Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been ….

“The use of cannabis, or marijuana, for medicinal purposes is deeply rooted though history, dating back to ancient times. It once held a prominent position in the history of medicine, recommended by many eminent physicians for numerous diseases, particularly headache and migraine.

Through the decades, this plant has taken a fascinating journey from a legal and frequently prescribed status to illegal, driven by political and social factors rather than by science.

However, with an abundance of growing support for its multitude of medicinal uses, the misguided stigma of cannabis is fading, and there has been a dramatic push for legalizing medicinal cannabis and research.

Almost half of the United States has now legalized medicinal cannabis, several states have legalized recreational use, and others have legalized cannabidiol-only use, which is one of many therapeutic cannabinoids extracted from cannabis.

Physicians need to be educated on the history, pharmacology, clinical indications, and proper clinical use of cannabis, as patients will inevitably inquire about it for many diseases, including chronic pain and headache disorders for which there is some intriguing supportive evidence…

The literature suggests that the medicinal use of cannabis may have a therapeutic role for a multitude of diseases, particularly chronic pain disorders including headache.

Supporting literature suggests a role for medicinal cannabis and cannabinoids in several types of headache disorders including migraine and cluster headache, although it is primarily limited to case based, anecdotal, or laboratory-based scientific research.

Cannabis contains an extensive number of pharmacological and biochemical compounds, of which only a minority are understood, so many potential therapeutic uses likely remain undiscovered.

Cannabinoids appear to modulate and interact at many pathways inherent to migraine, triptan mechanisms ofaction, and opiate pathways, suggesting potential synergistic or similar benefits.

Modulation of the endocannabinoid system through agonism or antagonism of its receptors, targeting its metabolic pathways, or combining cannabinoids with other analgesics for synergistic effects, may provide the foundation for many new classes of medications.”

http://www.ncbi.nlm.nih.gov/pubmed/26015168

http://www.thctotalhealthcare.com/category/headachemigraine/

(+/-)9,10-Dihydroxy-delta6a(10a)-tetrahydrocannabinol and (+/-)8,9-dihydroxy-delta6a(10a)-tetrahydrocannabinol: 2 new cannabinoids from Cannabis sativa L.

“The structures of 2 new polyhydroxylated cannabinoids, (+/-)9,10-dihydroxy-delta6a(10a)-tetrahydrocannabinol and (+/-)8,9-dihydroxy-delta6a(10a)-tetrahydrocannabinol, obtained from a hexane extract of an Indian Cannabis variant were determined by spectral means and correlation with cannabinol.”

http://www.ncbi.nlm.nih.gov/pubmed/720501

Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa.

“Seven new naturally occurring hydroxylated cannabinoids (1-7), along with the known cannabiripsol (8), have been isolated from the aerial parts of high-potency Cannabis sativa.

The structures of the new compounds were determined by 1D and 2D NMR spectroscopic analysis, GC-MS, and HRESIMS as 8α-hydroxy-Δ9-tetrahydrocannabinol (1), 8β-hydroxy-Δ9-tetrahydrocannabinol (2), 10α-hydroxy-Δ8-tetrahydrocannabinol (3), 10β-hydroxy-Δ8-tetrahydrocannabinol (4), 10α-hydroxy-Δ9,11-hexahydrocannabinol (5), 9β,10β-epoxyhexahydrocannabinol (6), and 11-acetoxy-Δ9-tetrahydrocannabinolic acid A (7).

The binding affinity of isolated compounds 1-8, Δ9-tetrahydrocannabinol, and Δ8-tetrahydrocannabinol toward CB1 and CB2 receptors as well as their behavioral effects in a mouse tetrad assay were studied.

The results indicated that compound 3, with the highest affinity to the CB1 receptors, exerted the most potent cannabimimetic-like actions in the tetrad assay, while compound 4 showed partial cannabimimetic actions. Compound 2, on the other hand, displayed a dose-dependent hypolocomotive effect only.”

http://www.ncbi.nlm.nih.gov/pubmed/26000707

Lipid nanoparticles as an emerging platform for cannabinoid delivery: physicochemical optimization and biocompatibility.

“This work aims at developing and optimizing a valuable oral delivery carrier for the cannabinoid derivative CB13, which presents a high therapeutic potential in chronic pain states that respond poorly to conventional analgesics, but also shows highly unfavorable physicochemical properties.

CB13-loaded lipid nanoparticles (LNP) formulations were developed…

The LNP formulation proposed proved to be a promising carrier for the oral delivery of CB13, a cannabinoid with high therapeutic potential in chronic pain states that currently lack a valid oral treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/25996463

Synthetic and endogenous cannabinoids protect retinal neurons from AMPA excitotoxicity in vivo, via activation of CB1 receptors: Involvement of PI3K/Akt and MEK/ERK signaling pathways.

“Cannabinoids have been suggested to protect retinal ganglion cells in different models of toxicity…

These results suggest that endogenous and synthetic cannabinoids protect retinal amacrine neurons from AMPA excitotoxicity in vivo via a mechanism involving the CB1 receptors, and the PI3K/Akt and/or MEK/ERK1/2 signaling pathways.”

http://www.ncbi.nlm.nih.gov/pubmed/25989217

A CB2-Selective Cannabinoid Suppresses T-Cell Activities and Increases Tregs and IL-10.

“We have previously shown that agonists selective for the cannabinoid receptor 2 (CB2), including O-1966, inhibit the Mixed Lymphocyte Reaction (MLR), an in vitro correlate of organ graft rejection, predominantly through effects on T-cells. Current studies explored the mechanism of this immunosuppression by O-1966 using mouse spleen cells…

These data support the potential of CB2-selective agonists as useful therapeutic agents to prolong graft survival in transplant patients, and strengthens their potential as a new class of immunosuppressive agents with broader applicability.”

http://www.ncbi.nlm.nih.gov/pubmed/25980325

Use of Prescription Pain Medications Among Medical Cannabis Patients: Comparisons of Pain Levels, Functioning, and Patterns of Alcohol and Other Drug Use.

“Management of chronic pain is one of the most common reasons given by individuals seeking medical cannabis. However, very little information exists about the concurrent use of cannabis and prescription pain medication (PPM).

This study fills this gap in knowledge by systematically comparing medical cannabis users who use or do not use PPM, with an emphasis on understanding whether concurrent use of cannabis and PPM is associated with more serious forms of alcohol and other drug involvement…

PPM users rated the efficacy of cannabis higher than PPM for pain management and indicated a strong desire to reduce PPM usage.

Use of PPM among medical cannabis users was not identified as a correlate for more serious forms of alcohol and other drug involvement.”

http://www.ncbi.nlm.nih.gov/pubmed/25978826

The successful use of dronabinol for failure to thrive secondary to intestinal dysmotility.

“Symptoms of severe intestinal dysmotility decrease patients’ quality of life and may prevent them from sustaining adequate oral intake. Dronabinol is a synthetic cannabinoid that is labeled for use in AIDS-related anorexia and chemotherapy-associated nausea and vomiting that has additional efficacy in patients with other etiologies of nausea, vomiting, and anorexia.

PRESENTATION OF CASE:

We present a 58-year-old female with a history of nausea, vomiting, abdominal pain, and inability to maintain oral intake after multiple laparotomies for ectopic pregnancy, recurrent caecal volvulus, and cholecystitis. After eight years of unsuccessful trials of medicines, dietary modifications, and a partial colectomy, she began a trial of dronabinol, which caused almost complete remission of her symptoms. When this medication was discontinued by her payer, she was unable to maintain oral intake and therefore, was admitted to the hospital for fluid resuscitation and resumption of dronabinol.

DISCUSSION:

The use of dronabinol in this patient with severe intestinal dysmotility allowed her to maintain her nutritional status orally and obviated the need for enteral or parenteral feeding. Unfortunately, it was not covered by her insurance company for this indication.

CONCLUSION:

Dronabinol has the potential to improve quality of life for patients beyond those undergoing chemotherapy or suffering from AIDS. Lack of access to this medicine for patients with intestinal dysmotility after all other modalities have been tried can lead to morbid and expensive complications, such as inpatient admission and surgery for enteral access.”

http://www.ncbi.nlm.nih.gov/pubmed/25974259

“Our experience with this demonstrates that dronabinol can be an effective and well-tolerated treatment option for nausea, vomiting, and abdominal pain secondary to intestinal dysmotility where other modalities have failed.”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446691/

The Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueduactal Grey.

“Emerging evidence indicates the involvement of GPR55 and its proposed endogenous ligand, lysophosphatidylinositol (LPI), in nociception…

Thus, we provide the first pharmacological evidence that GPR55 activation at central levels is pronociceptive, suggesting that interfering with GPR55 signaling in the PAG may promote analgesia.”

http://www.ncbi.nlm.nih.gov/pubmed/25972448