Safety, tolerability, and efficacy of orally administered cannabinoids in MS

Killestein, Joep; Hoogervorst, Erwin L.J.; Reif, Marcus; Kalkers, N. F.; Loenen, A. C. Van; Staats, P. G.M.; Gorter, R. W.; Uitdehaag, Bernard M. J.; Polman, CH

doi:10.1212/wnl.58.9.1404

Cited by 208 publications

(183 citation statements)

References 5 publications

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“…Maximum effects following a single dose of 10 mg oral THC administered on day 1 were noted between 1 and 5 h after drug administration. In contrast to several other trials in SCI and MS patients, which found no or minor effects on objective spasticity measures, 18,20,21,28 there were significant differences between placebo and verum as well as between baseline and treatment values in the SSS.…”

Section: Discussioncontrasting

confidence: 98%

“…Daily doses in recent studies on spasticity in MS and SCI varied between 5 and 10 mg oral THC, 28 10-25 mg, 19 15-30 mg 21 and 2.5-120 mg, 28 underlining the high interindividual variability. In our study, we determined comparatively high tolerated daily doses of 15-60 mg for oral THC, the mean dose being 31 mg compared to average daily doses of 0.46 mg THC/kg body weight.…”

Section: Discussionmentioning

confidence: 99%

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The treatment of spasticity with Δ9-tetrahydrocannabinol in persons with spinal cord injury

et al. 2006

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Study design: Open label study to determine drug dose for a randomized double-blind placebocontrolled parallel study. Objectives: To assess the efficacy and side effects of oral D 9 -tetrahydrocannabinol (THC) and rectal THC-hemisuccinate (THC-HS) in SCI patients. Setting: REHAB Basel, Switzerland. Method: Twenty-five patients with SCI were included in this three-phase study with individual dose adjustment, each consisting of 6 weeks. Twenty-two participants received oral THC open label starting with a single dose of 10 mg (Phase 1, completed by 15 patients). Eight subjects received rectal THC-HS (Phase 2, completed by seven patients). In Phase 3, six patients were treated with oral THC and seven with placebo. Major outcome parameters were the spasticity sum score (SSS) using the Modified Ashworth Scale (MAS) and self-ratings of spasticity. Results: Mean daily doses were 31 mg with THC and 43 mg with THC-HS. Mean SSS for THC decreased significantly from 16.72 (77.60) at baseline to 8.92 (77.14) on day 43. Similar improvement was seen with THC-HS. We observed a significant improvement of SSS with active drug (P ¼ 0.001) in the seven subjects who received oral THC in Phase 1 and placebo in Phase 3. Major reasons for drop out were increase of pain and psychological side effects. Conclusion: THC is an effective and safe drug in the treatment of spasticity. At least 15-20 mg per day were needed to achieve a therapeutic effect.

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Section: Discussioncontrasting

confidence: 98%

Section: Discussionmentioning

confidence: 99%

The treatment of spasticity with Δ9-tetrahydrocannabinol in persons with spinal cord injury

et al. 2006

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“…The CONTAM Panel noted that the data reported do not allow an evaluation of dose-response relationships. Killestein et al (2002) investigated safety, tolerability, and efficacy of oral Δ In a clinical study conducted by Holdcroft et al (2006) the potential of a single oral dose of a mixture of cannabinoid plant extracts to provide postoperative pain relief was investigated without placebo control. Pain intensity and side-effects were recorded over 6 hours.…”

Section: Extracts Of Cannabis Sativamentioning

confidence: 99%

Scientific Opinion on the risks for human health related to the presence of tetrahydrocannabinol (THC) in milk and other food of animal origin

2015

EFS2

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The European Food Safety Authority (EFSA) was asked to deliver a scientific opinion on the risks for human health related to the presence of tetrahydrocannabinol (THC) in milk and other food of animal origin. THC, more precisely delta-9-tetrahydrocannabinol (Δ 9 -THC) is derived from the hemp plant Cannabis sativa. In fresh plant material, up to 90 % of total Δ 9 -THC is present as the non-psychoactive precursor Δ 9 -THC acid. Since few data on ∆ 9 -THC levels in foods of animal origin were available, the Panel on Contaminants in the Food Chain (CONTAM Panel) estimated acute human dietary exposure to ∆ 9 -THC combining different scenarios for the presence of ∆ 9 -THC in hemp seed-derived feed materials. Acute exposure to ∆ 9 -THC from the consumption of milk and dairy products ranged between 0.001 and 0.03 µg/kg body weight (b.w.) per day in adults, and 0.006 and 0.13 µg/kg b.w. per day in toddlers. From human data, the CONTAM Panel concluded that 2.5 mg Δ 9 -THC/day, corresponding to 0.036 mg Δ 9 -THC/kg b.w. per day, represents the lowest observed adverse effect level. By applying an overall uncertainty factor of 30, an acute reference dose (ARfD) of 1 μg Δ 9 -THC/kg b.w. was derived. The exposure estimates are at most 3 % and 13 % the ARfD, in adults and toddlers, respectively. The CONTAM Panel concluded that exposure to ∆ 9 -THC via consumption of milk and dairy products, resulting from the use of hemp seed-derived feed materials at the reported concentrations, is unlikely to pose a health concern. A risk assessment resulting from the use of whole hemp plant-derived feed materials is currently not feasible due to a lack of occurrence data. The CONTAM Panel could also not conclude on the possible risks to public health from exposure to ∆ 9 -THC via consumption of animal tissues and eggs, due to a lack of data on the potential transfer and fate of ∆ 9 -THC. Tetrahydrocannabinol, more precisely delta-9-tetrahydrocannabinol (Δ 9 -THC) is the most relevant constituent derived from the hemp plant Cannabis sativa. Four stereoisomers of Δ 9 -THC are possible, with (-)-trans-Δ 9 -THC being the only naturally occurring isomer. Delta-9-tetrahydrocannabinolic acid, which is found in the growing and harvested plant, is the biosynthetic precursor of Δ 9 -THC. Besides 2-COOH-Δ 9 -THC, which in this opinion is referred to as Δ 9 -THCA-A, another positional isomer, 4-COOH-Δ 9 -THC, denoted as Δ 9-THCA-B, may also occur in the hemp plant. In fresh plant material of C. sativa, up to 90 % of the 'total' Δ 9 -THC is present as the non-psychoactive precursor Δ 9 -THCA-A. The rate and extent of transformation of the precursor acids into Δ 9 -THC in the plant material is dependent on physical effects, in particular temperature. In addition to Δ 9 -THC, C. sativa preparations may contain at least 60 other cannabinoids, several of which are biologically active. This risk assessment does not evaluate the exposure and associated risks of cannabis used as a medicinal drug or for recreational purposes, but as requested in the ter...

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“…Since it has been shown that glutamate excitotoxicity contributes to clinical symptoms and cell death of oligodendrocytes in a mice EAE-model of MS (Pitt et al, 2000), it is tempting to suggest that the amelioration of the symptoms in AEA-models by (endo)cannabinoids is due to their anti-excitotoxic properties (see above). Altogether, data from experimental animals do provide a scientific basis for the anecdotal reports in which MS patients alleviate their symptoms by using marijuana, but results from small-and short-term clinical trials have been equivocal (Killestein et al, 2002).…”

Section: Multiple Sclerosismentioning

confidence: 99%

Biosynthesis of endocannabinoids and their modes of action in neurodegenerative diseases

et al. 2003

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Endocannabinoids are thought to function as retrograde messengers, which modulate neurotransmitter release by activating presynaptic cannabinoid receptors. Anandamide and 2-arachidonoylglycerol (2-AG) are the two best studied endogenous lipids which can act as endocannabinoids. Together with the proteins responsible for their biosynthesis, inactivation and the cannabinoid receptors, these lipids constitute the endocannabinoid system. This system is proposed to be involved in various neurodegenerative diseases such as Parkinson's and Huntington's diseases as well as Multiple Sclerosis. It has been demonstrated that the endocannabinoid system can protect neurons against glutamate excitotoxicity and acute neuronal damage in both in vitro and in vivo models. In this paper we review the data concerning the involvement of the endocannabinoid system in neurodegenerative diseases in which neuronal cell death may be elicited by excitotoxicity. We focus on the biosynthesis of endocannabinoids and on their modes of action in animal models of these neurodegenerative diseases.

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Safety, tolerability, and efficacy of orally administered cannabinoids in MS

Cited by 208 publications

References 5 publications

The treatment of spasticity with Δ9-tetrahydrocannabinol in persons with spinal cord injury

The treatment of spasticity with Δ9-tetrahydrocannabinol in persons with spinal cord injury

Scientific Opinion on the risks for human health related to the presence of tetrahydrocannabinol (THC) in milk and other food of animal origin

Biosynthesis of endocannabinoids and their modes of action in neurodegenerative diseases

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