neurological health and pathophysiology - restorative medicine · neurological health and...

Neurological Health and Pathophysiology

Kevin Spelman, PhD, MCPP

Health, Education & Research in Botanical Medicine

Ashland, OR

Financial Disclosure

• Consultant for Restorative Formulations

• I have been a Natural Products and Cannabis Industry Consultant, for GMPs, Regulatory Issues, Pharmacology, Research Initiatives, New Product Development and Formulation

• I have financial interests in the Natural Products Industry

Introduction

Other Targets

DepressionAnxiety

Endocannabinoid System

Care & Feeding of the CNS

Mind Map of Lecture

Health Disease

Optimal Wellness

Functional

Disturbance

Energetic

Disturbance

Biochem

Disturb.

Histological

DiseaseAllostasis/Resilience

Subclinical Clinical

Acute

Defensive

Reaction

Phase

Detoxification

Phase

Compen

sation

Phase

Decompen

sation

Phase

Degeneration

Phase

Autoimmune

Neoplastic

Phase

Health as a Continuum The Wall

+++ Background Mood ++ + - - - Background Mood - - -

+++ Perception ++ + - - - Perception - - -

Informational flow dynamicscatecholamines, corticoids, NTs, peptides

gut, endocrine, immune

Informational flow disruption → → →

4Spelman K. 2004. Allostasis: stability through change. Australian J Medical Herbalism 16(4):99-109

Comorbidity and shared pathways to illness

Depression is highly comorbid with:

• heart disease

• type 2 diabetes

• obesity

• metabolic syndrome

Is the Model Working?

1949 - A Nobel Prize in Medicine was given to Egas Moniz for inventing the frontal lobotomy

Today - A 20 y/o who goes on disability for mental illness will collect over $1,000,000 in 40 yr

8

Is the Model Working

Children on SSI that were disabled due to mental illness

• 1987: 5.5% of total on SSI

• 2007: 50% of total on SSI

Social Security Administration reports 1987 - 2007

10

Leading cause of global disability

“It is both compelling and

daunting to consider that

dietary intervention at an

individual or population level

could reduce rates of

psychiatric disorders.”

AJP 2010

CVD

Stroke

Obesity

Type 2 Diabetes

Metabolic Syndrome

Some cancers

Dementia/Depression/Anxiety

Etiology Includes Food In:

The Power of Phytochemistry

• People whose diets were highest in whole foods were the least likely to develop signs of depression by the end of 5 yr(Akbaraly et al. 2009)

• Risk of depression/anxiety disorders is 34% lower among women who ate a Traditional diet (Jacka et al, 2010)

“Traditional” Diet – Dominated by vegetables, fruit, beef, lamb, fish, and whole-grain foods

Akbaraly TN, Brunner EJ, Ferrie JE, Marmot MG, Kivimaki M, Singh-Manoux A. Dietary pattern and depressive

symptoms in middle age. Br J Psychiatry. 2009 Nov;195(5):408-13.

Jacka FN, Pasco JA, Mykletun A, Williams LJ, Hodge AM, O’Reilly SL, Nicholson GC, Kotowicz MA, Berk M.

Association of Western and traditional diets with depression and anxiety in women. Am J Psychiatry. 2010

Mar;167(3):305-11. Epub 2010 Jan 4.

AN ABBREVIATED CARE AND FEEDING OF THE CENTRAL NERVOUS SYSTEM

This topic often skipped by Medical Schools

Discussion of optimum molecular concentrations, rates of reactions

…local cerebral deficiencies may lead to mental disease…

19

Epinephrine (adrenalin)

Adrenochrome

Whole Foods Diet

This can’t be stressed enough!

20

Researchers found that happiness and mental health rise in an

approximately dose-dependent response with the number of daily portions

of fruit and vegetables…“well-being peaks at approximately 7 portions per

day,”

“Our findings are consistent with the need for high levels of fruit-and-

vegetable consumption for mental health and not merely for physical

health.”

0

10

20

30

40

50

60

70

80

Q1 Q2 Q3 Q4 Q5

Survival Percentages

Fruits Vegetables

Gut-Brain Axis

• 35% of biopsy-proven CD cases have a history of psychiatric illness

• − Patients with schizophrenia are at least three times more likely to have CD (meaning 3% of schizophrenia patients) and, if the same pattern follows, three times more likely to have GS (18% of patients).

• − Odds are 33:1 that a patient with CD is unaware he/she has it.

• − Nearly half of patients with CD will not manifest it yet may how psychiatric symptoms from it.

• − Psychiatric manifestations will vary widely amongst CD patients.

• − A gluten-free (GF) diet of CD and GS patients could eliminate or dramatically reduce psychiatric symptoms.

Stradford D. The Role of Allergies, Poisons, and Toxins in Psychiatry in Complementary and Alternative

Medicine Treatments in Psychiatry. Stradford, Vicar, Berger, Cass 2012. Flying Publisher.

A Profound Adaptation…

We steep our genes daily in our dietary broth…

IMPORTANT NUTRIENTS

• Niacin (B3)

• Vitamin B6

• Folate (Vitamin B9)

• Vitamin B12

• SAM-e

• Omega 3s

• Vitamin D

• Zinc

• Calcium and Magnesium

Experimental evidence

Germ free mice (no commensal bacteria)• exaggerated HPA response to stress

• elevated stress hormones

• altered levels of BDNF in hippocampus

• altered levels of serotonin, noradrenaline

• increased permeability of the BBB

Human studies

• probiotics ameliorated psychological distress and reduce cortisol in healthy volunteers (Messaoudi et al.2011)

• probiotics improved psychological symptoms in patients with chronic fatigue syndrome (Rao et al.2009)

• fermented milk products with probiotics modulate brain activity in humans (Tillisch et al. 2013)

Lets Talk about Stress…

31

CRH

ACTH

corticoids

Bunney WE, Fawcett JA, Davis JM, Gifford S. 1969. Further evaluation of urinary 17-hydroxycorticosteroids in suicidal patients. Arch Gen Psychiatry. 21(2):138-50 36

26 % of the observers also experienced increases in cortisol levels, even though they were not directly exposed to stress

for observers who were watching loved ones go through the stressful tasks -- 40 percent experienced increased cortisol levels -- but lower for those watching a

stranger -- 10 percent.

the cortisol levels were still raised in 24 percent of observers when they watched through the video feed. This finding suggests that things like watching stressful

moments on TV might be enough to raise cortisol levels 37

The Stress Axis

Hypothalamus (−)

CRF

Pituitary (−)

ACTH

Adrenals cortisol

Higher Brain CentersPerception

IMPORTANT ACTIVITIES FOR THE CNS

• Play

• Exercise

• Breathing techniques

• Mindfulness practice

• Meditation

• Yoga

Attitude!!!!!Stress Buffers

The Brain: Predictive vs Sensory Analysis

• Our brains are selected to predict what is coming• Much of the information we use to predict our emotional states comes from

our viscera

40

Danziger et al. Extraneous factors in judicial decisions. PNAS. USA 2011 108 (17) 6889-6892

Mental illnesses are often not single diseases, but heterogenous syndromes

Physiology and Pathophysiology is not simple, nor is diagnosis

But ICD-10 codes are…

Depression

43

• Challenge serotonin hypothesis of depression – see anatomy of an epidemic

Age-standardized* percentage of adults meeting criteria for current depression

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5938a2.htm 45

Prevalence of current depression* among adults aged ≥20 years

http://www.cdc.gov/mmwr/preview/mmwrhtml/su6003a1.htm

47NCHS, National Health and Nutrition Examination Survey, 2013–2016

Percentage of persons aged 20 and over with depression, by family income level

https://www.nimh.nih.gov/health/statistics/major-depression.shtml

Major Depressive Disorder (MDD) Pathology:

• monoamine impairment (dysfunction in expression and receptor activity)

• lowering of monoamine production• secondary messenger system malfunction• cortisol excess:

• impeding neurogenesis via reducing brain-derived neurotrophic factor

• impaired endogenous opioid function• changes in GABAergic and/or glutamatergic

transmission• cytokine or steroidal alterations• abnormal circadian rhythm

50

Sarris J, Panossian A. Schweitzer I, Stough C, Scholey A. Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and clinical evidence. Eur Neuropsychopharmacol. 2011 Dec;21(12):841-60

Major Depressive Disorder (MDD)

Many herbal medicines may have a multitude of biological effects on reuptake and receptor binding in addition to “endocrine and psychoneuroimmunological modulation”

• Inhibition of monoamine re-uptake

• Enhanced binding and sensitization of serotonin receptors

• Monoamine oxidase inhibition

• Neuroendocrine modulation

• GABAergic effects

• Cytokine modulation

• Opioid and cannabinoid system effects

53


Serotonin?

“We propose that depressed states are high serotonin phenomena, which challenges the prominent role the low serotonin hypothesis

continues to have in depression research (Albert et al., 2012). We also propose that the direct serotonin-enhancing effects of antidepressants

disturb energy homeostasis and worsen symptoms. We argue that symptom reduction, which only occurs over chronic treatment, is

attributable to the compensatory responses of the brain attempting to restore energy homeostasis.”

59

Anxiety

62

Mother’s Little Helper 63

Valium

• Brought to Market in 1963

• 1968 – 1981 best selling drug in Western World

• 1970s: 2 million people addicted, 4 x that of heroin in the 1970s

• After BDZs hit market • 1,028/ → 3,182/100,000 patient-care episodes

65

Valium

• 2014• 2.6 % of population 18 to 35 y/o used a BDZ

• 8.7 % 65 to 80

• Of 65 to 80 y/o, 31.4 % received prescriptions for long-term use

• In all age groups, women were about twice as likely as men to receive benzodiazepines

66

MOAs Sedatives & Anxiolytics

Simplistically

• Induction of neuronal depression

• Inhibition of neuronal excitation

67

GABAA vs GABAB

Ionotropic vs Metabotropic

68

GABA

Several binding sites

69

GABA

• Reuptake inhibition (tiagabine)

• Increase of release (gabapentin)

• Enzymes• Synthesis - Glutamate decarboxylase (GAD 67)

• Breakdown - GABA transaminase

70

Anxiety

Herbal MOIs

• Inducing ionic channel transmission by blockage of voltage gates

• Blockage of GABA transaminase through alteration of membrane structures (Melissa officinalis)

• Blockage of glutamic acid decarboxylase inhibition through alteration of membrane structures (Matricaria recutita, Humuluslupulus)

• Binding with benzodiazepine receptor sites, leading to increased GABA production

71


GABA, Indirect Activity

72

September 2013, Volume 16, Issue 3, pp 363–369

Other Targets

73

Chaperones in Neurological Diseases

CytokinesSickness Behavior

Sickness Behavior

Defined as anxiety, anhedonia, social withdrawal, fatigue, and sleep disturbances

Sickness Behavior

Proinflammatory mediators have been shown to induce anxiety, anhedonia, social withdrawal, fatigue, and sleep disturbances, defined

as “sickness behavior”

Dantzer, R., et al. Maletic, V., and Raison, C. L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741.Johnson, R. W., and Kelley, K. W. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56. Miller, A. H., et al. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741

Sickness Behavior

Systemic administration of proinflammatory agents is able to promote the activation of microglial cells in the hippocampus and stimulate the

release of proinflammatory cytokines in the CNS

van Dam, A. M., et al. (1992). Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of nonspecific symptoms of sickness? Brain Res. 588, 291–296.Breder, C. D., et al. (1994). Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration. Proc. Natl. Acad. Sci. U.S.A. 91, 11393–11397.Riazi, K., Galic, M. A., Kuzmiski, J. B., Ho, W., Sharkey, K. A., and Pittman, Q. J. (2008). Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation. Proc. Natl. Acad. Sci. U.S.A. 105, 17151–17156.

Sickness Behavior

Activation of microglial cells in the hippocampus and the subsequent release of proinflammatory cytokines in the CNS is associated with

depression and anxiety

Reichenberg, A., et al. (2001). Cytokine-associated emotional and cognitive disturbances in humans. Arch. Gen. Psychiatry 58, 445–452.Miller, A. H., et al. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741.

Sickness Behavior

Central administration of IL-1β & TNF-α cytokines induces sickness behavior in animals

Dantzer, R., et al. Maletic, V., and Raison, C. L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741.Haji, N., Mandolesi, G., Gentile, A., Sacchetti, L., Fresegna, D., Rossi, S., et al. (2012). TNF-α-mediated anxiety in a mouse model of multiple sclerosis. Exp. Neurol. 237, 296–303. Rossi, S., Sacchetti, L., Napolitano, F., De Chiara, V., Motta, C., Studer, V., et al. (2012). Interleukin-1β causes anxiety by interacting with the endocannabinoid system. J. Neurosci. 32, 13896–13905.

Sickness Behavior

Inflammation appears to be part of the etiology in the pathophysiology of different psychiatric syndromes, including major depression

Maes, M., et al. (1995). Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J. Affect. Disord. 34, 301–309.Capuron, L., et al. (2002). Treatment of cytokine-induced depression. Brain Behav. Immun. 16, 575–580.

Sickness Behavior

Elevated biomarkers of systemic inflammation, as C-reactive protein, have been associated with depressive symptoms

Morris, A. A., Zhao, L., Ahmed, Y., Stoyanova, N., De Staercke, C., Hooper, W. C., et al. (2011). Association between depression and inflammation–differences by race and sex: The META-Health Study. Psychosom. Med. 73, 462–468

Sickness Behavior

Depressed patients show higher peripheral blood levels of proinflammatory cytokines

Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E. K., et al. (2010). A meta-analysis of cytokines in major depression. Biol. Psichiatry 67, 446–457.Haapakoski, R., Mathieu, J., Ebmeier, K. P., Alenius, H., and Kivimäki, M. (2015). Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav. Immun. 49, 206–215.Zorrilla, E. P., et al. (2001). The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav. Immun. 15, 199–226.

Sickness Behavior

Elevated inflammatory markers predict reduced response to antidepressant treatment

Strawbridge, R., Arnone, D., Danese, A., Papadopoulos, A., Herane Vives, A., and Cleare, A. J. (2015). Inflammation and clinical response to treatment in depression: a meta-analysis. Eur. Neuropsychopharmacol. 25, 1532–1543.

Sickness Behavior

Increased prevalence of depression has been observed in patients with autoimmune disorders

Blocking cytokine signaling can exert beneficial effects on mood

Zeher, H., et al. (2010). Coping with depression and anxiety in patients with psoriasis. Egypt. J. Psychiatry 31, 57–63.Tyring, S., et al. (2006). Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomized phase III trial. Lancet 367, 29–35.

Sickness Behavior

Post-mortem studies in patients with major depression evidenced that also the innate immune response is altered, possibly contributing to

the pathogenesis of depression

Martín-Hernández, D., Caso, J. R., Meana, J. J., Callado, L. F., Madrigal, J. L. M., García-Bueno, B., et al. (2018). Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants. J. Neuroinflammation 15, 251.

Hypothesis

The efficacy of different psychoactive treatments may be mediated by immunomodulatory properties

Maes, M., et al. (1999). Negative immunoregulatory effects of antidepressants: inhibition of interferongamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology 20, 370–379. Cattaneo, A., et al. (2013). Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology 38, 377–385.Horowitz, M. A., et al. (2015). Antidepressant compounds can be both pro- and antiinflammatory in human hippocampal cells. Int. J. Neuropsychopharmacol. 18, 3.

PerspectivesWhat is the primary substrate of the universe?

89

The Beginning

Matter → Consciousness

The Beginning

Matter Consciousness

The Endocannabinoid SystemThis is not necessarily about Cannabis but about basic physiology

92

Endocannabinoid Basics

• CB1 and CB2 receptors found throughout the body

• Anandamide (AEA) and 2-AG synthesized on-demand for homeostatic functions

• Enzymes to synthesize AEA & 2-AG

• Enzymes to metabolize AEA & 2-AG

CB1 Receptor Distribution in Human Brain

with the distribution of CB1 receptors (17), which de-

creased slowly over time. Radioactivity in the brain peaked

by approximately 30 min and was approximately 3.2 SUV

for all areas of the neocortex (Figs. 2 and 3A). Areas with

high CB1 receptor density (e.g., putamen) had an even

greater concentration of radioactivity, peaking over 4.0

SUV in most subjects. Radioactivity in the brain decreased

slowly, remaining within approximately 85% of thepeak by

2 h and within approximately 60% of the peak by 5 h. We

averaged radioactivity concentration from 20 to 60 min

after injection to represent brain uptake (brain uptake20–60;

Supplemental Table 3).

Two regions of the brain consistently demonstrated less

uptake of radioactivity than other regions. The first region,

pons, had a peak SUV of approximately 2.4 within 8 min.

After the peak, washout of radioactivity from the pons was

1.5–2 times faster than from other regions at 60–120 min

after injection. The second region, white matter, typical ly

peaked at an SUV of approximately 1.2 about 15 min after

injection and remained nearly constant until the end of the

scan, with minimal washout of radioactivity.

The skull had a significant uptake of radioactivity, which

could reflect bone or marrow (Fig. 3B). Among regions of

the skull, the clivus, which contains significant amounts of

marrow, had thegreatest uptake of radioactivity, suggesting

that marrow more avidly takes up 18F-FMPEP-d2 or its

radiometabolites.

Plasma Analysis

The concentration of 18F-FMPEP-d2 in arterial plasma

peaked at 1–2 min and then rapidly declined because of

distribution in the body, followed by a slow terminal phase

of elimination. To quantify theexposure of thebrain to 18F-

FMPEP-d2, we fitted the concentration of 18F-FMPEP-d2after its peak to a triexponential curve (Fig. 4A). Of the 3

associated half-lives, the first 2 (; 0.4 and 5.7 min) largely

reflected distribution and the last (; 82 min) reflected

elimination (i.e., metabolism and excretion). However,

the 3 components accounted for nearly equal portions of

the total AUC0-N : approximately 18%, 28%, and 33%. The

portion before the peak accounted for approximately 20%

of the AUC0-N . The concentration of18F-FMPEP-d2 in the

plasma of some subjects remained the same or slightly

increased during the2 later imaging intervals (150–180 and

210–240 min) but declined during the rest intervals (120–

150, 180–210, and 240–270min). During the rest intervals,

subjects arose from the camera and walked around,

suggesting that the shifting of fluid in the body may have

mobil ized and redistributed 18F-FMPEP-d2.

FIGURE 2. 18F-FMPEP-d2 in human brain. PET images

from 30 to 60 min after injection of 18F-FMPEP-d2 were

averaged (left column) and coregistered to subject’s MR

images (middle column). PET and MR images are overlaid in

right column.

FIGURE 3. Time–activity curves of 18F-FMPEP-d2 in brain

from single subject scanned for 300 min. (A) Decay-

corrected measurements from putamen (n), prefrontal cortex

(h ), cerebellum (d , pons (s ), and white matter (· ) were fitted

with unconstrained 2-tissue-compartment model (–). Puta-

men was consistently region of highest brain uptake. White

matter was consistently region of lowest brain uptake,

followed by pons. (B) Decay-corrected measurements from

same subject demonstrate uptake of radioactivity in clivus

(¤ ), occiput () ), and parietal bones (: ). Concentration

(Conc) is expressed as SUV, which normalizes for injected

activity and body weight.

IMAGING CB1 RECEPTORS USING18F-FMPEP-d2 • Terry et al. 115

by on July 5, 2014. For personal use only. jnm.snmjournals.org Downloaded from

Terry et al. Imaging and Quantitation of Cannabinoid CB1 Receptors in Human and Monkey Brains Using18F-Labeled Inverse Agonist Radioligands. J Nucl Med 2010;51(1):112-120

CB2 Receptor Distribution

Ahmed et al. Whole-body biodistribution and radiation dosimetry of the cannabinoid type 2 receptor ligand

[11C]-NE40 in healthy subjects.Mol Imaging Biol. 2013 Aug;15(4):384-90.

Anandamide (AEA)Devane, Mechoulam et al., 1992

Endogenous Cannabinoid Ligands: The Endocannabinoids

2-arachidonoylglycerol (2-AG)Mechoulam et al., 1995Sugiura et al., 1995

Anandamide (AEA) and 2-arachidonoylglycerol (2-AG):

• Retrograde messengers in nervous system.

• Autocrine or paracrine mediators elsewhere.

• Synthesized “on demand” from cell membrane precursors (arachidonic acid derivatives) and immediately released.

• Degraded by enzymatic hydrolysis

• AEA -> fatty acid amide hydrolase (FAAH)

• 2-AG -> monoacylglycerol lipase (MAGL)

(McPArtland, 2008)

Endogenous Cannabinoid Ligands: The Endocannabinoids

Numerous Other Endogenous Cannabinoids

(Kogan 2006)

Other Endocannabinoid Targets

• GPR55 (Ryberg, 2007; Staton, 2008)

• TRPV1 “capsaicin receptor” (Ross, 2003)

• PPARs: Peroxisome proliferator-activated receptors (O'sullivan, 2007)

• Voltage-gated ion channels

• Ca2+, Na+, and various types of K+ channels

• Ligand-gated ion channels

• 5-HT3 and nicotinic ACh receptors (Oz, 2006)

The Endocannabinoid System Function and Regulates the;

• Nervous System

• Connective Tissues

• Immune System

• Neoplasms

• Embryology

• Digestive System

• Hunger and Feeding

101Ashley NT, Demas GE. Neuroendocrine-immune circuits, phenotypes, and interactions. Horm Behav 87 (2017) 25–34.


Increasing Resilience

Neuroplastic effects such as synaptic plasticity, neurogenesis and neurotrophin expression in the hippocampus are modulated by

endogenous cannabinoids

Aguado et al. (2005). The endocannabinoid system drives neural progenitor proliferation. FASEB J. 19, 1704–1706.Jiang, W., Zhang, Y., Xiao, L., Van Cleemput, J., Ji, S. P., Bai, G., et al. (2005).Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J. Clin. Invest. 115:3104–3116.Campos, et al. (2013). The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int. J. Neuropsychopharmacol. 16:1407–1419.Zhang, Z., Wang, W., Zhong, P., Liu, S. J., Long, J. Z., Zhao, L., et al. (2015). Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity. Hippocampus 25:16–26.

Hypothalamus

Scarante et al. 2017. Cannabinoid Modulation of the Stressed Hippocampus. Front Mol Neurosci 10: 411.

Keys to Resilience

A range of human genes and polymorphisms associated with

• Neuropeptide Y

• Noradrenergic systems

• Dopaminergic systems

• Serotonergic systems

• Brain Derived Neurotropic Factor

• Hypothalamus-Pituitary-Adrenal axis

have been linked to resilience

Feder, et al. (2009). Psychobiology and molecular genetics of resilience. Nat.Rev.Neurosci. 10, 446–457.

Russo et al. (2012). Neurobiology of resilience. Nat.Neurosci. 15, 1475–1484.

CRH causes a reduction in the endocannabinoid anandamide within the amygdala

we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition

CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety

Several lines of evidence suggest that facilitation of cannabinoid signaling within the hippocampus brain region prevents stress-

induced behavioral changes.

there is reduced FAAH expression associated with a FAAH SNP that decreases anxiety-like behaviors

At the End of the Day

The Endocannabinoid System as a fundamental system overlapping with many other key systems alters our perception, the way we move

through the world and our physiological tone


Gut-Brain Axis

Neuro-Immuno-Endocrine

Cardiovascular System

Physiological Order

[email protected]

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