Endocannabinoid system dysfunction in mood and related disorders.

“The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders.

We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1 (CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement.

CONCLUSION:

Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential.”

http://www.ncbi.nlm.nih.gov/pubmed/21916860

Endocannabinoid system and mood disorders: Priming a target for new therapies.

“The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana’s psychoactive principle ∆(9)-tetrahydrocannabinol [∆(9)-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article.”

http://www.ncbi.nlm.nih.gov/pubmed/23261685

The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system.

“Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation.

 These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.”

http://www.ncbi.nlm.nih.gov/pubmed/23298518

Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects.

“Over the last few years considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of Cannabis. In Part I of this review we present a condensed survey of the chemistry of CBD; in Part II, to be published later, we shall discuss the anti-convulsive, anti-anxiety, anti-psychotic, anti-nausea and anti-rheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet unknown. In Part II we shall also present evidence that it is conceivable that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its anti-oxidative effect.”

http://www.ncbi.nlm.nih.gov/pubmed/12505688

http://www.scribd.com/doc/52920296/Cannabidiol-an-Overview-of-Some-Chemical-and-Pharmacological-Aspects-Part-I-Chemical-Aspects

Cannabidiol enhances consolidation of explicit fear extinction in humans.

“Whilst Cannabidiol (CBD), a non-psychotomimetic cannabinoid, has been shown to enhance extinction learning in rats, its effects on fear memory in humans have not previously been studied. These findings provide the first evidence that CBD can enhance consolidation of extinction learning in humans and suggest that CBD may have potential as an adjunct to extinction-based therapies for anxiety disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/23307069

Alzheimer’s, Mom and Cannabis

“It is Skunk PharmResearch’s policy to let patients tell their own story, but in the case of mom, as her daughter and 24/7 caregiver, I will speak for her.  She is in the late seventh and final stage of Alzheimer’s and would want her story told.

Mom was diagnosed as late stage six when she came to me from Seattle four years ago.  She was given six more months to live. She began displaying symptoms before 1998, but she wasn’t diagnosed until 2001, following her first husband’s death.  It took that long to resolve other health issues and get her to a neurologist.

Just the thought of Alzheimer’s frightened her so, that we eventually had to trick her, to get her to a doctor for testing.   Once tested and diagnosed, they put her on Aricept, which brought back cognitive skills, with slow decline for the next seven years while my step brother cared for her in her own home.  Along with other western meds, this was her medical course.

When Mom’s Alzheimer’s progressed to the point that she became combative and personal hygiene became an issue, my brother planned to put her in a nursing home, but I quit my job to look after her.  I moved her to Portland with me and took over her care, to focus on the quality of her remaining life.

For five months prior to her arrival, I immersed myself into learning as much about Alzheimer’s as possible, researching and joining The Alzheimer’s Association, as well as the Online Alzheimer’s Support Group, spending as much time as possible conversing with patients and caregivers alike, to prepare myself for the task.

When Mom arrived, besides being on five over the counter drugs, she was on three inhalers and a pill for asthma, blood pressure meds, allergy meds, anti psychotics that made her angry, anti seizure meds that made her delusional, plus three others I have no idea what they were used to combat.

We got her an OMMP card immediately upon her arrival.  She had smoked cannabis recreationally with me for over thirty years, but never medically until she came toOregon. Cannabis was my only means of mitigating her despicable behavior (psychotic).

Her physical health was also poor, so I changed her diet, eliminated dairy, wheat and gluten. I prepared and feed her home cooked meals, using whole organic ingredients, supplemented with quality vitamins and minerals.

I’ve continued to work with her doctor to straighten out her mishmash of meds.  He started with large doses of anti psychotics to combat the behavioral issues (with potential seizure/death side effect), and we systematically took her off as many of the other drugs as possible.  Meanwhile, I started trying the different forms of cannabis concentrates.

The first extractions were cannabis essential oils using hot grape seed oil, but she didn’t like the flavor and refused to ingest it.

Given that unused meds are 100% ineffective, I next tried honey elixir, thinking she might go for the sweetness of the honey, but no luck.

No luck with fudge either, even though she loves chocolate.

I quickly determined that the only way to get substantial doses into mom would be via concentrates, so after experimenting with bubble hash combined with coconut oil as a menstruum, I focused on hash oil in an effort to improve consistency and homogeneity for consistency in dosing.

More specifically I began to experiment on my version of the Holy Anointing Oil from Exodus, using coconut oil instead of olive oil, and brewed from essential oils, as opposed to using the biblical perfumer’s extraction practices.

More on that medication at:  http://skunkpharmresearch.com/holy-anointing-oil-and-holy-shit/

It worked beautifully!  The flavor of the cannabis was concealed by the remaining essential oils in the ingredients.  She loved it, and to my delight, she became happier and less combative.

Mom transformed from aggressive and angry to the cheerful woman I knew from childhood.  Instead of slapping my cheeks, she caressed them tenderly and moved my hair from my face as she told me she loved me.  From her isolation came the interaction and humor required to joke with us.   From frantic shuffling and hiding of objects she began offering them for my use.  Rather then kicking, biting and hitting, she became happily compliant, even cooperative.  She literally became a social butterfly!

Mom also suffered extensively from muscle spasms, particularly in her legs, typically relieved by dancing the night away together. But one night I thinned some HAO oral with coconut oil, to reduce the cinnamon oil below topical TLV as an irritant and to improve penetration.  After slathering her leg with the modified HAO, the cramps went away, allowing her to go back to sleep.  She woke 20 minutes later complaining of the other leg.  Again, HAO topical and back to sleep! HAOT was born.

It took nearly two years working with her doctor to get her medical care stabilized and a permanent “Primary Care Practitioner” (PCP) established.  We were able to get her off of most of the original drug regiment, and determined that her psychotic episodes were directly related to urinary tract infections, for which she is susceptible.

With cultures and medications, we were able to get the UTIs in check which eliminated the need for the anti psychotic, Seroquil.  We determined that it was medicating the behavioral issues related to UTI’s, rather then psychotic behavior associated with dementia.  Since Seroquil has black box warnings (death) for the elderly, I was more than pleased to eliminate it.

She had begun having seizures after starting seroquil. a potential side effect even with anti seizure meds.  The pharmaceutical consultation revealed anti seizure meds also cause seizures if doses are missed, late or low dose was taken.  Once on anti seizure meds, one must stay on them.  He warns that it permanently lowers the resistance to seizures, although other pharmacists suggested a slow taper is possible.

The delusional side effects of Dilantin, her original medication, are ill advised for a demented patient.   It took me nearly two and a half years to talk the doctors into letting me try a slow wean off the Dilantin, hoping the fact she had not taken Seroquil for over six months and that her cancer doses of cannabis might stop potential seizures.  Although her cognitive capabilities were notably and significantly improved, she still seized, even with using a slow taper and cannabis.

We next went to Depekote, which gave her diarrhea.  We weaned her slowly, as it is also an antidepressant.  That took nearly three weeks.  The diarrhea kept her in constant battles with UTIs, which tend to promote seizures in demented patients, a vicious downward spiral.  We began feeding her Metamucil cookies.  It seemed like that was all she ate.

We then put her on Lamotragine.  When she seized, the dose was increased…..which gave her diarrhea.  Back to that vicious cycle.  More cookies and holy root balm to rescue her poor little raw butt! I used MU’s recipe with my twist (thanks MU!).

Next we tried Gabapentin, hoping that she would acclimate to the initial drowsiness.  Again she seized on the dose, so we increased the night dose to compensate.  The results were diarrhea….more cookies.

Keppra is well accepted for seizures, but it too gives Mom diarrhea.  Opium tincture is the last choice drug for its control.  Dosing is easier and we have more time and room for nutritious/delicious food.  It was time for closer supervision; she was placed on in home hospice care.  Weekly she gets visits from health care, social and spiritual sectors.

I don’t know what we will try next; perhaps, if Mom had never gone on anti seizure meds (off label for muscle spasms), she would only be on cannabis today.  She has never had seizures until now, nor have there been any record of seizures in our family…ever!  She was given Dilantin for muscle spasms, when western medicine quit prescribing Quinine, deeming it damaging to the body, and seizures are not?  But, perhaps the seizures are caused by Alzheimer’s itself, an unusual but occasional occurrence.

The good and interesting news is, with all of what has been happening to mom, I began a mega dose (two plus grams/day) to try and alter her mood.  We dose her every two hours (or our life is hell).  During that period of time, I increased her dose to between .3 and .5 grams.  That is six or seven doses a day or on the light side, 62 grams per month….more then a cancer cure…in one month.

The results were quite unexpected.  The cognitive changes were unmistakably positive.  She began to interact appropriately, become more animated and loving, and appropriately reactive, choosing short phrases.  In short, her cognitive thinking had improved!  She even played jokes on us. When Dino came to visit; she hugged him and kissed him and said “it’s been so long since I seen you.”  Then demanded another round of hugs and kisses!

Even her doctor, whom does not normally sign for medical cannabis cards, noticed the dramatic improvement, saying, “I wish all my Alzheimer’s patients were on cannabis.  Look at her quality of life!”  She signs Mom’s renewals no questions asked.

Where everyone I know (even those with huge tolerances) would be stupid, asleep or puking on two plus grams of cannabis oil in ten hours; mom has gained cognitive capacity!  Who’d of thought?

I read that CBD’s are the anti seizure cannabinoid, so I grew some plants with balanced THC/CBD to see if they can save Mom from seizures and I can add mitigation of seizures, to the list of ailments for which she no longer takes western medication.  To date, those include asthma, arthritic pain, agitation and anxiety of Alzheimer’s, sleeplessness, blood pressure, and muscle spasms.

Mom lost another ten pounds from diarrhea trying the different western meds, but I have Hippie Chicken hanging and will be extracting her soon.  Hopefully, mom will eat then.  (It has become obvious that high CBD strains induce appetite.  She eats well after anti seizure cannabis medication. Hopefully others can watch that tendency to see if this is an isolated response.)

After getting Mom on the high CBD medications, we took our time weaning her off anti seizure meds, ten days on each reduction, with four total reductions.  She did fine during the reduction, but the balanced CBD cannabis did not give her the needed behavioral change of psychotic effects of THC, so we backed her off to .1 mg per dose in balanced CBD/THC oil and the rest of her cannabis dose in high THC strains.

Once off western anti seizure meds, she faired well for nearly three weeks before she seized, at which time we adjusted the dosing to try and compensate for the lowered level of CBD in her system.  Just prior to bed we gave her a full gram of balanced CBD/THC oil, then again as she slept in the morning such that it would wear off by the time she woke.    Six days later she seized again, so we put her on immediate doses of Lorazapam, then back on Keppra, with liquid Opium to combat the diarrhea.

Next I’d like to try Betane Hydrochloride to aid in digestion for the diarrhea.  Although Mom’s life is limited in length, it would be nice if she did not have to take the opiates.  Updates will follow.

For now, she is on anti seizure meds, opiates for diarrhea, cannabis for asthma, blood pressure, muscle spasms, arthritic pain and sleeplessness, anxiety, aggression of Alzheimer’s.  She weighs 86 pounds at 5’4” now.  She eats and drinks but not enough to sustain.  (Even hippie chicken didn’t work as well as i had hoped.)  But, fourteen years after initial symptoms, she is mostly happy and loving….as long as she gets her cannabis dose!”

http://skunkpharmresearch.com/alzheimers-mom-and-cannabis/

 

Cannabidiol affects the expression of genes involved in zinc homeostasis in BV-2 microglial cells.

“Cannabidiol (CBD) has been shown to exhibit anti-inflammatory, antioxidant and neuroprotective properties. Unlike Δ(9)-tetrahydrocannabinol (THC), CBD is devoid of psychotropic effects and has very low affinity for both cannabinoid receptors, CB(1) and CB(2). We have previously reported that CBD and THC have different effects on anti-inflammatory pathways in lipopolysaccharide-stimulated BV-2 microglial cells, in a CB(1)/CB(2) independent manner. Moreover, CBD treatment of BV-2 cells, was found to induce a robust change in the expression of genes related to oxidative stress, glutathione deprivation and inflammation. Many of these genes were shown to be controlled by Nrf2 and ATF4 transcription factors. Using the Illumina MouseRef-8 BeadChip platform, DAVID Bioinformatics and Ingenuity Pathway Analysis, we identified functional sets of genes and networks affected by CBD. A subset of genes was found to be regulated by the metal responsive element (MRE)-binding transcription factor-1 (MTF-1) and is shown to be related to zinc homeostasis. We found that CBD upregulates the expression of the mRNAs for metallothionein 2 (Mt2), N-myc-downstream regulated gene 1 and matrix metalloproteinase 23 as well as of the zinc transporters ZnT1/Slc30a1 and Zip4/Slc39a4 but downregulates the expression of the mRNA for the zinc transporter Zip10/Slc39a10 as well as for the zinc finger protein 472. Among these genes, ZnT1, Mt2 and the zinc transporters ZIPs are known to function together to control the intracellular zinc concentration. These results show that CBD, but much less so THC, affects the expression of genes involved in zinc homeostasis and suggest that the regulation of zinc levels could have an important role through which CBD may exert its antioxidant and anti-inflammatory effects.”

http://www.ncbi.nlm.nih.gov/pubmed/22178458

Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress

Figure 1

“Growing evidence suggests that the endocannabinoid system, which includes the CB1 and CB2 G protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system, but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development.

This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types I and II diabetes, atherosclerosis, Alzheimer’s disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain.

Cannabidiol (CBD) is the major nonpsychotropic cannabinoid compound derived from the plant Cannabis sativa, commonly known as marijuana…

Conclusions

Inflammation and oxidative stress are intimately involved in the genesis of many human diseases. Unraveling that relationship therapeutically has proven challenging, in part because inflammation and oxidative stress “feed off” each other. However, CBD would seem to be a promising starting point for further drug development given its anti-oxidant (although relatively modest) and anti-inflammatory actions on immune cells, such as macrophages and microglia. CBD also has the advantage of not having psychotropic side effects. Studies on models of human diseases support the idea that CBD attenuates inflammation far beyond its antioxidant properties, for example, by targeting inflammation-related intracellular signaling events. The details on how CBD targets inflammatory signaling remain to be defined.

The therapeutic utility of CBD is a relatively new area of investigation that portends new discoveries on the interplay between inflammation and oxidative stress, a relationship that underlies tissue and organ damage in many human diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085542/

Cannabidiol: a promising drug for neurodegenerative disorders?

“Neurodegenerative diseases represent, nowadays, one of the main causes of death in the industrialized country. They are characterized by a loss of neurons in particular regions of the nervous system. It is believed that this nerve cell loss underlies the subsequent decline in cognitive and motor function that patients experience in these diseases. A range of mutant genes and environmental toxins have been implicated in the cause of neurodegenerative disorders but the mechanism remains largely unknown. At present, inflammation, a common denominator among the diverse list of neurodegenerative diseases, has been implicated as a critical mechanism that is responsible for the progressive nature of neurodegeneration.

Since, at present, there are few therapies for the wide range of neurodegenerative diseases, scientists are still in search of new therapeutic approaches to the problem. An early contribution of neuroprotective and antiinflammatory strategies for these disorders seems particularly desirable because isolated treatments cannot be effective.

 In this contest, marijuana derivatives have attracted special interest, although these compounds have always raised several practical and ethical problems for their potential abuse. Nevertheless, among Cannabis compounds, cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.”

http://www.ncbi.nlm.nih.gov/pubmed/19228180

Israeli Research Shows Cannabidiol May Slow Alzheimer’s Disease

“An Israeli researcher has found that a non-psychoactive component of cannabis may help slow the progression of Alzheimer’s disease. The initial findings of a study at the Hebrew University of Jerusalem show that a non-psychoactive component of cannabis, marijuana, may hold out hope for slowing down the progression of Alzheimer’s disease.The research, still at an early stage, indicates that memory loss, the first and primary symptom of Alzheimer’s disease, can be slowed down significantly in mice by cannabidiol. Alzheimer’s disease, the most common form of dementia, affects some 24.3 million people worldwide.”

Read more: http://www.israelnationalnews.com/News/News.aspx/125564