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The “entourage effect: Synergistic actions of plant cannabinoids

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... On the other hand, one of the main limitations to the use of PEA in clinical practice lies in its poor pharmacokinetic profile, due to marked lipophilicity that limits solubility and in vivo absorption. Although some new formulations of PEA (micronized and ultramicronized forms) seem to show more favorable absorption kinetics [11,12], new research efforts to overcome pharmacokinetic limitations have focused on molecules capable of triggering the so-called "entourage" effect, i.e., the ability of some ALIAmides and cannabinoids to increase the endogenous levels and/or activity of endocannabinoid compounds [13,14] by inhibiting their catabolic pathways, increasing the biosynthetic ones and/or enhancing their receptor affinity. In this framework, Adelmidrol is a promising ALIAmide and a semi-synthetic analog of PEA. ...
... netic profile, due to marked lipophilicity that limits solubility and in vivo absorption. Although some new formulations of PEA (micronized and ultramicronized forms) seem to show more favorable absorption kinetics [11,12], new research efforts to overcome pharmacokinetic limitations have focused on molecules capable of triggering the so-called "entourage" effect, i.e., the ability of some ALIAmides and cannabinoids to increase the endogenous levels and/or activity of endocannabinoid compounds [13,14] by inhibiting their catabolic pathways, increasing the biosynthetic ones and/or enhancing their receptor affinity. In this framework, Adelmidrol is a promising ALIAmide and a semi-synthetic analog of PEA. ...
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Adelmidrol is a promising palmitoylethanolamide (PEA) analog which displayed up-and-coming anti-inflammatory properties in several inflammatory conditions. Recent studies demonstrated that Adelmidrol is an in vitro enhancer of PEA endogenous production, through the so called “entourage” effect. The present study investigated the ability of Adelmidrol (1 and 10 mg/Kg per os) to increase the endogenous level of PEA in the duodenum and colon of mice after 21-day oral administration in the presence and absence of PPAR-γ inhibitor (1 mg/kg). The level of PEA was analyzed by HPLC-MS. The expression of PEA-related enzymatic machinery was evaluated by western blot and RT-PCR analysis. Our findings demonstrated that Adelmidrol significantly increased PEA levels in the duodenum and colon in a dose/time-dependent manner. We also revealed that Adelmidrol up regulated the enzymatic machinery responsible for PEA metabolism and catabolism. Interestingly, the use of the selective irreversible PPAR-γ antagonist did not affect either PEA intestinal levels or expression/transcription of PEA metabolic enzymes following Adelmidrol administration. The “entourage effect” with Adelmidrol as an enhancer of PEA was thus PPAR-γ-independent. The findings suggest that Adelmidrol can maximize a PEA therapeutic-based approach in several intestinal morbidities.
... 108 Since then, the term has been extended to incorporate other cannabinoids and noncannabinoids that enhance the activity of cannabis preparations. 109 As stated by Mechoulam, "this type of synergism may play a role in the widely held view that in some cases, plants are better drugs than the natural products isolated from them". 110 At this stage, it is only logical to ask: what therapeutic advantage, if any, does utilizing the entire cannabis plant provide as opposed to the government-approved synthetic formulations like dronabinol? ...
... Since the original discovery of the entourage effect, it has been shown on several occasions that THC monotherapy is not as effective as the dual administration of THC in combination with CBD or terpenoids. 109 In 2010, Johnson and co-workers conducted a multicenter, double-blind, randomized placebo-controlled study of cannabis-based extracts in patients with cancer-related pain. 112 In their findings, the THC-predominant extract produced results similar to the placebo, whereas a plant extract containing a mixture of CBD and THC was statistically significantly better than both. ...
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At the intersection of science and medicine, government policy, and pop culture, cannabis has prompted society since the beginning of recorded history. And yet, there is comparatively little replicable data on the plant, its constituents, and their capacity to modify human physiology. Over the past decades, several findings have pointed toward the importance of the endogenous cannabinoid system in maintaining homeostasis, making it an important target for various diseases. Here, we summarize the current state of knowledge on endogenous- and plant-based cannabinoids, address the issues related to cannabinoid-based drug discovery, and incite efforts to utilize their polypharmacological profile toward tackling diseases with a complex underlying pathophysiology. By fusing modern science and technology with the empirical data that has been gathered over centuries, we propose an outlook that could help us overcome the dearth of innovation for new drugs and synchronously redefine the future of drug discovery. Simultaneously, we call attention to the startling disconnect between the scientific, regulatory, and corporate entities that is becoming increasingly evident in this booming industry.
... Mechoulam and Ben-Shabat that the endocannabinoid system demonstrated an effect known as the entourage effect, where a multitude of metabolites and related molecules modified the activity of the endogenous cannabinoids anandamide and 2arachidonoylglycerol [442]. This proposed concept was further extended to explain how whole botanical drugs were often more effective than their isolated components alone [443][444][445][446], but not everyone is convinced of the existence of this effect. The critics describe this effect as a claim with illdefined and unsubstantiated pharmacological activities that is "used toward the popularization and sale of ostensible therapeutic products" [447]. ...
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In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the treatment of various conditions. In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis. However, the therapeutic use of cannabinoids is currently limited to the treatment of symptoms and pain associated with chemotherapy, while their potential use as cytotoxic drugs in chemotherapy still requires validation in patients. Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of cannabinoids, terpenes and flavonoids, present in cannabis, are explored in this literature review.
... 9,10 It is thought that when CBD is administered alongside other phytocannabinoids, such as tetrahydrocannabinol (THC or Δ9-THC), there is an entourage effect that elevates the therapeutic properties of both CBD and THC. [11][12][13] Human research in this realm in relation to concussion is very limited, presumably due to ethical issues surrounding administration of intoxicating and often illegal compounds such as THC, even if CBD does have the potential to counteract THC psychosis. 14,15 Numerous animal studies have supported the idea that CBD and THC administered simultaneously can lead to changes in behavioral effects 16 and altered THC metabolism. ...
Article
Cannabidiol (CBD) has been generating increasing interest in medicine due to its therapeutic properties and an apparent lack of negative side effects. Research has suggested that high dosages of CBD can be taken acutely and chronically with little to no risk. This review focuses on the neuroprotective effects of a CBD, with an emphasis on its implications for recovering from a mild traumatic brain injury (TBI) or concussion. CBD has been shown to influence the endocannabinoid system, both by affecting cannabinoid receptors and other receptors involved in the endocannabinoid system such as vanilloid receptor 1, adenosine receptors, and 5-hydroxytryptamine via cannabinoid receptor-independent mechanisms. Concussions can result in many physiological consequences, potentially resulting in post-concussion syndrome. While impairments in cerebrovascular and cardiovascular physiology following concussion have been shown, there is unfortunately still no single treatment available to enhance recovery. CBD has been shown to influence the blood brain barrier, brain-derived neurotrophic factors, cognitive capacity, the cerebrovasculature, cardiovascular physiology, and neurogenesis, all of which have been shown to be altered by concussion. CBD can therefore potentially provide treatment to enhance neuroprotection by reducing inflammation, regulating cerebral blood flow, enhancing neurogenesis, and protecting the brain against reactive oxygen species. Double-blind randomized controlled trials are still required to validate the use of CBD as medication following mild TBIs, such as concussion.
... While 99% pure cannabinoids are more reproducible and standardized than whole-plant extract and thus preferred as a study drug, several studies suggest a synergistic effect for the numerous cannabis compounds in the whole-plant extract. 4,[14][15][16][17][18][19] This so-called "entourage effect" remains controversial. 20 Future studies should directly assess the effects of pure cannabinoids versus whole-plant extracts in various disorders among different target populations. ...
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The use of medical cannabis in children is rapidly growing. While robust evidence currently exists only for pure cannabidiol (CBD) to treat specific types of refractory epilepsy, in most cases, artisanal strains of CBD-rich medical cannabis are being used to treat children with various types of refractory epilepsy or irritability associated with autism spectrum disorder (ASD). Other common pediatric disorders that are being considered for cannabis treatment are Tourette syndrome and spasticity. As recreational cannabis use during youth is associated with serious adverse events and medical cannabis use is believed to have a relatively high placebo effect, decisions to use medical cannabis during childhood and adolescence should be made with caution and based on evidence. This review summarizes the current evidence for safety, tolerability, and efficacy of medical cannabis in children with epilepsy and in children with ASD. The main risks associated with use of Δ9-tetrahydrocannabinol (THC) and CBD in the pediatric population are described, as well as the debate regarding the use of whole-plant extract to retain a possible "entourage effect" as opposed to pure cannabinoids that are more standardized and reproducible.
... Yet another related important research question concerns the "entourage effect" (cf. Sanchez-Ramos, 2015). That is, what are the neuropsychopharmacological and phenomenological differences between the pure compound (synthesised 5-MeO-DMT) and the compound as found in nature within a whole complex organism (toad venom, tree bark, seed pods, etc.)? ...
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5-Methoxy-N,N-dimethyltryptamine (acronymized as 5-MeO-DMT) is sui generis among the numerous naturally-occurring psychoactive substances due to its unparalleled ego-dissolving effects which can culminate in a state of nondual consciousness (which is phenomenologically similar to transformative peak experiences described in various ancient contemplative traditions, e.g., Advaita Vedānta, Mahāyāna Buddhism). The enigmatic molecule is endogenous to the human brain and has profound psychological effects which are hitherto only very poorly understood due to the absence of scientifically controlled human experimental trials. Its exact neuronal receptor binding profile is a matter of ongoing scientific research, however, its remarkable psychoactivity is presumably mediated via agonism of the 5-HT2A (serotonin) receptor subtype. Anthropological/ethnopharmacological evidence indicates that various cultures utilized 5-MeO-DMT containing plants for medicinal, psychological, and spiritual purposes for millennia. In this paper we argue that this naturally occurring serotonergic compound could be fruitfully utilized as a neurochemical research tool which has the potential to significantly advance our understanding of the cognitive and neuronal processes which underpin cognition and creativity. An eclectic interdisciplinary perspective is adopted, and we present converging evidence from a plurality of sources in support of this conjecture. Specifically, we suggest that 5-MeO-DMT has great potential in this respect due to its incommensurable capacity to completely disintegrate self-referential cognitive/neuronal processes (viz.., ego death). In addition, the importance of unbiased systematic scientific research on naturally occurring endogenous psychoactive compounds is discussed from a Jamesian radical empiricism perspective and potential scenarios of abuse are discussed (particularly in the context of military torture).
... A recent review by Russo 48 supports this supposition stating that phytocannabinoids and combinations of cannabinoids can, in certain situations, be more effective than Δ 9 -THC or CBD alone. In 2015, Dr. Sanchez-Ramos described how physicians may not be aware that prescribing Δ 9 -THC alone (e.g., Marinol ® or dronabinol) may not be as efficacious as utilizing the full plant for many types of patients suffering from cancer, neuropathic pain, multiple sclerosis, and bladder-diseases 49 . Turner et al. 17 and Morales et al. 18 suggested that the relative proportions of each phytocannabinoid type will additionally influence the pharmacological effects of whole Cannabis extracts, either through a polypharmacological effect of the phytocannabinoids themselves, or through modulation of phytocannabinoid effects by the non-cannabinoid content of the plant since they act on multiple targets. ...
Article
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Most clinical studies of Cannabis today focus on the contents of two phytocannabinoids: (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), regardless of the fact that the plant contains over 100 additional phytocannabinoids whose therapeutic effects and interplay have not yet been fully elucidated. This narrow view of a complex Cannabis plant is insufficient to comprehend the medicinal and pharmacological effects of the whole plant. In this study we suggest a new ESI-LC/MS/MS approach to identify phytocannabinoids from 10 different subclasses, and comprehensively profile the identified compounds in diverse medical Cannabis plants. Overall, 94 phytocannabinoids were identified and used for profiling 36 of the most commonly used Cannabis plants prescribed to patients in Israel. In order to demonstrate the importance of comprehensive phytocannabinoid analysis before and throughout medical Cannabis clinical trials, treatments, or experiments, we evaluated the anticonvulsant effects of several equally high-CBD Cannabis extracts (50% w/w). We found that despite the similarity in CBD contents, not all Cannabis extracts produced the same effects. This study’s approach for phytocannabinoid profiling can enable researchers and physicians to analyze the effects of specific Cannabis compositions and is therefore critical when performing biological, medical and pharmacological-based research using Cannabis.
... The term 'entourage effect' was coined by Raphael Mechoulam (Ben-Shabat et al., 1998;Mechoulam & Hanus, 2000) as he elaborated on the fact that the presence of glycerol fatty acid esters, alongside 2-arachidonoyl glycerol (2-AG), an important endocannabinoid, reduced the rate of hydrolysis of 2-AG, which enhanced its activity. The term was later used by others (Fowler, 2003;Sanchez-Ramos, 2015) to highlight the contribution of other cannabinoids and non-cannabinoid constituents to the activity of cannabis preparations. Carlini, Karniol, Renault, and Schuster (1974) provided an early example of the entourage effect by demonstrating that two of three cannabis extracts, administered in multiple species, including humans, produced effects 2-4-times greater than what was observed after administration of pure THC at the same doses contained in the extracts. ...
Article
Accumulating evidence suggests that the endocannabinoid system is a promising target for the treatment of a variety of health conditions. Two paths of cannabinoid drug development have emerged. One approach is focused on developing medications that are directly derived from the cannabis plant. The other utilizes a single molecule approach whereby individual phytocannabinoids or novel cannabinoids with therapeutic potential are identified and synthesized for pharmaceutical development. This commentary discusses the unique challenges and merits of botanical vs single molecule cannabinoid drug development strategies, highlights how both can be impacted by legalization of cannabis via legislative processes, and also addresses regulatory and public health considerations that are important to consider as cannabinoid medicine advances as a discipline.
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Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization. Since plant-derived mixtures of cannabinoids and the Cannabis component myrcene have been suggested as pain therapeutics, we screened terpenes found in Cannabis for activity at TRPV1. We used inducible expression of TRPV1 to examine TRPV1-dependency of terpene-induced calcium flux responses. Terpenes contribute differentially to calcium fluxes via TRPV1 induced by Cannabis-mimetic cannabinoid/terpenoid mixtures. Myrcene dominates the TRPV1-mediated calcium responses seen with terpenoid mixtures. Myrcene-induced calcium influx is inhibited by the TRPV1 inhibitor capsazepine and Myrcene elicits TRPV1 currents in the whole-cell patch-clamp configuration. TRPV1 currents are highly sensitive to internal calcium. When Myrcene currents are evoked, they are distinct from capsaicin responses on the basis of Imax and their lack of shift to a pore-dilated state. Myrcene pre-application and residency at TRPV1 appears to negatively impact subsequent responses to TRPV1 ligands such as Cannabidiol, indicating allosteric modulation and possible competition by Myrcene. Molecular docking studies suggest a non-covalent interaction site for Myrcene in TRPV1 and identifies key residues that form partially overlapping Myrcene and Cannabidiol binding sites. We identify several non-Cannabis plant-derived sources of Myrcene and other compounds targeting nociceptive TRPs using a data mining approach focused on analgesics suggested by non-Western Traditional Medical Systems. These data establish TRPV1 as a target of Myrcene and suggest the therapeutic potential of analgesic formulations containing Myrcene.
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5-Methoxy-N,N-dimethyltryptamine (acronymized as 5-MeO-DMT) is sui generis among the numerous naturally occurring psychoactive substances due to its unparalleled ego-dissolving effects which can culminate in a state of nondual consciousness that is phenomenologically similar to transformative peak experiences described in various ancient contemplative traditions (e.g., Advaita Vedānta, Mahāyāna Buddhism, inter alia). The enigmatic molecule is endogenous to the human brain and has profound psychological effects which are hitherto only very poorly understood due to the absence of scientifically controlled human experimental trials. Its exact neuronal receptor binding profile is a matter of ongoing research; however, empirical evidence indicates that its remarkable psychoactivity is partially mediated via agonism of the 5-HT1A/2A (serotonin) receptor subtypes. Anthropological/ethnopharmacological evidence indicates that various cultures utilized 5-MeO-DMT containing plants for medicinal, psychological, and spiritual purposes for millennia. We propose that this naturally occurring serotonergic compound could be fruitfully utilized as a neurochemical research tool with the potential to significantly advance our understanding of the psychological and neuronal processes which underpin cognition and creativity (e.g., downregulation of the default mode network, increased global functional connectivity, neuroplasticity, σ1 receptor interactions, etc.). An eclectic interdisciplinary perspective is adopted, and we present converging evidence from a plurality of sources in support of our conjecture. Specifically, we argue that 5-MeO-DMT has significant neuropsychopharmacological potential due to its incommensurable capacity to completely disintegrate self-referential cognitive/neuronal processes (viz., ego death). The importance of unbiased systematic scientific research on naturally occurring endogenous psychoactive compounds is discussed from a Jamesian radical empiricism perspective, and potential scenarios of abuse are addressed, particularly in the context of neuroethics, cybernetic manipulation, and military research on torture.
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Finding a therapy for Alzheimer’s disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates. Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain. This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuroprotective effects that were greater than additive. Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. Structure-activity relationship (SAR) data show that functional antioxidant groups such as aromatic hydroxyls are necessary but not sufficient for neuroprotection. Therefore, there is a need to focus upon CB1 agonists that have these functionalities if neuroprotection is the goal. Pairwise combinations of THC and CBN lead to a synergistic neuroprotective interaction. Together, these results significantly extend the published data by showing that non-psychoactive cannabinoids are potential lead drug candidates for AD and other neurodegenerative diseases.
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Opinion statement: Use of cannabinoids as medications has a long history. Unfortunately, the prohibition of cannabis and its classification in 1970 as a schedule 1 drug has been a major obstacle in studying these agents in a systematic, controlled manner. The number of class 1 studies (randomized, double-blind, placebo-controlled) in patients with movement disorders is limited. Hence, it is not possible to make recommendations on the use of these cannabinoids as primary treatments for any of the movement disorders at this time. Fortunately, there is an expanding body of research in animal models of age-dependent and disease-related changes in the endocannabinoid system that is providing new targets for drug development. Moreover, there is growing evidence of a "cannabinoid entourage effect" in which a combination of cannabinoids derived from the plant are more effective than any single cannabinoid for a number of conditions. Cannabis preparations may presently offer an option for compassionate use in severe neurologic diseases, but at this point, only when standard-of-care therapy is ineffective. As more high-quality clinical data are gathered, the therapeutic application of cannabinoids will expand.
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Constituents of the Cannabis plant, cannabinoids, may be of therapeutic value in neurologic diseases. The most abundant cannabinoids are Δ(9)-tetrahydrocannabinol, which possesses psychoactive properties, and cannabidiol, which has no intrinsic psychoactive effects, but exhibits neuroprotective properties in preclinical studies. A small number of high-quality clinical trials support the safety and efficacy of cannabinoids for treatment of spasticity of multiple sclerosis, pain refractory to opioids, glaucoma, nausea and vomiting. Lower level clinical evidence indicates that cannabinoids may be useful for dystonia, tics, tremors, epilepsy, migraine and weight loss. Data are also limited in regards to adverse events and safety. Common nonspecific adverse events are similar to those of other CNS 'depressants' and include weakness, mood changes and dizziness. Cannabinoids can have cardiovascular adverse events and, when smoked chronically, may affect pulmonary function. Fatalities are rare even with recreational use. There is a concern about psychological dependence, but physical dependence is less well documented. Cannabis preparations may presently offer an option for compassionate use in severe neurologic diseases, but at this point, only when standard-of-care therapy is ineffective. As more high-quality clinical data are gathered, the therapeutic application of cannabinoids will likely expand.
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Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL -1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.
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To determine the efficacy of medical marijuana in several neurologic conditions. We performed a systematic review of medical marijuana (1948-November 2013) to address treatment of symptoms of multiple sclerosis (MS), epilepsy, and movement disorders. We graded the studies according to the American Academy of Neurology classification scheme for therapeutic articles. Thirty-four studies met inclusion criteria; 8 were rated as Class I. The following were studied in patients with MS: (1) Spasticity: oral cannabis extract (OCE) is effective, and nabiximols and tetrahydrocannabinol (THC) are probably effective, for reducing patient-centered measures; it is possible both OCE and THC are effective for reducing both patient-centered and objective measures at 1 year. (2) Central pain or painful spasms (including spasticity-related pain, excluding neuropathic pain): OCE is effective; THC and nabiximols are probably effective. (3) Urinary dysfunction: nabiximols is probably effective for reducing bladder voids/day; THC and OCE are probably ineffective for reducing bladder complaints. (4) Tremor: THC and OCE are probably ineffective; nabiximols is possibly ineffective. (5) Other neurologic conditions: OCE is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson disease. Oral cannabinoids are of unknown efficacy in non-chorea-related symptoms of Huntington disease, Tourette syndrome, cervical dystonia, and epilepsy. The risks and benefits of medical marijuana should be weighed carefully. Risk of serious adverse psychopathologic effects was nearly 1%. Comparative effectiveness of medical marijuana vs other therapies is unknown for these indications.