Louis B. Cady, MD, FAPA – CEO & Founder – Cady Wellness Institute Louis B. Cady, MD, FAPA – CEO & Founder – Cady Wellness Institute Adjunct Clinical Lecturer – Indiana University School of Medicine

Department of PsychiatryFunctional & Integrative Medicine – Evansville, Indiana

The Endocannabinoid System:A Review of the Literature

February 2, 2018 – Cady Wellness Institute

H - 2

“There are two objects of medical education: to heal the sick and to advance the science.”

- Dr. Charles H. Mayo, MD

“The glory of medicine is that it is always moving forward, that there is always more to learn.”

- Dr. William J. Mayo

Disclaimer: Zilis full spectrum hemp oil is not FDA approved for the

diagnosis, treatment, prevention, or cure of ANY disease or “medical

condition.”This type of non-THC containing hemp oil MAY

be appropriate to support the structure and function of the human body.

Hemp• One of the oldest known cultivated plants• 12,000 years of usage• Used for clothes, soap and rope• Has a wide array of nutrients in

it of almost all sources.• Medicinal use: 6,000 years• 3rd most prescribed medicinal agent for 60 years

prior to its prohibition in 1937

4,336 citations as of 12/18/2017

4,382 results – Feb 2, 2018 6:26 am4,382 results – Feb 2, 2018 6:26 am

2018 - 57 already

684 citations estimated

*

Search on “endocannabinoid system” www.pubmed.gov Feb 2, 2018

Study: evaluate CB1 ligands + other agents “that possess antidepressant potential.”CONCLUSIONS: “The simultaneous modulation of the cannabinoid system and supplementation of magnesium or zinc produce at least additive antidepressant-like effect.”

Study: evaluate CB1 ligands + other agents “that possess antidepressant potential.”CONCLUSIONS: “The simultaneous modulation of the cannabinoid system and supplementation of magnesium or zinc produce at least additive antidepressant-like effect.”

The results of the present study suggest that CB1r, CB2r, and MAGL are closely related to the neuropathological processes of PD. Therefore, the pharmacological modulation of these targets could represent a new potential therapeutic tool for the management of PD.

The results of the present study suggest that CB1r, CB2r, and MAGL are closely related to the neuropathological processes of PD. Therefore, the pharmacological modulation of these targets could represent a new potential therapeutic tool for the management of PD.

Smith SC. Neuro Endocrinol Lett. 2014;35(3):198-201. Smith SC. Neuro Endocrinol Lett. 2014;35(3):198-201.

CONCLUSION: 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.

CONCLUSION: 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.

SEVERAL INTERENTIONS UPREGULATE THE ECS SYSTEM:

•Analgesics, anti-inflammatories•Antidepressants, antipsychotics, anxiolytics,

anticonvulsants•Massage and manipulation

•Acupuncture•Dietary supplements and herbal medicines.

SEVERAL INTERENTIONS UPREGULATE THE ECS SYSTEM:

•Analgesics, anti-inflammatories•Antidepressants, antipsychotics, anxiolytics,

anticonvulsants•Massage and manipulation

•Acupuncture•Dietary supplements and herbal medicines.

McPartland JM et al. PLoS One. 2014, Mar 12;9(3):e89566McPartland JM et al. PLoS One. 2014, Mar 12;9(3):e89566

Getting high on cannabis makes you less likely to work hard for money, study says – The Independent Sept 1, 2016http://www.independent.co.uk/news/science/cannabis-marijuana-weed-effects-getting-high-working-hard-money-motivation-a7220441.html

Way back in April 14-15, 1912

Purdue University & Mr. Fred A. Miler, botanist to Eli Lilly & Co. partner for “medicinal extract of Hemp (CBD) Research,” c. 1912-13

Endocannibinoid system – the body’s primary tool of homeostasis

• Most significant neurotransmitter system in the body

• Regulates & balances:– Nerve function, stress recovery,

inflammation levels, immune function, energy intake and storage, cell life-cycles/apoptosis/reproduction, circulatory ystem

Endogenous cannabinoids• Synthesized in OUR body: ENDOcannabinoids

– 2-AG (2-arachidonylgylerol)

– Anadamide (N-arachidonoylethanolamine “AEA”)

• These are fatty acid neurotransmitters• 2-AG – most abundant endocannabinoid in the

body

• Regulates appetite, immune function, pain signals, energy storage, among others

•

The endocanninoid receptors by the numbers…

• CB1– Brain spinal cord, reproductive & connective tissues

• CB2– Modulates immune system. Found on spleen, tonsils,

thymus, all white blood cells (receptors) • T cells, B-eta cells, macrophages

• GPR55 – linked to bone development and cancer cell proliferation

Endocannabinoids 101

• YOU make ENDO-cannabinoids– 2-AG (2 arachidonoylglycerol)

• Most abundant• Regulates appetite, immune function, pain signals, energy

storage.

– Anandamide (N-arachidonoylethanolamine “AEA”)

• HEMP plant makes PHYTO-cannabinoids– Interacts well with human CB receptors.

CECD: Clinical endocannabinoid deficiency

• Implicated in many hard-to-treat disease states:– Fibromyalgia – Chronic migraines – Depression/anxiety– Irritable bowel syndrome

Russo EB. Neuro End Lett 2008 April; 29(2): 192-200.

Anandamide• From Sanskrit for “bliss” or “happiness.” • Regulates pleasurable activities – food intake,

reproduction, sleep, and pain relief

• Found in mother’s milk, chocolate, and release during ovulation

• Produced during meditation, yoga, and causes RUNNER’S HIGH.

• A “bridge” between mind and body.

But what happens if you don’t make enough???

56 citations 12 18 2017

19 results – Feb 2, 2018 7:26 am19 results – Feb 2, 2018 7:26 am

• Stimulating ECS:• Reduction in alcohol consumption with +ECS input• Antihyperalgesic activities of EC in Mouse Model of

neuropathic pain• Effects in migraine, fibromyalgia, irritable bowel, and

“other treatment-resistant syndromes” (Russo EB, 2016)• CB2 deficient mice have pro-inflammatory obesity

• Stimulating ECS:• Reduction in alcohol consumption with +ECS input• Antihyperalgesic activities of EC in Mouse Model of

neuropathic pain• Effects in migraine, fibromyalgia, irritable bowel, and

“other treatment-resistant syndromes” (Russo EB, 2016)• CB2 deficient mice have pro-inflammatory obesity

B

“Endocannabinoid deficiency syndrome” – 2001•“In certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes.” •many brain disorders are based on deficient neurotransmitters.

“Endocannabinoid deficiency syndrome” – 2001•“In certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes.” •many brain disorders are based on deficient neurotransmitters.

Inflammation and CBD• CBD tested on mice that had a

version of RA– CBD reduced mouse inflammation

by 50% at correct dosage– Malfait AM et al. The nonpsychoactive cannabis

constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen- induced arthritis. PNAS vol 97 no 17, 9561-9566

• one dosage of CBD immediately following a heart attack can reduce infarct size by c. 66%

– Durst R et al. Am J Physiol Heart Circ Physiol.2007Dec;293(6): H3602-7.

Bluett RJ. Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid

augmentation.Transl Psych 2014 Jul 8;4:e 408

• Pharmacological augmentation of central endogenous cannabinoid (eCB) signaling may be an effective therapeutic strategy to mitigate the adverse behavioral and physiological consequences of stress.

• These studies provide further support that eCB-augmentation is a viable pharmacological strategy for the treatment of stress-related neuropsychiatric disorders.

• Pharmacological augmentation of central endogenous cannabinoid (eCB) signaling may be an effective therapeutic strategy to mitigate the adverse behavioral and physiological consequences of stress.

• These studies provide further support that eCB-augmentation is a viable pharmacological strategy for the treatment of stress-related neuropsychiatric disorders.

B

CONCLUSIONS: Our findings demonstrate that the deletion of Dagla [dacylgerol lipase alpha (DAGLalpha)] adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses.

CONCLUSIONS: Our findings demonstrate that the deletion of Dagla [dacylgerol lipase alpha (DAGLalpha)] adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses.

BThese data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor.

These data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor.

B

Both endocannabinoids exhibited neuroprotective activity at LOWER dose, but were neurotoxic at higher dose.

Both endocannabinoids exhibited neuroprotective activity at LOWER dose, but were neurotoxic at higher dose.

B

CONCLUSIONS. This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR.

CONCLUSIONS. This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR.

B“…due to its interaction with PPAR-gamma, CBD was observed to stimulate hippocampal neurogenesis.”

“…due to its interaction with PPAR-gamma, CBD was observed to stimulate hippocampal neurogenesis.”

Source: PLOS One. 2011: 6(12); e28668. Free article online here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230631/

Bioavailability problems of commercial products

• Commercial hemp oil– Not THC free. – Only 6% of what is ingested gets absorbed. – 90% is wasted.

• Micellized hemp oil = 85% bioavailability– Onset of action drops from 1-2 hours down to 5

– 15 min.

Full Spectrum Hemp Oil

NOT just CBD…

• Cannabinoids

• Terpenes

• Flavonoids

• Fatty Acids

• Vitamins

• Minerals7

Micellation

Hemp oil and Ultracell

Legal in Indiana

Legal in Indiana

• 2000 inappropriate online health claims; 1000 still online• www.truthinadvertising.org ,

2017

• 158 direct selling companies• 62 sell nutritional supplements

• 60/62 (97%) have made health claims that...

• “their products can diagnose, treat, cure, prevent, or alleviate the symptoms of and/or reduce the risk of developing a multitude of diseases.”

Personal collection Louis B. Cady,

M.D.

Contact information and slide resourcesLouis B. Cady, MDCady Wellness Institute4727 Rosebud Lane – Suite FNewburgh, IN 47630 USAOffice (812) 429-0772

• www.cadywellness.com• info@cadywellness.com • www.facebook.com/cadywellnes

• Twitter: @LouisCadyMD