglycerol Protects Primary Cultured Neurons Against LPS-Induced Impairments in Rat Caudate Nucleus.
  Lu Y, Peng F, Dong M, Yang H.
  J Mol Neurosci. 2014 Feb 9. [Epub ahead of print]
  PMID: 24510751 [PubMed - as supplied by publisher]

VII. Nervous System (Alzheimer’s/Dementia) and CS
“The altered CB1 levels appear, rather, to be age-and/or pathology-dependent, indicating an involvement of the endocannabinoid system in AD pathology and supporting the ECS as a potential novel therapeutic target for treatment of AD.”

Altered Expression of the CB1 Cannabinoid Receptor in the Triple Transgenic Mouse Model of Alzheimer's Disease.
  Bedse G, Romano A, Cianci S, Lavecchia AM, Lorenzo P, Elphick MR, Laferla FM, Vendemiale G, Grillo C, Altieri F, Cassano
  T, Gaetani S.
  J Alzheimers Dis. 2014 Feb 4. [Epub ahead of print]
  PMID: 24496074 [PubMed - as supplied by publisher]

~.~
February's Video
What if Cannabinoids in Cannabis Cured Cancer & Other Diseases?

  Posted by bwb.

0 Comments

    Author

    Brickner has a 1997 political science doctorate from Purdue University, cofounded Illinois NORML in 2001, and was a 2007 National NORML Cannabis Advocate Awardee. He is also publisher and coauthor of the 2011 book banned by the Illinois Department of Corrections – The Cannabis Papers: A Citizen’s Guide to Cannabinoids.

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