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Cannabinoids☆
Cannabinoidsq Susan H Fox and Achinoam Faust-Socher, University of Toronto, Toronto, ON, Canada © 2017 Elsevier Inc. All rights reserved.
Definitions History Cannabinomimetic Effects Cannabinoid Receptors Cannabinoid CB1 Receptors Memory Analgesia Thermoregulation Antiemetic Motor Functions Other Locations Cannabinoid CB2 Receptor Non-CB Receptors That Mediate Cannabinomimetic Effects Endocannabinoid System Function of Endocannabinoids Cannabinoid Receptor Antagonists Cannabinoids in Movement Disorders Endocannabinoid System in Parkinson Disease FAAH Inhibitors CB1 Cannabinoid Receptor Antagonists Other Cannabinoids Endocannabinoid System in Levodopa-Induced Dyskinesia (LID) CB1 Receptor Agonists CB1 Receptor Antagonists Endocannabinoids in Dystonia Endocannabinoids in Tourette’s Syndrome Cannabinoids in Huntington’s Disease Frequently Used Cannabis Preparations/Methods of Administration Pharmacokinetics of Currently Available Cannabis and Synthetic Cannabinoid Preparations References Further Reading Relevant Websites
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Glossary Cannabinoid A compound that is structurally related to compounds derived from the Cannabis sativa plant. Inverse agonist A compound that binds to a receptor but reverses the constituent activity of the receptor. Long term depression Synaptic plasticity resulting in the release of endocannabinoids and long-lasting inhibition of neurotransmitter release. Psychoactive Having properties that induce psychotic symptoms such as altered perceptions, hallucinations, and delusions.
Definitions Cannabinoids are C21 compounds that are present in Cannabis sativa as well as structurally related to the main psychoactive component, delta-9-tetrahydrocannabinol (delta-9-THC).
History Medicinal properties of the exogenous cannabinoid Cannabis sativa (marijuana) have been known for millennia. The proposed uses include antinausea, pain control, muscle spasms and epileptic seizures. Until recently, however, most treatments were generally unsubstantiated, and there was a lack of scientific rationale or clinical trial evidence to support the claims. In addition, concerns
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Cannabinoids
Table 1
Clinically available synthetic and phytocannabinoid drugs
Name of drug
Type of cannabinoid
Licensed indication
Nabilone
Mixture of D9THC, cannabinol, cannabidiol and other cannabinoids.
Tetrahydrocannabinol
D9THC.
TetrahydrocannabinolCannabidiol mix
Buccal spray of Cannabis sativa extract (plant and non plant-based extracts) containing D9THC and cannabidiol.
Tetrahydrocannabinol– Cannabidiol mix
Oral cannabis extract of Cannabis sativa (plant and non-plant extract) containing D9THC and cannabidiol. CB1 receptor antagonist.
Treatment of chemotherapy-induced nausea and vomiting that has not responded to conventional antiemetics. Treatment of anorexia and weight loss in patients with AIDS. Treatment of severe nausea and vomiting with chemotherapy that has not responded to conventional antiemetics and AIDS-related anorexia. Symptomatic relief of neuropathic pain and adjunctive analgesic treatment in advanced cancer for pain control despite opioid therapy. Approved in Canada as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis. FDA/Orphan disease Epilepsy syndromes; Lennox Gastaut; Brain tumors.
Rimonabant
Withdrawn from market due to adverse effects.
regarding cognitive and psychotropic effects of cannabinoids have generally limited clinical development of these drugs. To date, well over 100 naturally occurring cannabinoids have been identified. The main psychoactive component is delta-9-THC. Several other components have been identified, and they include cannabidiol and cannabinol. Following the discovery of these components, several closely related cannabinoid drugs have been synthesized (Table 1).
Cannabinomimetic Effects Acute effects of cannabinoids in humans may include euphoria, relaxation, perceptual alterations, time distortion, and intensive sensory experiences, as well as impaired short-term memory, motor skills and reaction times. In animal studies, cannabinoids produce four classical cannabinomimetic effects including antinociception (analgesia) without respiratory suppression, reduced spontaneous activity, catalepsy and hypothermia. The effect on motor activity depends on the dose of the agent; low doses induce hyperactivity but higher doses catalepsy. These behavioral properties have now been confirmed in cannabinoid receptor knockout mice models.
Cannabinoid Receptors The biological effects of cannabinoids are now known to be mediated by two cannabinoid receptors, CB1 (cloned in 1990) and CB2 (cloned in 1993) (Table 2). Cannabinoid receptors are members of the G protein-coupled receptor superfamily and CB1 receptors activate Gi/o resulting in inhibition of adenylyl cyclase. In addition, they activate potassium and calcium channels. The cannabinoid system is unusual in that despite the wide distribution of cannabinoid receptors, to date only two types of receptors have been classified. Thus, all actions of cannabinoids are mediated through these two receptors, the CB1 and CB2 receptor, and as such the therapeutic potential for cannabinoid agonists is potentially limited by unwanted actions and side effects.
Cannabinoid CB1 Receptors CB1 receptors are widely distributed in both the peripheral and central nervous systems. Cannabinomimetic effects are related to CB1 receptors within particular brain regions.
Memory CB1 receptors are located in the hippocampus, particularly in CA3 field of Ammon’s horn and the molecular layer of the dentate gyrus.
Analgesia CB1 receptors are located on the peripheral terminals of primary sensory neurons and in the dorsal horn of the spinal cord, in addition to central sites that may mediate pain including the amygdala, thalamus, superior colliculus and rostral ventromedial medulla.
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Table 2 Relative affinity of exogenous and endogenous cannabinoids at cannabinoid CB1 and cannabinoid CB2 receptors Cannabinoid
Name
CB1
CB2
Exogenous cannabinoids
D9THC D8THC Cannabinol Cannabidiol D9Tetrahydrocannabivarin Cannabivarin 11-hydroxy D8THC (HU 210) CP55,940 WIN55, 212–2 Arachidonyl-2-chloroethylamide (ACEA) Arachidonylcyclopropylamide (ACPA) Methanandamide O-1812 AM 1241 JWH 133 HU 308 GW 405833 JWH 015 BAY 38–7271 Anandamide 2-AG Noladin ether
þþ þþ (þ) 0 – (þ) þþþ þþþ þþþ þþþ þþþ þþ þþþ þ þ 0 (þ) (þ) þþþ þ þ þþ
þ þ (þ) 0 þ (þ) þþþ þþþ þþþ 0 (þ) þ 0 þþþ þþþ þþþ þþþ þþ þþþ (þ) þ 0
Synthetic cannabinoids
Endocannabinoids
0 ¼ no affinity; (þ) ¼ very low; þ ¼ low; þþ ¼ moderate; þþþ ¼ high affinity for the receptor; D9THC ¼ D9tetrahydrocannabinol; D8THC ¼ D8tetrahydrocannabinol. Adapted from Pertwee, R.G., 2005. Pharmacological actions of cannabinoids. Handb. Exp. Pharmacol. (168), 1–51.
Thermoregulation CB1 receptors are located within the hypothalamus.
Antiemetic CB1 receptors are located in the dorsal vagal complex, consisting of the area postrema (the chemoreceptor trigger zone for emetic reflexes), nucleus of the solitary tract, and the dorsal motor nucleus of the vagus in the brainstem.
Motor Functions The basal ganglia have one of the highest concentrations of CB1 receptors in the brain. CB1 receptors are located on the presynaptic terminals of the GABAergic striatopallidal pathways in the globus pallidus (GP) (both internal (GPi) and external (GPe) segments) and the substantia nigra pars reticulata (SNpr). In addition, CB1 receptors are found on the corticostriatal glutamatergic projection neurons as well as the parvalbumin-positive interneurons of the striatum. In the cerebellum, CB1 receptors are located in the molecular layer, which contains fibers and dendritic processes originating from Purkinje cells.
Other Locations CB1 receptors are also found in the periphery in the vasculature, heart, bladder, small intestine and vas deferens. Several synthetic cannabinoids are now available (Table 1 and Table 2).
Cannabinoid CB2 Receptor The CB2 receptor is principally located in the immune system both in the brain and periphery. The receptor was initially derived from a human promyelocytic leukemia (HL60) cell line and is found in high amounts in B-cells and natural killer cells. In addition, CB2 receptors are located in microglia and blood vessels. Until recently, CB2 receptors were not thought to be located in neuronal tissue, but
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have now been demonstrated in the brainstem as well the hippocampus and cerebellum. In the basal ganglia they were found to be expressed on neurons in the SNpr as well as in the globus pallidus. The CB2 receptor shares 68% homology with the CB1 receptor. Compared to the undesired psychotropic actions, which are produced by CB1 agonists, the activation of CB2 receptors does not appear to produce these psychotropic effects. Although CB2 agonists had looked promising in a range of preclinical models including pain syndromes, neuroinflammatory and neurodegenerative processes, their efficacy in clinical studies has been relatively disappointing.
Non-CB Receptors That Mediate Cannabinomimetic Effects Several actions of cannabinoids appear to be mediated by non-CB1 or CB2 receptors. Thus, vasodilatory and some analgesic properties of cannabinoids appear to be due to an action at capsaicin (vanilloid VR-1 or TRPV1) receptors. Other targets of cannabinoids include N-type and T-type calcium channels, sodium channels, voltage-gated potassium channels, nicotinic receptors, glycine receptors, and 5-HT2 and 5-HT3 receptors.
Endocannabinoid System The discovery of the cannabinoid receptors led to the detection of endogenous ligands, termed endocannabinoids, for these receptors. Several endocannabinoids have now been described, but arachidonoyl ethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG) are the best characterized. These are eicosanoid phospholipids produced on receptor-mediated demand in response to elevated intracellular calcium and immediately released. This is in contrast to the classical neurotransmitters that are synthesized and stored in vesicles in presynaptic nerve terminals. Anandamide is produced by the hydrolysis of membrane phosphatidylethanolamine, and is released and removed by active reuptake, via an anandamide transporter and hydrolysis by fatty acid aminohydrolase (FAAH). 2-AG is produced from sequential hydrolysis of phosphatidylinositol (4,5)-biphosphate, and the effects are terminated by active uptake into cells and hydrolysis.
Function of Endocannabinoids The function of the endocannabinoid system is to modulate neurotransmission. Thus, depolarization of the postsynaptic membrane results in the release of endocannabinoids that diffuse to the presynaptic membrane and inhibit GABA and glutamate activity. In addition, endocannabinoids function as retrograde messengers and are implicated in synaptic plasticity in the hippocampus, thus potentially having a role in memory and learning. Within the striatum, endocannabinoids also act as retrograde messengers and mediate long term depression by interacting with dopamine D2 receptors in the indirect striatopallidal pathway.
Cannabinoid Receptor Antagonists All cannabinoid receptor antagonists currently available are competitive antagonists at CB1 or CB2 receptors of endogenously released endocannabinoids. However, these compounds also have inverse agonist properties by negative, possibly allosteric, modulation of the constitutive activity of CB receptors and by shifting the receptor from a constitutively active to an inactive state. In addition, these compounds may also block non-CB-mediated effects, for example antagonism of endogenously released adenosine action at A1 receptors.
Cannabinoids in Movement Disorders The potential role of the endocannabinoid system in movement disorders stems from the high concentration of CB1 receptors found within the basal ganglia as well as elevated levels of endocannabinoids. To date, there is no consensus on changes in CB1 receptor numbers in PD. Investigating the localization of cannabinoid receptors has been difficult due to the highly lipophilic nature of their ligands and has been restricted to in vitro studies with inconsistent results. A recent cannabinoid ligand [18F]MK-9470 has been developed for in vivo use in PET imaging. Using [18F]MK-9470 to measure CB1 levels in PD patients versus healthy controls; there was a decrease in CB1 availability in the substantia nigra (SN) of PD patients compared to controls. However, a higher CB1 availability was found in PD compared to controls in the mesolimbic, nigrostriatal and mesocortical dopaminergic projection areas.
Endocannabinoid System in Parkinson Disease FAAH Inhibitors Increased endocannabinoids are found in untreated PD patients (in CSF) and in the striatum of animal models of untreated PD. This may be a compensatory effect for the loss of dopamine. Stimulation of CB1 receptors decreases corticostriatal glutamatergic
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transmission and enhanced endocannabinoids may thus be an attempt to decrease the increased glutamate input in PD. Further enhancing endocannabinoid levels may therefore result in the alleviation of PD motor symptoms. Inhibition of FAAH prevents the breakdown of endocannabinoids and reduces excitatory striatal glutamate activity in 6-OHDA lesioned rats. In addition, in PD overactivity of the indirect striatopallidal pathway may be in part due to loss of long-term depression (LTD), an effect mediated by both dopamine D2 receptors and endocannabinoids. Thus, combined treatment of 6-OHDA-lesioned or reserpine-lesioned rat models of PD with a dopamine D2 agonist and a selective FAAH inhibitor URB597 reversed PD-like symptoms. To date, FAAH inhibitors have demonstrated reduced levodopa-induced hyperactivity in a MPTP primate model of PD; however none of these agents are clinically available.
CB1 Cannabinoid Receptor Antagonists Alternatively, enhanced endocannabinoids within other regions of the basal ganglia may be mediating parkinsonian symptoms. Thus, in reserpine treated rats and untreated MPTP-lesioned primates, increased levels of endocannabinoids in the GPe are found. These endocannabinoids, by stimulating CB1 receptors within the GPe, and by reducing GABA reuptake may lead to reduced activity of the GPe, a key abnormality in PD. Thus, CB1 antagonists may have an antiparkinsonian action. The CB1 selective antagonist, rimonabant, had a mild effect on reversal of motor symptoms in the 6-OHDA-lesioned rat and MPTP-lesioned primate models, while another CB1 antagonist carboxylic acid amide benzenesulfonate (CE) had no antiparkinsonian action alone but enhanced the antiparkinsonian actions of levodopa in the MPTP lesioned primate. In clinical studies, in four advanced PD patients, there was no effect on PD motor symptoms using rimonabant (20 mg/d) compared to placebo as add-on therapy, but no adverse effects were noticed. To date, no further clinical studies have been performed.
Other Cannabinoids There have been few clinical studies that have assessed the benefits of other cannabinoid preparations for the treatment of PD. Several uncontrolled and observational studies found positive effects for the use of cannabidiol (CBD) on psychosis, REM sleep behavior disorder. One study that examined patients before and after smoking cannabis found an improvement of motor functions as well as in non-motor functions such as sleep and pain awareness. However DBRCT did not show a clear benefit from the use of cannabis; thus 21 PD patients were treated with either placebo, 75 mg/d CBD or 300 mg/d CBD. There was no significant improvement in UPDRS scores or neuroprotective measures (BDNF, H1-MRS) in the patients who received CBD compared to the placebo group. Further studies are needed to evaluate the efficacy and particularly the tolerability of cannabinoids in PD.
Endocannabinoid System in Levodopa-Induced Dyskinesia (LID) CB1 Receptor Agonists In PD patients following long term treatment with levodopa, involuntary movements (dyskinesia) may develop. The neural mechanism underlying levodopa-induced dyskinesia (LID) involves overactive corticostriatal glutamate activity; CB1 receptor stimulation reduces glutamate release from corticostriatal inputs in the striatum, and thus CB1 receptor agonists may be useful in reducing LID. An alternative site of action may be via activation of CB1 receptors on the striatopallidal terminals of the indirect GABAergic pathway, which reduces GABA reuptake and thus reduces the firing rate of neurons in the GPe. In preclinical studies, the CB1 agonist WIN55,212 reduced LID in reserpine and 6-OHDA-lesioned rats. An alternative action of cannabinoids may be at TRPV1 (vanilloid) receptors and the TRPV1 agonist, capsaicin, reduces levodopa-induced hyperkinesia in reserpine treated rats. In the MPTP lesioned marmoset model of LID, nabilone reduced dyskinesia without affecting the antiparkinsonian action of levodopa. In clinical studies, nabilone was shown to have a mild effect on reducing dyskinesia in a Phase IIa trial using a cross-over acute challenge study design in seven PD patients. There was no effect on parkinsonian disability, and all patients had a nonsignificant fall in systolic blood pressure and experienced side effects of mild sedation and dizziness. Another Phase II randomized controlled trial (RCT) study using CannadorW, showed no significant effect on LID or any significant adverse effects in 19 PD patients when treated for 4 weeks. The variable effects may relate to the different cannabinoid agents used as well as to differences in the trial designs. To date, no further studies have been performed in PD patients to assess the effects of cannabinoids on LID.
CB1 Receptor Antagonists Cannabinoid antagonists have also been proposed to reduce dyskinesia as increased levels of anandamide are found in the striatum in MPTP-primates after long term levodopa. CB1 receptor stimulation on corticostriatal inputs may reduce overactive glutamate transmission, a key abnormality underlying dyskinesia. Preclinical studies in rodents and MPTP-lesioned primates have suggested that the CB1 cannabinoid receptor antagonist rimonabant and another CB1 receptor antagonist AVE1625 may reduce dyskinesia, without affecting parkinsonian disability and PD activity. As discussed, rimonabant has been assessed in a single study and also had no significant effect on dyskinesia.
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Endocannabinoids in Dystonia The neural mechanism underlying idiopathic dystonia is less well-defined but probably involves reduced output from the GPi and SNpr, an effect that may be driven by increased activity of the GPe. Animal models of the phenomenology of idiopathic dystonia are limited, but a genetic model of paroxysmal dystonia has been used for pharmacological investigation into potential therapies for dystonia. In this model, the CB1 agonist WIN55,212 reduced dystonia, an effect blocked by the CB1 antagonist rimonabant. Several case reports have suggested a potential for cannabinoids in focal dystonia. An RCT of acute treatment with nabilone in idiopathic generalized dystonia failed to show a benefit (Fox et al., 2002). Another small RCT of dronabinol (CB1 agonist) for cervical dystonia found no effect compared to placebo on primary or secondary outcome measures. There were side effects including hypotension, vertigo, lightheadedness and dry mouth, and one patient withdrew from the study due to insomnia and a feeling of ‘heart racing’. Further investigations of cannabinoids for the treatment of dystonia are ongoing.
Endocannabinoids in Tourette’s Syndrome Several case reports and observational studies have reported that smoking cannabis or taking oral delta-9-THC has a beneficial effect on tics and behavioral symptoms in Tourette’s patients. Two small RCTs that examined the effects of delta-9-THC on tics and behavioral-psychiatric symptoms in Tourette patients supported these preliminary reports. The first was a single dose (5–10 mg oral delta-9-THC) study, which suggested that this was an effective and safe treatment for both tics and obsessivecompulsive behavior. The second was a 6-week trial of oral delta-9-THC10 mg (17 patients studied). They found a significant improvement in self-rated Tourette’s syndrome symptoms after 10 days of treatment. Other rating scales demonstrated marked tic reduction during the treatment period as well. There were no serious adverse events reported in this study. Tourette’s syndrome is associated with psychiatric and cognitive comorbidities and the use of cannabis is suspected to cause cognitive impairment in the healthy subjects, thus the investigators of the previous studies conducted a RCT assessing neuropsychological performance in the same cohort of patients. They investigated the effect of treatment with 10 mg/day of delta-9-THC over the treatment (6 weeks) and withdrawal period. The results of their study suggest that in Tourette’s syndrome patients, treatment with delta-9-THC was not associated with either acute or longer term cognitive decline. The aforementioned studies had several limitations mostly due to the short time of the treatment interval and the small population studied. As a result, a recent Cochran review investigating the efficacy of cannabinoids treatment for Tourette’s syndrome concluded that there is insufficient data to support the use of cannabinoids in treating tics and behavioral symptoms in people with Tourette’s syndrome. Although not yet considered ‘evidence based medicine’, delta-9-THC may be used in adult patients with resistant Tourette’s syndrome according to several experts. There is a need for larger and longer duration s in order to estimate the effects of cannabinoids for the treatment of Tourette’s syndrome.
Cannabinoids in Huntington’s Disease One of the earliest neurochemical alterations in animal models of Huntington’s disease (HD) was found to be a reduction in CB1 receptor signaling in the striatum as well as reductions of other components of the endocannabinoid system. Both CB1, CB2 as well as non-CB receptor-mediated pathways were studied and suggested as possible targets for neuroprotective treatment in HD. In addition several drugs reduced hyperkinesia in animal studies (CB1 and endovanilloid receptor agonists, anandamide reuptake inhibitors). In humans, reduced CB1 receptors were found in brains of HD patients in both PET imaging studies and post mortem studies. There are few clinical studies that have investigated the effects of cannabinoids in HD patients; however, currently, there is insufficient evidence for a benefit of cannabinoids in treating HD symptoms. A randomized placebo controlled study in 15 HD patients receiving either 10 mg/kg/day of CBD or placebo found no significant changes in the symptomatic measures or adverse effects profile between patients receiving CBD compared to placebo. Another double-blind placebo-controlled study of nabilone 1 mg or 2 mg per day in 37 HD patients found significant improvement with treatment in the chorea subscore of the UHDRS as well as in the neuropsychiatric inventory, and there was a trend towards improvement in the behavior subscore of the UHDRS. There was no significant difference in outcome measures between nabilone 1 mg or 2 mg/day. Nabilone was well tolerated and did not increase psychosis or chorea (as reported in a previous case report). There is a need for larger RCTs of cannabinoids in HD patients in order to achieve a better understanding of their potential benefits. There is an ongoing phase II double blind placebo controlled trial assessing the possible neuroprotective effects of cannabinoid spray (Sativex) in HD.
Frequently Used Cannabis Preparations/Methods of Administration Currently, cannabis for medical use is approved in only a few countries such as the Netherlands and Israel and in a number of USA states. In some countries, the legal status of medical cannabis is complicated. For example, in Canada, dried marijuana is not an approved drug or medicine and the government of Canada does not endorse the use of marijuana, but the courts have required there be ‘reasonable access’ to a legal source of marijuana when authorized by a healthcare practitioner.
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Pharmacokinetics of Currently Available Cannabis and Synthetic Cannabinoid Preparations Smoked cannabis results in a relatively rapid onset of action (within minutes), higher blood levels of cannabinoids, and a shorter duration of pharmacodynamics effects compared to oral administration. Individual differences between smokers, the source of the cannabis plant, and the composition of the cigarette, combined with the method of smoking used by the subject affect the amount of active ingredient (e.g., delta-9-THC) delivered from the smoked cannabis. Vaporized cannabis was explored as an alternative to smoking as it results in smaller amounts of toxic by-products such as carbon monoxide, as well as a more efficient extraction of delta-9-THC from the cannabis material. Oral administration of cannabis results in a slower onset of action, lower peak blood levels, and a longer duration of pharmacodynamic effects compared to smoking. For orally administered prescription cannabinoid medicines such as synthetic delta-9-THC Ò (dronabinol, marketed as Marinol ), only 10%–20% of the administered dose enters the systemic circulation indicating extensive first-pass metabolism. Delta-9-THC can also be absorbed orally by ingestion of foods containing cannabis (e.g., butters, oils, brownies, cookies), and teas prepared from leaves and flowering tops. Ò Oro-mucosal administration of nabiximols (Sativex ) (four sprays totaling 10.8 mg delta-9-THC and 10 mg CBD); the mean peak plasma concentrations of both delta-9-THC and CBD usually occurs within 2–4 h. However, there is wide inter-individual variation in the peak cannabinoid plasma concentrations as well as in the time to onset and maximal benefit. Currently, there are a few preliminary studies using rectal cannabis and topical (dermal) cannabis preparations.
References Fox, S.H., Kellett, M., Moore, A.P., Crossman, A.R., Brotchie, J.M., January 2002. Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia. Mov. Disord. 7 (1), 145–149.
Further Reading Di Marzo, V., 2008. Targeting the endocannabinoid system: to enhance or reduce? Nat. Rev. Drug Discov. 7, 438–455. Fox, S.H., Lang, A.E., Brotchie, J.M., 2006. Translation of non-dopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure. Mov. Disord. 21, 1578–1594. García, C., Palomo-Garo, C., Gómez-Gálvez, Y., Fernández-Ruiz, J., 2016. Cannabinoid-dopamine interactions in the physiology and physiopathology of the basal ganglia. Br. J. Pharmacol. 173, 2069–2079. Kluger, B., Triolo, P., Jones, W., et al., 2015. The therapeutic potential of cannabinoids for movement disorders. Mov. Disord. 30 (3), 313–327. Kreitzer, A.C., Malenka, R.C., 2007. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models. Nature 445, 643–647. More, S.V., Choi, D.K., 2015. Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection. Mol. Neurodegener. 10, 17. Sagredo, O., García-Arencibia, M., de Lago, E., et al., 2007. Cannabinoids and neuroprotection in basal ganglia disorders. Mol. Neurobiol. 36, 82–91. van der Stelt, M., Fox, S.H., Hill, M., et al., 2005. A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson’s disease. Fed. Am. Soc. Exp. Biol. J. 19, 1140–1142.
Relevant Websites www.clinicaltrials.org. www.hc-sc.gc.ca.
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Change History: July 2016. SH Fox and A Faust-Socher updated the sections ‘Cannabinoid Receptors’, ‘Cannabinoids in Movement Disorders’,‘Further Reading’ and ‘Relevant Websites’ and added new sections ‘Frequently used Cannabis preparations/methods of administration’ and ‘Pharmacokinetics of currently available cannabis and synthetic cannabinoid preparations’.
Definitions History Cannabinomimetic Effects Cannabinoid Receptors Cannabinoid CB1 Receptors Memory Analgesia Thermoregulation Antiemetic Motor Functions Other Locations Cannabinoid CB2 Receptor Non-CB Receptors That Mediate Cannabinomimetic Effects Endocannabinoid System Function of Endocannabinoids Cannabinoid Receptor Antagonists Cannabinoids in Movement Disorders Endocannabinoid System in Parkinson Disease FAAH Inhibitors CB1 Cannabinoid Receptor Antagonists Other Cannabinoids Endocannabinoid System in Levodopa-Induced Dyskinesia (LID) CB1 Receptor Agonists CB1 Receptor Antagonists Endocannabinoids in Dystonia Endocannabinoids in Tourette’s Syndrome Cannabinoids in Huntington’s Disease Frequently Used Cannabis Preparations/Methods of Administration Pharmacokinetics of Currently Available Cannabis and Synthetic Cannabinoid Preparations References Further Reading Relevant Websites
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Glossary Cannabinoid A compound that is structurally related to compounds derived from the Cannabis sativa plant. Inverse agonist A compound that binds to a receptor but reverses the constituent activity of the receptor. Long term depression Synaptic plasticity resulting in the release of endocannabinoids and long-lasting inhibition of neurotransmitter release. Psychoactive Having properties that induce psychotic symptoms such as altered perceptions, hallucinations, and delusions.
Definitions Cannabinoids are C21 compounds that are present in Cannabis sativa as well as structurally related to the main psychoactive component, delta-9-tetrahydrocannabinol (delta-9-THC).
History Medicinal properties of the exogenous cannabinoid Cannabis sativa (marijuana) have been known for millennia. The proposed uses include antinausea, pain control, muscle spasms and epileptic seizures. Until recently, however, most treatments were generally unsubstantiated, and there was a lack of scientific rationale or clinical trial evidence to support the claims. In addition, concerns
1
2
Cannabinoids
Table 1
Clinically available synthetic and phytocannabinoid drugs
Name of drug
Type of cannabinoid
Licensed indication
Nabilone
Mixture of D9THC, cannabinol, cannabidiol and other cannabinoids.
Tetrahydrocannabinol
D9THC.
TetrahydrocannabinolCannabidiol mix
Buccal spray of Cannabis sativa extract (plant and non plant-based extracts) containing D9THC and cannabidiol.
Tetrahydrocannabinol– Cannabidiol mix
Oral cannabis extract of Cannabis sativa (plant and non-plant extract) containing D9THC and cannabidiol. CB1 receptor antagonist.
Treatment of chemotherapy-induced nausea and vomiting that has not responded to conventional antiemetics. Treatment of anorexia and weight loss in patients with AIDS. Treatment of severe nausea and vomiting with chemotherapy that has not responded to conventional antiemetics and AIDS-related anorexia. Symptomatic relief of neuropathic pain and adjunctive analgesic treatment in advanced cancer for pain control despite opioid therapy. Approved in Canada as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis. FDA/Orphan disease Epilepsy syndromes; Lennox Gastaut; Brain tumors.
Rimonabant
Withdrawn from market due to adverse effects.
regarding cognitive and psychotropic effects of cannabinoids have generally limited clinical development of these drugs. To date, well over 100 naturally occurring cannabinoids have been identified. The main psychoactive component is delta-9-THC. Several other components have been identified, and they include cannabidiol and cannabinol. Following the discovery of these components, several closely related cannabinoid drugs have been synthesized (Table 1).
Cannabinomimetic Effects Acute effects of cannabinoids in humans may include euphoria, relaxation, perceptual alterations, time distortion, and intensive sensory experiences, as well as impaired short-term memory, motor skills and reaction times. In animal studies, cannabinoids produce four classical cannabinomimetic effects including antinociception (analgesia) without respiratory suppression, reduced spontaneous activity, catalepsy and hypothermia. The effect on motor activity depends on the dose of the agent; low doses induce hyperactivity but higher doses catalepsy. These behavioral properties have now been confirmed in cannabinoid receptor knockout mice models.
Cannabinoid Receptors The biological effects of cannabinoids are now known to be mediated by two cannabinoid receptors, CB1 (cloned in 1990) and CB2 (cloned in 1993) (Table 2). Cannabinoid receptors are members of the G protein-coupled receptor superfamily and CB1 receptors activate Gi/o resulting in inhibition of adenylyl cyclase. In addition, they activate potassium and calcium channels. The cannabinoid system is unusual in that despite the wide distribution of cannabinoid receptors, to date only two types of receptors have been classified. Thus, all actions of cannabinoids are mediated through these two receptors, the CB1 and CB2 receptor, and as such the therapeutic potential for cannabinoid agonists is potentially limited by unwanted actions and side effects.
Cannabinoid CB1 Receptors CB1 receptors are widely distributed in both the peripheral and central nervous systems. Cannabinomimetic effects are related to CB1 receptors within particular brain regions.
Memory CB1 receptors are located in the hippocampus, particularly in CA3 field of Ammon’s horn and the molecular layer of the dentate gyrus.
Analgesia CB1 receptors are located on the peripheral terminals of primary sensory neurons and in the dorsal horn of the spinal cord, in addition to central sites that may mediate pain including the amygdala, thalamus, superior colliculus and rostral ventromedial medulla.
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Table 2 Relative affinity of exogenous and endogenous cannabinoids at cannabinoid CB1 and cannabinoid CB2 receptors Cannabinoid
Name
CB1
CB2
Exogenous cannabinoids
D9THC D8THC Cannabinol Cannabidiol D9Tetrahydrocannabivarin Cannabivarin 11-hydroxy D8THC (HU 210) CP55,940 WIN55, 212–2 Arachidonyl-2-chloroethylamide (ACEA) Arachidonylcyclopropylamide (ACPA) Methanandamide O-1812 AM 1241 JWH 133 HU 308 GW 405833 JWH 015 BAY 38–7271 Anandamide 2-AG Noladin ether
þþ þþ (þ) 0 – (þ) þþþ þþþ þþþ þþþ þþþ þþ þþþ þ þ 0 (þ) (þ) þþþ þ þ þþ
þ þ (þ) 0 þ (þ) þþþ þþþ þþþ 0 (þ) þ 0 þþþ þþþ þþþ þþþ þþ þþþ (þ) þ 0
Synthetic cannabinoids
Endocannabinoids
0 ¼ no affinity; (þ) ¼ very low; þ ¼ low; þþ ¼ moderate; þþþ ¼ high affinity for the receptor; D9THC ¼ D9tetrahydrocannabinol; D8THC ¼ D8tetrahydrocannabinol. Adapted from Pertwee, R.G., 2005. Pharmacological actions of cannabinoids. Handb. Exp. Pharmacol. (168), 1–51.
Thermoregulation CB1 receptors are located within the hypothalamus.
Antiemetic CB1 receptors are located in the dorsal vagal complex, consisting of the area postrema (the chemoreceptor trigger zone for emetic reflexes), nucleus of the solitary tract, and the dorsal motor nucleus of the vagus in the brainstem.
Motor Functions The basal ganglia have one of the highest concentrations of CB1 receptors in the brain. CB1 receptors are located on the presynaptic terminals of the GABAergic striatopallidal pathways in the globus pallidus (GP) (both internal (GPi) and external (GPe) segments) and the substantia nigra pars reticulata (SNpr). In addition, CB1 receptors are found on the corticostriatal glutamatergic projection neurons as well as the parvalbumin-positive interneurons of the striatum. In the cerebellum, CB1 receptors are located in the molecular layer, which contains fibers and dendritic processes originating from Purkinje cells.
Other Locations CB1 receptors are also found in the periphery in the vasculature, heart, bladder, small intestine and vas deferens. Several synthetic cannabinoids are now available (Table 1 and Table 2).
Cannabinoid CB2 Receptor The CB2 receptor is principally located in the immune system both in the brain and periphery. The receptor was initially derived from a human promyelocytic leukemia (HL60) cell line and is found in high amounts in B-cells and natural killer cells. In addition, CB2 receptors are located in microglia and blood vessels. Until recently, CB2 receptors were not thought to be located in neuronal tissue, but
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have now been demonstrated in the brainstem as well the hippocampus and cerebellum. In the basal ganglia they were found to be expressed on neurons in the SNpr as well as in the globus pallidus. The CB2 receptor shares 68% homology with the CB1 receptor. Compared to the undesired psychotropic actions, which are produced by CB1 agonists, the activation of CB2 receptors does not appear to produce these psychotropic effects. Although CB2 agonists had looked promising in a range of preclinical models including pain syndromes, neuroinflammatory and neurodegenerative processes, their efficacy in clinical studies has been relatively disappointing.
Non-CB Receptors That Mediate Cannabinomimetic Effects Several actions of cannabinoids appear to be mediated by non-CB1 or CB2 receptors. Thus, vasodilatory and some analgesic properties of cannabinoids appear to be due to an action at capsaicin (vanilloid VR-1 or TRPV1) receptors. Other targets of cannabinoids include N-type and T-type calcium channels, sodium channels, voltage-gated potassium channels, nicotinic receptors, glycine receptors, and 5-HT2 and 5-HT3 receptors.
Endocannabinoid System The discovery of the cannabinoid receptors led to the detection of endogenous ligands, termed endocannabinoids, for these receptors. Several endocannabinoids have now been described, but arachidonoyl ethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG) are the best characterized. These are eicosanoid phospholipids produced on receptor-mediated demand in response to elevated intracellular calcium and immediately released. This is in contrast to the classical neurotransmitters that are synthesized and stored in vesicles in presynaptic nerve terminals. Anandamide is produced by the hydrolysis of membrane phosphatidylethanolamine, and is released and removed by active reuptake, via an anandamide transporter and hydrolysis by fatty acid aminohydrolase (FAAH). 2-AG is produced from sequential hydrolysis of phosphatidylinositol (4,5)-biphosphate, and the effects are terminated by active uptake into cells and hydrolysis.
Function of Endocannabinoids The function of the endocannabinoid system is to modulate neurotransmission. Thus, depolarization of the postsynaptic membrane results in the release of endocannabinoids that diffuse to the presynaptic membrane and inhibit GABA and glutamate activity. In addition, endocannabinoids function as retrograde messengers and are implicated in synaptic plasticity in the hippocampus, thus potentially having a role in memory and learning. Within the striatum, endocannabinoids also act as retrograde messengers and mediate long term depression by interacting with dopamine D2 receptors in the indirect striatopallidal pathway.
Cannabinoid Receptor Antagonists All cannabinoid receptor antagonists currently available are competitive antagonists at CB1 or CB2 receptors of endogenously released endocannabinoids. However, these compounds also have inverse agonist properties by negative, possibly allosteric, modulation of the constitutive activity of CB receptors and by shifting the receptor from a constitutively active to an inactive state. In addition, these compounds may also block non-CB-mediated effects, for example antagonism of endogenously released adenosine action at A1 receptors.
Cannabinoids in Movement Disorders The potential role of the endocannabinoid system in movement disorders stems from the high concentration of CB1 receptors found within the basal ganglia as well as elevated levels of endocannabinoids. To date, there is no consensus on changes in CB1 receptor numbers in PD. Investigating the localization of cannabinoid receptors has been difficult due to the highly lipophilic nature of their ligands and has been restricted to in vitro studies with inconsistent results. A recent cannabinoid ligand [18F]MK-9470 has been developed for in vivo use in PET imaging. Using [18F]MK-9470 to measure CB1 levels in PD patients versus healthy controls; there was a decrease in CB1 availability in the substantia nigra (SN) of PD patients compared to controls. However, a higher CB1 availability was found in PD compared to controls in the mesolimbic, nigrostriatal and mesocortical dopaminergic projection areas.
Endocannabinoid System in Parkinson Disease FAAH Inhibitors Increased endocannabinoids are found in untreated PD patients (in CSF) and in the striatum of animal models of untreated PD. This may be a compensatory effect for the loss of dopamine. Stimulation of CB1 receptors decreases corticostriatal glutamatergic
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transmission and enhanced endocannabinoids may thus be an attempt to decrease the increased glutamate input in PD. Further enhancing endocannabinoid levels may therefore result in the alleviation of PD motor symptoms. Inhibition of FAAH prevents the breakdown of endocannabinoids and reduces excitatory striatal glutamate activity in 6-OHDA lesioned rats. In addition, in PD overactivity of the indirect striatopallidal pathway may be in part due to loss of long-term depression (LTD), an effect mediated by both dopamine D2 receptors and endocannabinoids. Thus, combined treatment of 6-OHDA-lesioned or reserpine-lesioned rat models of PD with a dopamine D2 agonist and a selective FAAH inhibitor URB597 reversed PD-like symptoms. To date, FAAH inhibitors have demonstrated reduced levodopa-induced hyperactivity in a MPTP primate model of PD; however none of these agents are clinically available.
CB1 Cannabinoid Receptor Antagonists Alternatively, enhanced endocannabinoids within other regions of the basal ganglia may be mediating parkinsonian symptoms. Thus, in reserpine treated rats and untreated MPTP-lesioned primates, increased levels of endocannabinoids in the GPe are found. These endocannabinoids, by stimulating CB1 receptors within the GPe, and by reducing GABA reuptake may lead to reduced activity of the GPe, a key abnormality in PD. Thus, CB1 antagonists may have an antiparkinsonian action. The CB1 selective antagonist, rimonabant, had a mild effect on reversal of motor symptoms in the 6-OHDA-lesioned rat and MPTP-lesioned primate models, while another CB1 antagonist carboxylic acid amide benzenesulfonate (CE) had no antiparkinsonian action alone but enhanced the antiparkinsonian actions of levodopa in the MPTP lesioned primate. In clinical studies, in four advanced PD patients, there was no effect on PD motor symptoms using rimonabant (20 mg/d) compared to placebo as add-on therapy, but no adverse effects were noticed. To date, no further clinical studies have been performed.
Other Cannabinoids There have been few clinical studies that have assessed the benefits of other cannabinoid preparations for the treatment of PD. Several uncontrolled and observational studies found positive effects for the use of cannabidiol (CBD) on psychosis, REM sleep behavior disorder. One study that examined patients before and after smoking cannabis found an improvement of motor functions as well as in non-motor functions such as sleep and pain awareness. However DBRCT did not show a clear benefit from the use of cannabis; thus 21 PD patients were treated with either placebo, 75 mg/d CBD or 300 mg/d CBD. There was no significant improvement in UPDRS scores or neuroprotective measures (BDNF, H1-MRS) in the patients who received CBD compared to the placebo group. Further studies are needed to evaluate the efficacy and particularly the tolerability of cannabinoids in PD.
Endocannabinoid System in Levodopa-Induced Dyskinesia (LID) CB1 Receptor Agonists In PD patients following long term treatment with levodopa, involuntary movements (dyskinesia) may develop. The neural mechanism underlying levodopa-induced dyskinesia (LID) involves overactive corticostriatal glutamate activity; CB1 receptor stimulation reduces glutamate release from corticostriatal inputs in the striatum, and thus CB1 receptor agonists may be useful in reducing LID. An alternative site of action may be via activation of CB1 receptors on the striatopallidal terminals of the indirect GABAergic pathway, which reduces GABA reuptake and thus reduces the firing rate of neurons in the GPe. In preclinical studies, the CB1 agonist WIN55,212 reduced LID in reserpine and 6-OHDA-lesioned rats. An alternative action of cannabinoids may be at TRPV1 (vanilloid) receptors and the TRPV1 agonist, capsaicin, reduces levodopa-induced hyperkinesia in reserpine treated rats. In the MPTP lesioned marmoset model of LID, nabilone reduced dyskinesia without affecting the antiparkinsonian action of levodopa. In clinical studies, nabilone was shown to have a mild effect on reducing dyskinesia in a Phase IIa trial using a cross-over acute challenge study design in seven PD patients. There was no effect on parkinsonian disability, and all patients had a nonsignificant fall in systolic blood pressure and experienced side effects of mild sedation and dizziness. Another Phase II randomized controlled trial (RCT) study using CannadorW, showed no significant effect on LID or any significant adverse effects in 19 PD patients when treated for 4 weeks. The variable effects may relate to the different cannabinoid agents used as well as to differences in the trial designs. To date, no further studies have been performed in PD patients to assess the effects of cannabinoids on LID.
CB1 Receptor Antagonists Cannabinoid antagonists have also been proposed to reduce dyskinesia as increased levels of anandamide are found in the striatum in MPTP-primates after long term levodopa. CB1 receptor stimulation on corticostriatal inputs may reduce overactive glutamate transmission, a key abnormality underlying dyskinesia. Preclinical studies in rodents and MPTP-lesioned primates have suggested that the CB1 cannabinoid receptor antagonist rimonabant and another CB1 receptor antagonist AVE1625 may reduce dyskinesia, without affecting parkinsonian disability and PD activity. As discussed, rimonabant has been assessed in a single study and also had no significant effect on dyskinesia.
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Endocannabinoids in Dystonia The neural mechanism underlying idiopathic dystonia is less well-defined but probably involves reduced output from the GPi and SNpr, an effect that may be driven by increased activity of the GPe. Animal models of the phenomenology of idiopathic dystonia are limited, but a genetic model of paroxysmal dystonia has been used for pharmacological investigation into potential therapies for dystonia. In this model, the CB1 agonist WIN55,212 reduced dystonia, an effect blocked by the CB1 antagonist rimonabant. Several case reports have suggested a potential for cannabinoids in focal dystonia. An RCT of acute treatment with nabilone in idiopathic generalized dystonia failed to show a benefit (Fox et al., 2002). Another small RCT of dronabinol (CB1 agonist) for cervical dystonia found no effect compared to placebo on primary or secondary outcome measures. There were side effects including hypotension, vertigo, lightheadedness and dry mouth, and one patient withdrew from the study due to insomnia and a feeling of ‘heart racing’. Further investigations of cannabinoids for the treatment of dystonia are ongoing.
Endocannabinoids in Tourette’s Syndrome Several case reports and observational studies have reported that smoking cannabis or taking oral delta-9-THC has a beneficial effect on tics and behavioral symptoms in Tourette’s patients. Two small RCTs that examined the effects of delta-9-THC on tics and behavioral-psychiatric symptoms in Tourette patients supported these preliminary reports. The first was a single dose (5–10 mg oral delta-9-THC) study, which suggested that this was an effective and safe treatment for both tics and obsessivecompulsive behavior. The second was a 6-week trial of oral delta-9-THC10 mg (17 patients studied). They found a significant improvement in self-rated Tourette’s syndrome symptoms after 10 days of treatment. Other rating scales demonstrated marked tic reduction during the treatment period as well. There were no serious adverse events reported in this study. Tourette’s syndrome is associated with psychiatric and cognitive comorbidities and the use of cannabis is suspected to cause cognitive impairment in the healthy subjects, thus the investigators of the previous studies conducted a RCT assessing neuropsychological performance in the same cohort of patients. They investigated the effect of treatment with 10 mg/day of delta-9-THC over the treatment (6 weeks) and withdrawal period. The results of their study suggest that in Tourette’s syndrome patients, treatment with delta-9-THC was not associated with either acute or longer term cognitive decline. The aforementioned studies had several limitations mostly due to the short time of the treatment interval and the small population studied. As a result, a recent Cochran review investigating the efficacy of cannabinoids treatment for Tourette’s syndrome concluded that there is insufficient data to support the use of cannabinoids in treating tics and behavioral symptoms in people with Tourette’s syndrome. Although not yet considered ‘evidence based medicine’, delta-9-THC may be used in adult patients with resistant Tourette’s syndrome according to several experts. There is a need for larger and longer duration s in order to estimate the effects of cannabinoids for the treatment of Tourette’s syndrome.
Cannabinoids in Huntington’s Disease One of the earliest neurochemical alterations in animal models of Huntington’s disease (HD) was found to be a reduction in CB1 receptor signaling in the striatum as well as reductions of other components of the endocannabinoid system. Both CB1, CB2 as well as non-CB receptor-mediated pathways were studied and suggested as possible targets for neuroprotective treatment in HD. In addition several drugs reduced hyperkinesia in animal studies (CB1 and endovanilloid receptor agonists, anandamide reuptake inhibitors). In humans, reduced CB1 receptors were found in brains of HD patients in both PET imaging studies and post mortem studies. There are few clinical studies that have investigated the effects of cannabinoids in HD patients; however, currently, there is insufficient evidence for a benefit of cannabinoids in treating HD symptoms. A randomized placebo controlled study in 15 HD patients receiving either 10 mg/kg/day of CBD or placebo found no significant changes in the symptomatic measures or adverse effects profile between patients receiving CBD compared to placebo. Another double-blind placebo-controlled study of nabilone 1 mg or 2 mg per day in 37 HD patients found significant improvement with treatment in the chorea subscore of the UHDRS as well as in the neuropsychiatric inventory, and there was a trend towards improvement in the behavior subscore of the UHDRS. There was no significant difference in outcome measures between nabilone 1 mg or 2 mg/day. Nabilone was well tolerated and did not increase psychosis or chorea (as reported in a previous case report). There is a need for larger RCTs of cannabinoids in HD patients in order to achieve a better understanding of their potential benefits. There is an ongoing phase II double blind placebo controlled trial assessing the possible neuroprotective effects of cannabinoid spray (Sativex) in HD.
Frequently Used Cannabis Preparations/Methods of Administration Currently, cannabis for medical use is approved in only a few countries such as the Netherlands and Israel and in a number of USA states. In some countries, the legal status of medical cannabis is complicated. For example, in Canada, dried marijuana is not an approved drug or medicine and the government of Canada does not endorse the use of marijuana, but the courts have required there be ‘reasonable access’ to a legal source of marijuana when authorized by a healthcare practitioner.
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Pharmacokinetics of Currently Available Cannabis and Synthetic Cannabinoid Preparations Smoked cannabis results in a relatively rapid onset of action (within minutes), higher blood levels of cannabinoids, and a shorter duration of pharmacodynamics effects compared to oral administration. Individual differences between smokers, the source of the cannabis plant, and the composition of the cigarette, combined with the method of smoking used by the subject affect the amount of active ingredient (e.g., delta-9-THC) delivered from the smoked cannabis. Vaporized cannabis was explored as an alternative to smoking as it results in smaller amounts of toxic by-products such as carbon monoxide, as well as a more efficient extraction of delta-9-THC from the cannabis material. Oral administration of cannabis results in a slower onset of action, lower peak blood levels, and a longer duration of pharmacodynamic effects compared to smoking. For orally administered prescription cannabinoid medicines such as synthetic delta-9-THC Ò (dronabinol, marketed as Marinol ), only 10%–20% of the administered dose enters the systemic circulation indicating extensive first-pass metabolism. Delta-9-THC can also be absorbed orally by ingestion of foods containing cannabis (e.g., butters, oils, brownies, cookies), and teas prepared from leaves and flowering tops. Ò Oro-mucosal administration of nabiximols (Sativex ) (four sprays totaling 10.8 mg delta-9-THC and 10 mg CBD); the mean peak plasma concentrations of both delta-9-THC and CBD usually occurs within 2–4 h. However, there is wide inter-individual variation in the peak cannabinoid plasma concentrations as well as in the time to onset and maximal benefit. Currently, there are a few preliminary studies using rectal cannabis and topical (dermal) cannabis preparations.
References Fox, S.H., Kellett, M., Moore, A.P., Crossman, A.R., Brotchie, J.M., January 2002. Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia. Mov. Disord. 7 (1), 145–149.
Further Reading Di Marzo, V., 2008. Targeting the endocannabinoid system: to enhance or reduce? Nat. Rev. Drug Discov. 7, 438–455. Fox, S.H., Lang, A.E., Brotchie, J.M., 2006. Translation of non-dopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure. Mov. Disord. 21, 1578–1594. García, C., Palomo-Garo, C., Gómez-Gálvez, Y., Fernández-Ruiz, J., 2016. Cannabinoid-dopamine interactions in the physiology and physiopathology of the basal ganglia. Br. J. Pharmacol. 173, 2069–2079. Kluger, B., Triolo, P., Jones, W., et al., 2015. The therapeutic potential of cannabinoids for movement disorders. Mov. Disord. 30 (3), 313–327. Kreitzer, A.C., Malenka, R.C., 2007. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models. Nature 445, 643–647. More, S.V., Choi, D.K., 2015. Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection. Mol. Neurodegener. 10, 17. Sagredo, O., García-Arencibia, M., de Lago, E., et al., 2007. Cannabinoids and neuroprotection in basal ganglia disorders. Mol. Neurobiol. 36, 82–91. van der Stelt, M., Fox, S.H., Hill, M., et al., 2005. A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson’s disease. Fed. Am. Soc. Exp. Biol. J. 19, 1140–1142.
Relevant Websites www.clinicaltrials.org. www.hc-sc.gc.ca.
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Change History: July 2016. SH Fox and A Faust-Socher updated the sections ‘Cannabinoid Receptors’, ‘Cannabinoids in Movement Disorders’,‘Further Reading’ and ‘Relevant Websites’ and added new sections ‘Frequently used Cannabis preparations/methods of administration’ and ‘Pharmacokinetics of currently available cannabis and synthetic cannabinoid preparations’.