D9THC is the most common cannabinoid from the cannabis plant. Better known as THC, it has psychoactive properties and its effects include altered sensory perception and reduced short-term memory. THC has also many non-psychotropic effects like reduction of pain (analgesia), stimulation of appetite and nausea reduction. THC is the most studied cannabinoid from scientific research and shows potential to treat a large ammount of diseases and symptoms, including several types of cancer, Multiple Sclerosis or Parkinson's Disease.
In rhesus macaques, THC (0.32 mg/kg, twice daily, intramuscular) was found to significantly decrease viral load development and decrease mortality from Simian Immunodeficiency Virus (the monkey equivalent of Human Immunodeficiency Virus)(Molina et al., 2011). This protective effect is at least partially due to a THC-driven change in microRNA expression towards an anti-inflammatory profile (Chandra et al., 2014). Negative side effects of THC use (loss of memory, attention and motor function) were only transient. Thus it seems that the negative side effects of THC are transient while the therapeutic effects remain in the treatment of Immunodeficiency Viruses (Winsauer et al., 2011).
In cultured astrocytes, Aβ1-42 reduced cell viability and PPARγ expression and increased cellular inflammation and anti-oxidant capacity. Specific CB1 stimulation (with WIN55,212-2, a synthetic analog of THC) prevented all these effects and increased cellular viability (Aguirre-Rueda et al., 2015).
THC showed anti cancer properties in several studies through CB1 and CB2 receptors (Caffarel et al., 2008). For an excellent publicly available review on therapeutic cannabinoids in cancer please see: Chakravarti et al. (2014).
CB2 agonists as anandamide or THC affect the inflammatory process of bone cancer cells by modulating interleukin, tumor necrosis factor α and nuclear factor-κB expression and cofilin-1 protein (Hsu et al., 2007; Lu et al., 2015; Yang et al., 2015).
Studies in THC and synthetic CB2 agonists shown downregulation of MMP-2, cell invasion and cell viability related to Glioblastoma (Blázquez et al., 2008; Galanti et al., 2008; Hernán Pérez de la Ossa et al., 2013). CBD improves effectiveness of THC and is also effective in Glioblastoma THC-resistant cells (Marcu et al., 2010; Solinas et al., 2013). The action of cannabinoids on Glioblastoma receptors produces an antitumoral response against cancer cell growth, migration, angiogenesis and proliferation (Moreno et al., 2014). However, this response does not affect non-tumor cells, making cannabinoids a safe cancer treatment (Rocha et al., 2014). In glioma xenografts 7.5 mg/kg/day CBD decreased tumor growth by about 20%. 7.5 mg/kg/day THC produced similar results and combined application of CBD and THC reduced tumor growth by approximately 50% suggesting synergy between both pathways (Torres et al., 2011). In mice a combination of CBD and THC was found to work synergistically with radiation therapy to reduce tumor size (Scott et al., 2014).
In cancer cell lines (A549 and H460) and human metastatic lung cancer cells CBD as well as THC promote ICAM-mediated Lymphokine-Activated Killer cell adhesion and cancer cell lysis (Haustein et al., 2014).
The six major plant cannabinoids, THC, CBD, CBC, CBG, CBDA and THCV were tested for their effect on bronchoconstriction, inflammation and coughing in guinea pigs. Only THC reduced all three parameters through activation of CB1 and CB2 receptors (Makwana et al., 2015).
THC was found to help maintain healthy blood-glucose levels and counteract diabetic oxidative stress (Coskun and Bolkent, 2014). THC showed immunosupressive effects reducing the incidence and slowing-down the development of type 1 Diabetes (Li et al., 2001).
Topical application of THC also suppresses skin inflammation, but in a CB1- and CB2-independent way (Gaffal et al., 2013). A comparative study into the topical anti-inflammatory activity of cannabinoids (on croton oil-inflamed skin in mice) showed that Δ8THC, Δ9THC and THCV are about half as effective in reducing inflammation as Indometacin (a commonly used Non-steroid anti-inflammatory drug), but approximately 5 times more effective than CBCV and CBD. CBC and CBDV had no appreciable anti-inflammatory activity (Tubaro et al., 2010).
THC and other synthetic CB1 agonists, reduces synchronous firing of hippocampal principal neurons, suggesting a direct role for THC in seizure prevention (Goonawardena et al., 2011). In heterologous cells (HEK293), THC and CBD were found to inhibit T-type calcium channels with an IC50 of approximately 1μM (Ross et al., 2008). Preclinical studies shows that, in addition to CBD, CBDV and THC also have anti-convulsant properties (Hill et al., 2013; Wallace et al., 2001). In a mouse model of Epilepsy (Maximal Electro Shock), the following cannabinoids were found to be anti-convulsive (ED50)(referenced within: Devinsky et al., 2014): CBD 120 mg/kg Δ9THC 100 mg/kg 11-OH-Δ9THC 14 mg/kg 8β-OH-Δ9THC 100 mg/kg Δ9THCA 200-400 mg/kg Δ8THC 80 mg/kg CBN 230 mg/kg Δ9α/β-OH-hexahydro-CBN 100 mg/kg Apart from that the doses reported above are incredibly high, it does provide a proof of principle that many cannabinoids exert anti-convulsive effects.
Functional Gastro-Intestinal Disorders
Many Crohn’s disease patients self-administer cannabis suggesting a role for cannabinoids in the treatment of Crohn’s or in the alleviation of its symptoms. Although many patients reported symptomatic improvement of abdominal pain (83.9%), abdominal cramping (76.8%), joint pain (48.2%) and diarrhea (28.6%), cannabis use was also associated with increased hospitalization (Storr et al., 2014). This could be explained as cannabis (or the vehicle it comes in, like tobacco) being harmful in Crohn’s. Alternatively, patients with more severe Crohn’s disease may be sooner inclined to use cannabis to alleviate the symptoms. In rats, intra-colonic application of 1 to 10 mg/kg cannabis extract dose-dependently reduced colitis severity but oral application did not (Wallace et al., 2013). This effect was independent of CB1 or CB2 receptors. However, oral extract did prevent NSAID-induced gastric damage at 10 mg/kg in a CB1-dependent way. Cannabis extract also reduced visceral pain at 3 mg/kg in a CB2-dependent way suggesting cannabis extract has distinct beneficial effects in gastro-intestinal disorders via CB1/2-dependent and independent pathways (Wallace et al., 2013). Interestingly, injection of 100 mg/kg THC produced strong diarrhea in CB1 deficient mice but not in controls suggesting complex involvement of CB1 in the regulation of intestinal transit (Zimmer et al., 1999).
Administration of THC in people with Insomnia showed decreased time to fall asleep compared to controls (Cousens and DiMascio, 1973). In a different study, administration of smoked cannabis containing THC also showed benefits to fall asleep and increased stage 4 sleep (Schierenbeck et al., 2008). Symptoms with higher reports of cannabis use are pain, Anxiety and Insomnia (Walsh et al., 2013). In two different studies, subjects with high scores of PTSD reported benefits of using cannabis to cope with PTSD-related Insomnia (Bonn-Miller et al., 2010, 2014). In a study focusing on sleep disorders and cannabis use, 81 participants reported use of cannabis to treat Insomnia and 14 participants reported use of cannabis to reduce nightmares (Belendiuk et al., 2015). A cannabinoid dependent study showed that subjects reported residual effects during daytime after the administration of THC before sleeping. CBD would eliminate those residual effects but subjects reported sleepiness after CBD administration (Nicholson et al., 2004). For more information, please read a review on the topic by Gates et al. (2014).
Morphine shows enhanced potency when is combined with THC in animal models (Smith et al., 1998; Tham et al., 2005). This synergy effect is shown to be useful to avoid tolerance when both THC and Morphine are administered together in low doses (Cichewicz and McCarthy, 2003; Smith et al., 2007).
In a mouse model of MS (Theiler's murine encephalomyelitis), Sativex (50/50% THC/CBD oromucoso spray was compared with CBD-enriched or THC-enriched cannabis extract. Motor deterioration and inflammation (astrogliosis) were equally reduced by Sativex and CBD-enriched extract but THC-enriched extract was less effective. The effects of CBD were PPARγ-mediated whereas THC signaling was CB1/2 dependent (Feliú et al., 2015).
In mice, inhibition of opioid-degrading enzymes potentiates the analgesic effect of THC, suggesting cross talk or synergy between the opioid- and endocannabinoid systems in pain management (Reche et al., 1998). In humans, on the other hand, THC was found not so much to enhance the analgesic effect of morphine but to inhibit the experienced discomfort that is normally associated with pain (Roberts et al., 2006). In a rat model, THC was found to suppress muscle pain via activation of CB1 (Bagüés et al., 2014).
In human neuroblastoma cells, THC, but not CBD was found to be neuroprotective. Neuroprotection was mediated by PPARγ (Carroll et al., 2012). In animal models THC and CBD were neuroprotective via CB1 or CB2 receptors (Lastres-Becker et al., 2005). In cultured midbrain neurons, CBD, THCA and THC had anti-oxidative properties.Moreover, THCA and THC were shown to be neuroprotective (Moldzio et al., 2012). In a marmoset model of Parkinson’s THC improved locomotor activity (van Vliet et al., 2006).
THC, CBD, CBN and CBG were found to inhibit human keratinocyte (skin cell) proliferation suggesting therapeutic potential in Psoriasis (Wilkinson and Williamson, 2007). The effect of THC is at least partially dependent on CB1. Given its affinity for CB receptors, CBN is also likely to function through CB1/2. CBD and CBG do not function through classical CB receptors and none of the phytocannabinoids depended on TRPV1 for their effect (in contrast to endocannabinoid function below), but PPARγ and GPR55 may be involved (Wilkinson and Williamson, 2007).
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In one randomized cross-over trial, smoked cannabis was found to significantly reduce neuropathic pain associated with AIDS (Ellis et al., 2009). Subjects in this study were resistant/refractory to at least two other classes of analgesic. Of the 28 patients that completed both cannabis and placebo treatment, 46% found cannabis to relief pain by at least 30% compared to 18% for placebo. Also the amount of pain reduction was significantly greater for cannabis than placebo.
In another study among seroconverted patients, high-intensity cannabis use was associated with significantly lower viral loads (Milloy et al., 2014).
In one case report, dronabinol (synthetic THC) was successfully used to treat, otherwise intractable, failure to thrive secondary to intestinal dysmotility, supporting its use to treat symptoms of AIDS or cancer (Taylor and Schwaitzberg, 2015).
THC and CBD have been used to treat symptoms of Alzheimer's such as anxiety, night-time agitation or anorexia. http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=183&&search_pattern=alzheimer
THC was found to induce eating, allowing anorexic patients to gain weight (Andries et al., 2014).
In one 16-patient trial, inhaled THC lowered the pain associated with diabetic peripheral neuropathy. Low (1%), medium (4%) and high (7%) doses all reduced perceived pain and while higher doses were more effective, they also reduced cognitive testing scores as THC does impair short-term memory (Wallace et al., 2015).
n 1949, the anti-convulsant activity of THC was tested on 5 children with severe grand mal Epilepsy. In 3 children, THC was equally effective as previously tried therapies, in one child seizures were almost completely prevented and in the last one all seizures were stopped (Davis and Ramsey, 1949). In one very public case, a girl with Dravet syndrome (loss of function mutation in the sodium channel SCN1A), went from having more than 50 convulsive seizures per day to less than 3 nocturnal seizures per month by using extract from a Cannabis variety Charlotte’s Web, which has a THC content of 0.5% and a CBD content of 17% (Maa and Figi, 2014).
Functional Gastro-intestinal disorders
In one clinical trial, smoked cannabis suppressed the symptoms of Crohn’s disease in patients that were unresponsive to conventional medication. Full remission was achieved in 45% of patients compared to 10% for placebo (Naftali et al., 2013).
In a 13-patient trial, inhaled cannabis increased weight, the perception of general health and the abilities to perform daily tasks (Lahat et al., 2012).
Until the 1920s cannabis was often used to treat gastro-intestinal problems such as diarrhea and abdominal pain (Storr et al., 2006).
In a small-scale trial, 5 mg of oral THC (CB1 agonist) decreased colonic motility and increased colonic compliance in patients with IBS (Wong et al., 2011) and in healthy volunteers (Esfandyari et al., 2007), while antagonizing CB1 with rimonabant increases defecation (Wong et al., 2011).
The effect of THC on colonic motility depended to some extent on a CB1 polymorphism (CNR1 rs806378 with faster colonic motility for the CC phenotype) but not on FAAH or MAGL polymorphisms (Camilleri et al., 2013; Wong et al., 2011, 2012).
In a survey among patients with inflammatory bowel disease 16.4% found cannabis helpful to treat abdominal pain, lack of appetite and nausea but not to reduce diarrhea (Ravikoff Allegretti et al., 2013).
In 2006, the group of Guzman et al. (Guzmán et al., 2006) performed the first phase I clinical trial about the antitumoral properties of THC. 9 patients with Glioblastoma where treated with intracraneal THC administration. The trial showed that cannabinoid administration is safe and has promising tumor-shrinking properties.
There is one clinical case reporting a 14 year old patient with lymphoblastic Leukemia with Philadelphia chromosome mutation treated with cannabis oil with significant dose-dependent decrease of Leukemia cells (Singh and Bali, 2013).
One clinical has addressed the therapeutic effects of cannabinoids on COPD. The study was very small scale but concluded that cannabinoids (THC/CBD) do not improve lung function but do reduce the amount of discomfort associated with COPD (Pickering et al. 2010).
In one study, the effect of medical cannabis on Migraine was tested. Without selecting for application route or dose, the use of medical cannabis highly significantly reduced the frequency of Migraine headaches from 10.4 to 4.6 per month (p<0.0001)(Rhyne et al., 2016).
There are some analgesic effects when combining THC with Morphine, but more research is needed to find the best dose combination and to improve the time and route of administration depending on the pharmacokinetics of both drugs (Naef et al., 2003).
In several clinical trials, cannabis extracts or Sativex, a 50/50% mixture of synthetic THC and CBD were successfully used to treat spasticity, muscle stiffness, neuropathic pain etc. in patients that were not responsive to conventional treatment (Rog et al., 2007; Zajicek et al., 2012). In one study, the THC/CBD mixture produced symptomatic relief in 75% of patients (Flachenecker et al., 2014). However, not every clinical trial found a therapeutic effect of cannabinoids on symptoms of MS (Ball et al., 2015; Centonze et al., 2009). Typical side-effects of THC treatment, such as dizziness or nausea, and in extreme cases even seizures, have been reported (Wade et al., 2006).
One meta-study assessed the effect of cannabinoids on multiple MS symptoms (Koppel et al., 2014). Their conclusions were that cannabinoids (particularly THC and CBD) effectively reduced muscle spasms and central pain but are ineffective in treating tremors associated with MS.
Cannabinoids were found to synergistically increase the analgesic effect of opioids by 27% (compared to opioids alone) (Abrams et al., 2011).
A mix of THC/CBD (oral spray) was used to suppress pain related to cancer. In general, the THC/CBD mix provided long-lasting pain relief without desensitization (the need to increase the dose to reach the desired effect) (Johnson et al., 2013).
Oral cannabis extract was found to effectively reduce post-operative pain (Holdcroft et al., 2006).
In a 22-patient trial, smoking 0.5g cannabis significantly improved tremor and bradykinesia (slow movement) within 30 minutes of consumption (Lotan et al., 2014).
In a patient survey, 25% of Parkinson’s patients reported smoking cannabis for symptom relief. Of these, almost 50% reported moderate to substantial relief of symptoms (Venderová et al., 2004).
Self-medicating patients (n=47) reported symptomatic relief from Tourette’s after consumption of nicotine (7%), alcohol (69%) or cannabis (85%), indicating therapeutic potential for cannabinoids in Tourette’s (Müller-Vahl et al., 1997). In a 17-patient trial, 6 weeks of treatment with up to 10 mg THC/day produced significant symptomatic relief (Müller-Vahl et al., 2003).
Several single-patient case reports mention significant to complete symptomatic relief after using cannabis (see references within: Kluger et al., 2015).
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