Tag Archives: tetrahydrocannabinol

Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review.

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“Spasticity, an involuntary increase in muscle tone or rapid muscle contractions, is one of the more common and distressing symptoms of multiple sclerosis (MS). Medicinal treatment may reduce spasticity, but may also be ineffective, difficult to obtain, or associated with intolerable side effects. Cannabis, a psychotropic drug known for its analgesic properties, also has a long history as an effective and tolerable treatment for spasticity]. Demographic evidence has shown that many people with MS use cannabis for symptom management.

Clinical studies, animal models, and anecdotal reports have suggested that cannabis may be an effective treatment of MS spasticity. The antispastic effect of cannabis has been supported through a demonstration of the inhibitory properties in exogenous agonists for cannabis receptors found in the CNS. Early clinical trials reporting the efficacy and safety of cannabis use in MS have focused on the effects of Δ9-tetrahydrocannabinol (THC). Although these clinical studies reported a therapeutic benefit for MS symptoms, there were concerns of potential intoxication and other side effects of cannabis-based treatment. Another clinical study using a cannabidiol (CBD) extract documented a reduction in spasticity-related pain but not in spasticity..

More recent combination therapies using whole plant extracts of both THC and CBD have been introduced and there is evidence that CBD, which is not psychotropic, may reduce THC levels in the brain and attenuate its psychotropic side effects. Such therapies may potentially provide a tolerable yet effective treatment for MS symptoms. A number of recent studies have investigated the potential efficacy and safety of whole plant extracts of THC and CBD. One of the first large-scale studies of cannabis treatment for MS-related spasticity compared whole plant cannabis extracts with THC and a placebo, and found mixed evidence for the therapeutic benefit of spasticity in MS. A recent review that included a number of these recent studies provided additional support for the benefit of cannabinoids in MS-related spasticity but called for further study into long-term treatment and side effects. A systematic evaluation of recent research had not previously been conducted, and was needed in order to provide organized evidence of cannabinoid treatments and direction for future clinical studies. We therefore systematically reviewed studies that used a combination extract of THC and CBD for the treatment of spasticity.

We found evidence that combined THC and CBD extracts may provide therapeutic benefit for MS spasticity symptoms…

Finally, there is evidence that cannabinoids may provide neuroprotective and anti-inflammatory benefits in MS. Neuroinflammation, found in autoimmune diseases such as MS, has been shown to be reduced by cannabinoids through the regulation of cytokine levels in microglial cells. The therapeutic potential of cannabinoids in MS is therefore comprehensive and should be given considerable attention.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793241/

Sativex for the management of multiple sclerosis symptoms.

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Abstract

“Sativex (R) is a cannabis-based pharmaceutical product containing delta 9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:1 ratio, delivered in an oromucosal (mouth) spray. It has been approved as adjunctive treatment for neuropathic pain in patients with multiple sclerosis (MS). It is being investigated for the management of other MS symptoms, such as spasticity. THC:CBD spray is regulated as a narcotic. Five randomized controlled trials (RCTs) compared the benefits and harms of THC:CBD spray with placebo. A total of 368 patients with various neurological conditions (including MS) were recruited. In some trials, THC:CBD spray significantly reduced neuropathic pain, spasticity, muscle spasms and sleep disturbances. The most common adverse events (AEs) reported in trials were dizziness, sleepiness, fatigue, feeling of intoxication and a bad taste. Long-term safety and the potential for dependence, abuse, misuse and diversion are unknown.”

http://www.ncbi.nlm.nih.gov/pubmed/16317825

Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain.

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Abstract

“Sativex is one of the first cannabis-based medicines to undergo conventional clinical development and to be approved as a prescription medicine. It is an oromucosal spray that allows flexible, individualised dosing. Patients self titrate their overall dose and pattern of dosing according to their response to and tolerance of the medicine. This usually results in the administration of approximately 8-12 sprays/day. Each spray delivers tetrahydrocannabinol 2.7 mg and cannabidiol 2.5 mg, giving an approximate average dose of tetrahydrocannabinol 22-32 mg/day and cannabidiol 20-30 mg/day. Development has concentrated on the treatment of symptoms of multiple sclerosis, notably spasticity and neuropathic pain, as well as the treatment of neuropathic pain of other aetiologies. Positive results in placebo-controlled trials of the use of Sativex as an add-on therapy in these indications demonstrate that Sativex is efficacious and well tolerated in the treatment of these symptoms. Sativex has been approved for use in neuropathic pain due to multiple sclerosis in Canada. If ongoing studies replicate the results already observed, further approvals for the treatment of spasticity in multiple sclerosis and for neuropathic pain are likely.”

http://www.ncbi.nlm.nih.gov/pubmed/16553576

THC and CBD oromucosal spray (Sativex®) in the management of spasticity associated with multiple sclerosis.

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“People with multiple sclerosis may present with a wide range of disease symptoms during the evolution of the disease; among these, spasticity can have a marked impact on their well-being and quality of life. Symptom control, including spasticity, remains a key management strategy to improve the patient’s well-being and functional status. However, available drug therapies for spasticity sometimes have limited benefit and they are often associated with poor tolerability.

 Sativex is a 1:1 mix of 9-delta-tetrahydrocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, which is available as an oromucosal spray. Clinical experience with Sativex in patients with multiple sclerosis is accumulating steadily. Results from randomized, controlled trials have reported a reduction in the severity of symptoms associated with spasticity, leading to a better ability to perform daily activities and an improved perception of patients and their carers regarding functional status when Sativex was added to the current treatment regimen. Adverse events such as dizziness, diarrhea, fatigue, nausea, headache and somnolence occur quite frequently with Sativex, but they are generally of mild-to-moderate intensity and their incidence can be markedly reduced by gradual ‘uptitration’.

 In summary, initial well-controlled studies with Sativex oromucosal spray administered as an add-on to usual therapy have produced promising results and highlight encouraging avenues for future research.”

http://www.ncbi.nlm.nih.gov/pubmed/21456949

Clinical efficacy and effectiveness of Sativex, a combined cannabinoid medicine, in multiple sclerosis-related spasticity.

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Abstract

“Multiple sclerosis (MS) is associated with a wide range of disease symptoms and amongst these, spasticity is one of the most disabling and has the greatest impact on patient well-being and quality of life. Until now, available drug therapies for spasticity appear to have limited benefit and are often associated with poor tolerability. In a recent Spanish survey it was noted that multidrug therapy and a low control rate were common features for a large proportion of patients with MS-related spasticity, suggesting that currently available monotherapies lack significant activity. Sativex is a 1:1 mixture of δ-9-tetrahydrocannabinol and cannabidiol derived from Cannabis sativa chemovars, which is available as an oromucosal spray. Clinical experience with Sativex in patients with MS-related spasticity is steadily accumulating. Results from randomized, controlled trials have reported a reduction in the severity of symptoms associated with spasticity, leading to a better ability to perform daily activities and an improved perception of patients and their carers regarding functional status. These are highly encouraging findings that provide some much needed optimism for the treatment of this disabling and often painful symptom of MS.”

http://www.ncbi.nlm.nih.gov/pubmed/22509985

Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease.

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Abstract

“We studied whether combinations of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington’s disease (HD). We used rats intoxicated with 3-nitropropionate (3NP) that were given combinations of Δ(9)-THC- and CBD-enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Δ(9)-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB(1) receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Δ(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB(1) and CB(2) receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Δ(9)-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies.”

http://www.ncbi.nlm.nih.gov/pubmed/21674569

Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells

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Journal of Neuro-Oncology

“Normal tissue toxicity limits the efficacy of current treatment modalities for glioblastoma multiforme (GBM).

We evaluated the influence of cannabinoids on cell proliferation, death, and morphology of human GBM cell lines and in primary human glial cultures, the normal cells from which GBM tumors arise. The influence of a plant derived cannabinoid agonist, Delta(9)-tetrahydrocannabinol Delta(9)-THC), and a potent synthetic cannabinoid agonist, WIN 55,212-2, were compared using time lapse microscopy.

We discovered that Delta(9)-THC decreases cell proliferation and increases cell death of human GBM cells more rapidly than WIN 55,212-2. Delta(9)-THC was also more potent at inhibiting the proliferation of GBM cells compared to WIN 55,212-2. The effects of Delta(9)-THC and WIN 55,212-2 on the GBM cells were partially the result of cannabinoid receptor activation.

The same concentration of Delta(9)-THC that significantly inhibits proliferation and increases death of human GBM cells has no significant impact on human primary glial cultures. Evidence of selective efficacy with WIN 55,212-2 was also observed but the selectivity was less profound, and the synthetic agonist produced a greater disruption of normal cell morphology compared to Delta(9)-THC.”

https://www.ncbi.nlm.nih.gov/pubmed/16078104

https://link.springer.com/article/10.1007%2Fs11060-004-5950-2

Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells.

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“The active components of Cannabis sativa L., Cannabinoids, traditionally used in the field of cancer for alleviation of pain, nausea, wasting and improvement of well-being have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory activity and induction of tumor regression. Here we used several experimental approaches, which identified delta-9-tetrahydrocannabinol (Delta(9)-THC) as an essential mediator of cannabinoid antitumoral action.”

“CONCLUSIONS:

Delta(9)-THC is shown to significantly affect viability of GBM cells via a mechanism that appears to elicit G(1) arrest due to downregulation of E2F1 and Cyclin A. Hence, it is suggested that Delta(9)-THC and other cannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain tumors.”

http://www.ncbi.nlm.nih.gov/pubmed/17934890

A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme

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“One of the most devastating forms of cancer is glioblastoma multiforme (grade IV astrocytoma), the most frequent class of malignant primary brain tumours. Current standard therapeutic strategies for the treatment of glioblastoma multiforme (surgical resection and focal radiotherapy) are only palliative…”

“The hemp plant Cannabis sativa L. produces approximately 60 unique compounds known as cannabinoids, of which Δ9-tetrahydrocannabinol (THC) is the most important owing to its high potency and abundance in cannabis. Δ9-Tetrahydrocannabinol exerts a wide variety of biological effects by mimicking endogenous substances – the so-called endocannabinoids – that bind to and activate specific cell surface receptors. cannabinoids have been proposed as potential antitumoral agents owing to their ability to inhibit the growth and angiogenesis of various types of tumour xenografts in animal models.”

“Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration… Cannabinoid delivery was safe and could be achieved without overt psychoactive effects…. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360617/

Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain.

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Image result for journal of pain and symptom management impact factor

“This study compared the efficacy of a tetrahydrocannabinol:cannabidiol (THC:CBD) extract, a nonopioid analgesic endocannabinoid system modulator, and a THC extract, with placebo, in relieving pain in patients with advanced cancer. This study shows that THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids.”  http://www.ncbi.nlm.nih.gov/pubmed/19896326

“In conclusion, THC:CBD extract, a nonopioid analgesic, endocannabinoid system modulator, has been shown to be a useful adjunctive treatment for relief of pain in patients with advanced cancer who experience inadequate analgesia despite chronic opioid therapy. The reductions in pain scores were neither because of a change in opioid background medications nor because of an increase in use of breakthrough medication. Therefore, we can conclude that the observed reduction in pain scores is attributable to the positive analgesic effects of THC:CBD extract.” http://www.jpsmjournal.com/article/S0885-3924(09)00787-8/fulltext