Treatment of spasticity in multiple sclerosis: new perspectives regarding the use of cannabinoids.

“Spasticity remains a prevalent symptom in multiple sclerosis, with a significant associated disability and quality of life impairment… Cannabinoids provide a new way for therapy.

A delta-9-tetrahydrocannabinol plus cannabidiol (1:1) association, administered through an oromucosal route, has been approved in several countries including Spain; it causes a specific effect on CB(1) and CB(2) receptors, with traditional psychotropic cannabis actions being minimized.

Randomized, placebo-controlled trials, as well as longer-term open-label extensions, have shown a clear-cut efficacy to reduce spasticity and their associated symptoms in those patients refractory to other therapies, with a good tolerability/safety profile.

No tolerance, abuse or addictive issues have been found…”

http://www.ncbi.nlm.nih.gov/pubmed/23011861

Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial.

“Clinical reports indicate that cannabinoids may alleviate pain in different pain conditions, including multiple sclerosis related pain…

Randomised double blind placebo controlled crossover trial… To evaluate the effect of the oral synthetic delta-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis…

CONCLUSIONS:

Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC498019/

The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway.

“Delta9-tetrahydrocannabinol and other cannabinoids exert pro-apoptotic actions in tumor cells via the CB2 cannabinoid receptor…

 Here we used the human leukemia cell line Jurkat-that expresses CB2 as the unique CB receptor-to investigate…

 In summary, results presented here show that CB2 receptor activation signals apoptosis via a ceramide-dependent stimulation of the mitochondrial intrinsic pathway.”

http://www.ncbi.nlm.nih.gov/pubmed/16624285

Δ9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria

“Cannabinoids, the biologically active constituents of marijuana (Cannabis sativa)…

Plant-derived cannabinoids, including Δ9-tetrahydrocannabinol (THC), induce apoptosis in leukemic cells…

cannabinoids were shown to inhibit the proliferation of several human cancer cell lines, including leukemia…

Together, these data suggested that Raf-1/MEK/ERK/RSK-mediated Bad translocation played a critical role in THC-induced apoptosis in Jurkat cells…

THC and other cannabinoids can induce apoptosis in a variety of tumor cell lines, thereby raising the possibility of the use of cannabinoids as novel anticancer agents…”

Full text: http://mcr.aacrjournals.org/content/4/8/549.long

Enhancing the in vitro cytotoxic activity of Delta9-tetrahydrocannabinol in leukemic cells through a combinatorial approach.

“Delta(9)-Tetrahydrocannabinol (THC) is the active metabolite of cannabis, which has demonstrable cytotoxic activity in vitro. In support of our previously published data, we have investigated the interactions between THC and anti-leukemia therapies and studied the role of the signalling pathways in mediating these effects.

 Results showed clear synergistic interactions between THC and the cytotoxic agents in leukemic cells…

 Overall, these results demonstrate for the first time that a combination approach with THC and established cytotoxic agents may enhance cell death in vitro. Additionally the MAPK/ERK pathway appears responsible in part for these effects.”

http://www.ncbi.nlm.nih.gov/pubmed/18608861

Cannabidiol, unlike synthetic cannabinoids, triggers activation of RBL-2H3 mast cells

“Plant-derived cannabinoids, such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the main psychoactive and nonpsychoactive components of cannabis, respectively, possess myriad pharmacological properties…

Cannabidiol (CBD), a prominent psychoinactive component of cannabis with negligible affinity for known cannabinoid receptors, exerts numerous pharmacological actions, including anti-inflammatory and immunosuppressive effects…

Together, these results support existence of yet-to-be identified sites of interaction, i.e., receptors and/or ion channels associated with Ca2+ influx of natural cannabinoids such as CBD and THC, the identification of which has the potential to provide for novel strategies and agents of therapeutic interest.”

Full text: http://www.jleukbio.org/content/81/6/1512.long

Tetrahydrocannabinol inhibits adenyl cyclase in human leukemia cells.

“Delta 9-tetrahydrocannabinol has been shown to induce incomplete maturation in ML2 human leukemia cell lines.

We extend the observation of its induction of morphologic maturation to HL60 cells and of its induction of growth restriction to HL60 and K562 cells.

 We show that tetrahydrocannabinol reduces the cyclic AMP content of ML2 cells.

 Finally we demonstrate that this agent inhibits adenyl cyclase activity in ML2 cell membrane-enriched fractions.

This finding in myeloid cells is compatible with one hypothesis of cannabinoid action in neuronal cells.”

http://www.ncbi.nlm.nih.gov/pubmed/2154651

Cannabinoids induce incomplete maturation of cultured human leukemia cells.

“Monocyte maturation markers were induced in cultured human myeloblastic ML-2 leukemia cells after treatment for 1-6 days with 0.03-30 microM delta 9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana…

 Cannabinoids induce incomplete maturation of cultured human leukemia cells…

Findings obtained from this system may have important implications for studies of cannabinoid effects on normal human bone-marrow progenitor cells.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC298868/

Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease

“In the current study, we examined whether ligation of CB2 receptors would lead to induction of apoptosis in tumors of immune origin and whether CB2 agonist could be used to treat such cancers.

 Exposure of murine tumors EL-4, LSA, and P815 to delta-9-tetrahydrocannabinol (THC) in vitro led to a significant reduction in cell viability and an increase in apoptosis…

Culture of primary acute lymphoblastic leukemia cells with THC in vitro reduced cell viability and induced apoptosis.

Together, the current data demonstrate that CB2 cannabinoid receptors expressed on malignancies of the immune system may serve as potential targets for the induction of apoptosis. Also, because CB2 agonists lack psychotropic effects, they may serve as novel anticancer agents to selectively target and kill tumors of immune origin.”

http://bloodjournal.hematologylibrary.org/content/100/2/627.long

“We examined whether treatment of tumor-bearing mice with THC was effective at killing tumor cells in vivo… These data suggest that THC was effective in vivo to induce apoptosis and kill the tumor cells… THC treatment can cure tumor-bearing mice… they were completely cured…Taken together, these results suggest that THC can exert anticancer properties in vivo.” http://bloodjournal.hematologylibrary.org/content/100/2/627.long?sso-checked=1

 

Targeting cannabinoid receptors to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in Delta9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells.

“Targeting cannabinoid receptors has recently been shown to trigger apoptosis and offers a novel treatment modality against malignancies of the immune system.

  In this study, we used human Jurkat leukemia cell lines with defects in intrinsic and extrinsic signaling pathways to elucidate the mechanism of apoptosis induced by Delta9-tetrahydrocannabinol (THC)…

Together, these data suggest that the intrinsic pathway plays a more critical role in THC-induced apoptosis while the extrinsic pathway may facilitate apoptosis via cross-talk with the intrinsic pathway.”

http://www.ncbi.nlm.nih.gov/pubmed/15978942