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.

THC is often combined with CBD to reduce its psychoactivity.

Chemical Name: 
(−)-trans-Δ9-tetrahydrocannabinol
IUPHAR entry: 
Wikipedia entry: 
Degradation Pathways: 

THC metabolism (mostly from (Huestis, 2007) unless otherwise stated).

Pharmacokinetics (what the body does to THC).

After administration, THC is broken down/metabolized by the body. How THC is broken down primarily depends on the route of administration.

When THC is smoked, up to 30% is incinerated straight away. Oral ingestion leads to degradation by stomach acid (up to 50% reduction) followed by first-pass liver metabolism (again up to 50% reduction). Smoking, transdermal, rectal and sublingual application avoid first-pass liver metabolism.

THC is metabolized is most tissues, but primarily by the liver through cytochrome p450 enzymes (Cyp).

The main primary metabolite of THC is 11-OH-THC which is primarily produced by Cyp2C9 and possibly Cyp2C19 and Cyp2D6 (Stott et al., 2013).

The ratio of THC:11-OH-THC after smoking is ± 10:1 (compared to ± 1:1 after oral application due to extensive liver metabolism).

Like THC, 11-OH-THC is psychoactive.

11-OH-THC is further oxidized to 11-COOH-THC and then potentially glucuronidated by UGT enzymes.

11-COOH-THC is not psychoactive. The therapeutic potential still remains to be elucidated.

11-COOH-THC is cleared relatively slowly (terminal half-life of up to 12.6 days in regular users) making it the main detectable THC metabolite.

Another primary metabolite of THC is 8-OH-THC, which is primarily produced by Cyp3A isoforms.

Over 100 minor THC metabolites have been identified.

 

References:

Huestis, M.A. (2007). Human cannabinoid Pharmacokinetics. Chem. Biodivers. 4, 1770–1804.

Stott, C., White, L., Wright, S., Wilbraham, D., and Guy, G. (2013). A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. SpringerPlus 2, 236.

Distribution: 

THC that enters the blood stream is rapidly distributed to the organs and to fatty tissues. Re-distribution of THC from fatty tissues is rate-limiting in THC metabolism.

In one study in pigs (which are physiologically very similar to humans) 200 μg/kg THC was injected IV, followed by analysis of tissue distribution after 0.5, 2, 6 and 24 hours (Brunet et al., 2006).

 

Hours

ng/g THC

0,5

2

6

24

Blood

24

4,8

1,6

0,2

Kidney

272

57,1

3,3

0

Heart

178

17,4

3,2

0

Lung

1888

387

47,2

47,2

Muscle

55

14,1

0,6

0

Spleen

34

15,5

0,8

0

Fat

91

50,1

33,9

31,6

Liver

155

4,2

0

0

Brain

49

14,6

4,4

0

Bile

0,4

1,4

2,7

1,1

Vitreous humor

1,2

0,3

0,1

0

Notably:

-Most tissues have a higher THC content than blood after 30 minutes.

-The lungs initially receive and maintain the highest levels of THC. This is in line with the lungs being the most blood-perfused organ in the body but is also likely to reflect active binding of THC.

-The brain receives a fairly modest dose of THC (possibly limited by the blood-brain-barrier) but retains THC relatively strongly (possibly due to its high lipid content).

-The liver is very fast at clearing THC.

-Fat tissue acts as a THC reservoir.

References:

Brunet, B., Doucet, C., Venisse, N., Hauet, T., Hébrard, W., Papet, Y., Mauco, G., and Mura, P. (2006). Validation of Large White Pig as an animal model for the study of cannabinoids metabolism: application to the study of THC distribution in tissues. Forensic Sci. Int. 161, 169–174.

Literature Discussion: 

Receptors

THC binds to CB1, CB2, TRPV2, TRPV3, TRPV4, TRPA1, TRM8, PPARγ, GlyR, GPR55, GPR18 and 5HT3A (Morales, Hurst, & Reggio, 2017).

AIDS

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).

Alzheimer's Disease

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).

Autism

In a mouse model of Autism (BTBR T+tf/J mice), THC was found to alleviate aberrant locomotor behavior associated to Autism (Onaivi et al., 2011).

cancer

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).

Bone Cancer

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).

Cervical Cancer

THC overexpress TIMP-1 with anti invasive and apoptotic functions on cancer cells (Ramer and Hinz, 2008).

Glioblastoma

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).

Leukemia

Studies with THC shown cytotoxic properties induced by apoptosis in Leukemia cells (Herrera et al., 2005; Jia et al., 2006; Liu et al., 2008).

Lung Cancer

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).

Pancreatic cancer

In one study, THC effectively killed pancreatic cancer cells (in Panc1, Capan2, BxPc2 and MIA PaCa-2 cell lines) at 2 μM and higher concentrations (Carracedo et al., 2006). The authors found that both CB1 and CB2 were upregulated in cancer cells. Apoptosis was CB2-dependent. In mice, 15 mg/kg/d THC induced tumor cell-specific apoptosis and significantly reduced tumor growth (Carracedo et al., 2006).

COPD

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).

depression

In animal models for depression (forced swimming test, tail suspension test), Δ9THC showed anti-depressant properties at a dose of 2.5 mg/kg (El-Alfy et al., 2010).

Diabetes

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).

Eczema

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).

Epilepsy

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).

Insomnia

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).

MDMA comedown

In rats, the after-effects of MDMA (2 x 10 mg/kg) include hyperthermia, increased Anxiety-like behavior and reduced exploration. Administration of THC reduced these behavioral effects. In addition, THC normalized serotonin levels and prevented MDMA-induced neurotoxicity (Shen et al., 2011)

Migraine

In rats, THC dose dependently suppressed Cortical Spreading depression (CSD) amplitude, duration and propagation through CB1 but not CB2 activation (Kazemi et al., 2012).

morphine Interaction

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).

Multiple Sclerosis

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).

pain

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).

Parkinson's Disease

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).

Psoriasis

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).

Psychosis and Schizophrenia

CB1 receptor agonist THC has been reported to mimic psychotic symptoms in healthy volunteers, supporting the argument of a role of the endocannabinoid system in Schizophrenia (Bossong et al., 2014). Some studies suggest that THC is the responsible of the Psychosis symptoms while CBD would act as antipsychotic and anxiolytic.

References:

Aguirre-Rueda, D., Guerra-Ojeda, S., Aldasoro, M., Iradi, A., Obrador, E., Mauricio, M.D., Vila, J.M., Marchio, P., and Valles, S.L. (2015). WIN 55,212-2, Agonist of cannabinoid Receptors, Prevents Amyloid β1-42 Effects on Astrocytes in Primary Culture. PloS One 10, e0122843.

Bagüés, A., Martín, M.I., and Sánchez-Robles, E.M. (2014). Involvement of central and peripheral cannabinoid receptors on antinociceptive effect of tetrahydrocannabinol in muscle pain. Eur. J. Pharmacol. 745C, 69–75.

Belendiuk, K.A., Babson, K.A., Vandrey, R., and Bonn-Miller, M.O. (2015). Cannabis species and cannabinoid concentration preference among sleep-disturbed medicinal cannabis users. Addict. Behav. 50, 178–181.

Blázquez, C., Salazar, M., Carracedo, A., Lorente, M., Egia, A., González-Feria, L., Haro, A., Velasco, G., and Guzmán, M. (2008). cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. cancer Res. 68, 1945–1952.

Bonn-Miller, M.O., Babson, K.A., Vujanovic, A.A., and Feldner, M.T. (2010). Sleep Problems and PTSD Symptoms Interact to Predict Marijuana Use Coping Motives: A Preliminary Investigation. J. Dual Diagn. 6, 111–122.

Bonn-Miller, M.O., Babson, K.A., and Vandrey, R. (2014). Using Cannabis To Help You Sleep: Heightened Frequency of Medical Cannabis Use among Those with PTSD. Drug Alcohol Depend. 136, 162–165.

Bossong, M.G., Jansma, J.M., Bhattacharyya, S., and Ramsey, N.F. (2014). Role of the endocannabinoid system in brain functions relevant for Schizophrenia: an overview of human challenge studies with cannabis or 9-tetrahydrocannabinol (THC). Prog Neuropsychopharmacol Biol Psychiatry 52, 53–69.

Caffarel, M.M., Moreno-Bueno, G., Cerutti, C., Palacios, J., Guzman, M., Mechta-Grigoriou, F., and Sanchez, C. (2008). JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene 27, 5033–5044.

Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzmán, M., Velasco, G., and Iovanna, J.L. (2006). cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. cancer Res. 66, 6748–6755.

Carroll, C.B., Zeissler, M.-L., Hanemann, C.O., and Zajicek, J.P. (2012). Δ9-tetrahydrocannabinol (Δ9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease. Neuropathol. Appl. Neurobiol. 38, 535–547.

Chakravarti, B., Ravi, J., and Ganju, R.K. (2014). cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget 5, 5852–5872.

Chandra, L.C., Kumar, V., Torben, W., Stouwe, C.V., Winsauer, P., Amedee, A., Molina, P.E., and Mohan, M. (2014).Chronic administration of Δ9-tetrahydrocannabinol induces intestinal anti-inflammatory microRNA expression during acute SIV infection of rhesus macaques.

Cichewicz, D.L., and McCarthy, E.A. (2003). Antinociceptive Synergy between Δ9-Tetrahydrocannabinol and Opioids after Oral Administration. J. Pharmacol. Exp. Ther. 304, 1010–1015.

Cousens, K., and DiMascio, A. (1973). (−)δ9 THC as an hypnotic. Psychopharmacologia 33, 355–364. Gates, P.J., Albertella, L., and Copeland, J. (2014). The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med. Rev. 18, 477–487.

Coskun, Z.M., and Bolkent, S. (2014). Oxidative stress and cannabinoid receptor expression in type-2 diabetic rat pancreas following treatment with Δ9-THC. Cell Biochem. Funct. 32, 612–619.

Devinsky, O., Cilio, M.R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., Katz, R., Di Marzo, V., Jutras-Aswad, D., Notcutt, W.G., et al. (2014). Cannabidiol: pharmacology and potential therapeutic role in Epilepsy and other neuropsychiatric disorders. Epilepsia 55, 791–802.

Feliú, A., Moreno-Martet, M., Mecha, M., Carrillo-Salinas, F.J., de Lago, E., Fernández-Ruiz, J., and Guaza, C. (2015). A sativex-like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.

Gaffal, E., Cron, M., Glodde, N., and Tüting, T. (2013). Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy 68, 994–1000.

Galanti, G., Fisher, T., Kventsel, I., Shoham, J., Gallily, R., Mechoulam, R., Lavie, G., Amariglio, N., Rechavi, G., and Toren, A. (2008). Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human Glioblastoma multiforme cells. Acta Oncol. Stockh. Swed. 47, 1062–1070.

Gates, P.J., Albertella, L., and Copeland, J. (2014). The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med. Rev. 18, 477–487.

Goonawardena, A.V., Riedel, G., and Hampson, R.E. (2011). cannabinoids alter spontaneous firing, bursting, and cell synchrony of hippocampal principal cells. Hippocampus 21, 520–531.

El-Alfy, A.T., Ivey, K., Robinson, K., Ahmed, S., Radwan, M., Slade, D., Khan, I., ElSohly, M., and Ross, S. (2010). Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Pharmacol. Biochem. Behav. 95, 434–442.

Haustein, M., Ramer, R., Linnebacher, M., Manda, K., & Hinz, B. (2014). cannabinoids increase Lung Cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1. Biochemical Pharmacology, 92(2), 312-325. https://doi.org/10.1016/j.bcp.2014.07.014

Hernán Pérez de la Ossa, D., Lorente, M., Gil-Alegre, M.E., Torres, S., García-Taboada, E., Aberturas, M.D.R., Molpeceres, J., Velasco, G., and Torres-Suárez, A.I. (2013). Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of Glioblastoma multiforme. PloS One 8, e54795.

Herrera, B., Carracedo, A., Diez-Zaera, M., Guzmán, M., and Velasco, G. (2005). p38 MAPK is involved in CB2 receptor-induced apoptosis of human leukaemia cells. FEBS Lett. 579, 5084–5088.

Hill, T.D.M., Cascio, M.-G., Romano, B., Duncan, M., Pertwee, R.G., Williams, C.M., Whalley, B.J., and Hill, A.J. (2013). Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br. J. Pharmacol. 170, 679–692.

Hsu, S.-S., Huang, C.-J., Cheng, H.-H., Chou, C.-T., Lee, H.-Y., Wang, J.-L., Chen, I.-S., Liu, S.-I., Lu, Y.-C., Chang, H.-T., et al. (2007).Anandamide-induced Ca2+ elevation leading to p38 MAPK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. Toxicology 231, 21–29.

Jia, W., Hegde, V.L., Singh, N.P., Sisco, D., Grant, S., Nagarkatti, M., and Nagarkatti, P.S. (2006). Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat Leukemia T cells is regulated by translocation of Bad to mitochondria. Mol. cancer Res. MCR 4, 549–562.

Kazemi, H., Rahgozar, M., Speckmann, E.-J., and Gorji, A. (2012). Effect of cannabinoid receptor activation on spreading depression. Iran. J. Basic Med. Sci. 15, 926–936.

Lastres-Becker, I., Molina-Holgado, F., Ramos, J.A., Mechoulam, R., and Fernández-Ruiz, J. (2005). cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol. Dis. 19, 96–107.

Li, X., Kaminski, N.E., and Fischer, L.J. (2001). Examination of the immunosuppressive effect of delta9-tetrahydrocannabinol in streptozotocin-induced autoimmune diabetes. Int. Immunopharmacol. 1, 699–712.

Liu, W.M., Scott, K.A., Shamash, J., Joel, S., and Powles, T.B. (2008). Enhancing the in vitro cytotoxic activity of Delta9-tetrahydrocannabinol in leukemic cells through a combinatorial approach. Leuk. Lymphoma 49, 1800–1809.

Lu, C., Liu, Y., Sun, B., Sun, Y., Hou, B., Zhang, Y., Ma, Z., and Gu, X. (2015).Intrathecal Injection of JWH-015 Attenuates Bone Cancer pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord. Inflammation.

Makwana, R., Venkatasamy, R., Spina, D., and Page, C. (2015). The effect of phytocannabinoids on airway hyperresponsiveness, airway inflammation and cough. J. Pharmacol. Exp. Ther.

Marcu, J.P., Christian, R.T., Lau, D., Zielinski, A.J., Horowitz, M.P., Lee, J., Pakdel, A., Allison, J., Limbad, C., Moore, D.H., et al. (2010). Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human Glioblastoma cell proliferation and survival. Mol. cancer Ther. 9, 180–189

Massi, P., Solinas, M., Cinquina, V., and Parolaro, D. (2013). Cannabidiol as potential anticancer drug. Br. J. Clin. Pharmacol. 75, 303–312.

Moldzio, R., Pacher, T., Krewenka, C., Kranner, B., Novak, J., Duvigneau, J.C., and Rausch, W.-D. (2012). Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine Int. J. Phytother. Phytopharm. 19, 819–824.

Molina, P.E., Winsauer, P., Zhang, P., Walker, E., Birke, L., Amedee, A., Stouwe, C.V., Troxclair, D., McGoey, R., Varner, K., et al. (2011).cannabinoid administration attenuates the progression of simian immunodeficiency virus. AIDS Res. Hum. Retroviruses 27, 585–592.

Morales, P., Hurst, D. P., & Reggio, P. H. (2017). Molecular Targets of the Phytocannabinoids-A Complex Picture. Progress in the chemistry of organic natural products, 103, 103-131. https://doi.org/10.1007/978-3-319-45541-9_4

Moreno, E., Andradas, C., Medrano, M., Caffarel, M.M., Pérez-Gómez, E., Blasco-Benito, S., Gómez-Cañas, M., Pazos, M.R., Irving, A.J., Lluís, C., et al. (2014). Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. J. Biol. Chem. 289, 21960–21972.

Nicholson, A.N., Turner, C., Stone, B.M., and Robson, P.J. (2004). Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J. Clin. Psychopharmacol. 24, 305–313.

Onaivi, E.S., Benno, R., Halpern, T., Mehanovic, M., Schanz, N., Sanders, C., Yan, X., Ishiguro, H., Liu, Q.-R., Berzal, A.L., et al. (2011). Consequences of cannabinoid and monoaminergic system disruption in a mouse model of Autism spectrum disorders. Curr. Neuropharmacol. 9, 209–214.

Ramer, R., and Hinz, B. (2008). Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J. Natl. cancer Inst. 100, 59–69.

Roberts, J.D., Gennings, C., and Shih, M. (2006). Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Eur. J. Pharmacol. 530, 54–58.  

Rocha, F.C.M., Santos Júnior, J.G. Dos, Stefano, S.C., and da Silveira, D.X. (2014). Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. J. Neurooncol. 116, 11–24.

Ross, H.R., Napier, I., and Connor, M. (2008). Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol. J. Biol. Chem. 283, 16124–16134.

Schierenbeck, T., Riemann, D., Berger, M., and Hornyak, M. (2008). Effect of illicit recreational drugs upon sleep: cocaine, ecstasy and marijuana. Sleep Med. Rev. 12, 381–389.

Scott, K.A., Dalgleish, A.G., and Liu, W.M. (2014). The Combination of Cannabidiol and Δ9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model. Mol. cancer Ther.

Shen, E.Y., Ali, S.F., and Meyer, J.S. (2011). Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats. Neuropharmacology 61, 1183–1192.

Smith, F.L., Cichewicz, D., Martin, Z.L., and Welch, S.P. (1998). The Enhancement of morphine Antinociception in Mice by Δ9-Tetrahydrocannabinol. Pharmacol. Biochem. Behav. 60, 559–566.

Smith, P.A., Selley, D.E., Sim-Selley, L.J., and Welch, S.P. (2007). Low dose combination of morphine and Δ9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. Eur. J. Pharmacol. 571, 129–137.

Solinas, M., Massi, P., Cinquina, V., Valenti, M., Bolognini, D., Gariboldi, M., Monti, E., Rubino, T., and Parolaro, D. (2013). Cannabidiol, a Non-Psychoactive cannabinoid Compound, Inhibits Proliferation and Invasion in U87-MG and T98G Glioma Cells through a Multitarget Effect. PLoS ONE 8.

Storr, M., Devlin, S., Kaplan, G.G., Panaccione, R., and Andrews, C.N. (2014). Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn’s disease. Inflamm. Bowel Dis. 20, 472–480.

Tham, S.M., Angus, J.A., Tudor, E.M., and Wright, C.E. (2005). Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α2-adrenoceptor agonists in acute pain models in mice. Br. J. Pharmacol. 144, 875–884.  

Torres, S., Lorente, M., Rodríguez-Fornés, F., Hernández-Tiedra, S., Salazar, M., García-Taboada, E., Barcia, J., Guzmán, M., and Velasco, G. (2011). A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol. cancer Ther. 10, 90–103.

Tubaro, A., Giangaspero, A., Sosa, S., Negri, R., Grassi, G., Casano, S., Della Loggia, R., and Appendino, G. (2010). Comparative topical anti-inflammatory activity of cannabinoids and cannabivarins. Fitoterapia 81, 816–819.

van Vliet, S.A.M., Vanwersch, R.A.P., Jongsma, M.J., van der Gugten, J., Olivier, B., and Philippens, I.H.C.H.M. (2006). Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects. Behav. Pharmacol. 17, 453–462.

Wallace, J.L., Flannigan, K.L., McKnight, W., Wang, L., Ferraz, J.G.P., and Tuitt, D. (2013). Pro-resolution, protective and anti-nociceptive effects of a cannabis extract in the rat gastrointestinal tract. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 64, 167–175.

Wallace, M.J., Wiley, J.L., Martin, B.R., and DeLorenzo, R.J. (2001). Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. Eur. J. Pharmacol. 428, 51–57.

Walsh, Z., Callaway, R., Belle-Isle, L., Capler, R., Kay, R., Lucas, P., and Holtzman, S. (2013). Cannabis for therapeutic purposes: Patient characteristics, access, and reasons for use. Int. J. Drug Policy 24, 511–516

Wilkinson, J.D., and Williamson, E.M. (2007). cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of Psoriasis. J. Dermatol. Sci. 45, 87–92.

Winsauer, P.J., Molina, P.E., Amedee, A.M., Filipeanu, C.M., McGoey, R.R., Troxclair, D.A., Walker, E.M., Birke, L.L., Stouwe, C.V., Howard, J.M., et al. (2011).Tolerance to chronic delta-9-tetrahydrocannabinol (Δ9-THC) in rhesus macaques infected with simian immunodeficiency virus. Exp. Clin. Psychopharmacol. 19, 154–172.

Yang, L., Li, F.-F., Han, Y.-C., Jia, B., and Ding, Y. (2015).cannabinoid receptor CB2 is involved in tetrahydrocannabinol-induced anti-inflammation against lipopolysaccharide in MG-63 cells. Mediators Inflamm. 2015, 362126.  

Zimmer, A., Zimmer, A.M., Hohmann, A.G., Herkenham, M., and Bonner, T.I. (1999). Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. U. S. A. 96, 5780–5785.

 

Clinical Trials: 

Addiction

In one fMRI study, THC was shown to blunt anticipatory responses to nicotine showing the involvement of the endocannabinoid system in addictive behavior (Jansma et al., 2013).

AIDS

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).

Alzheimer's Disease

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

Anorexia

THC was found to induce eating, allowing anorexic patients to gain weight (Andries et al., 2014).

Arthritis

In one trial, a mixture of THC and CBD (Sativex) was found to be effective in reducing pain and stiffness and improving sleep (Blake et al., 2006). 

Diabetes

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).  

Epilepsy

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).

cancer

Glioblastoma

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.

Leukemia

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).  

COPD

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).

Migraine

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).

morphine Interaction

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). THC shown synergic effects in combination with morphine only in the affective component of pain (Roberts et al., 2006).

Multiple Sclerosis

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.

pain

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). A THC/CBD mix was also effective against central pain experienced in MS (Rog et al., 2005). Smoked cannabis was found to significantly reduce pain sensation in chronic neuropathic pain (Ware et al., 2010; Wilsey et al., 2013). Oral THC was found to effectively reduce chronic non-cancer pain in some, but not all, patients (Haroutiunian et al., 2008). In HIV patients with neuropathic pain that did not respond to conventional pain medication, smoked cannabis provided effective in 46% of patients (compared to 18% for placebo)(Ellis et al., 2009). Oral cannabis extract was found to effectively reduce post-operative pain (Holdcroft et al., 2006).

Parkinson's Disease

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).

Psychosis and Schizophrenia

In one clinical trial, THC was actually used to alleviate psychotic symptoms in patients that did not respond to conventional anti-psychotics. This result indicates that the role of cannabinoids in the development or treatment of Psychosis is not straightforward and warrants further investigation (Schwarcz et al., 2009).

PTSD

CBD and THC were found to speed up/enhance fear extinction which should help prevent the development of PTSD (Das et al., 2013; Rabinak et al., 2013).

Stroke

Several clinical trials have tested the therapeutic potential of cannabinoids after Stroke. Meta-analysis revealed that both endocannabinoids like AEA, OEA or PEA and plant cannabinoids like THC or CBD can significantly reduce neuronal degeneration after Stroke (England et al., 2015).

Tourette's

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).

References:

Abrams, D.I., Couey, P., Shade, S.B., Kelly, M.E., and Benowitz, N.L. (2011). cannabinoid-opioid interaction in chronic pain. Clin. Pharmacol. Ther. 90, 844–851.

Andries, A., Frystyk, J., Flyvbjerg, A., and Støving, R.K. (2014). Dronabinol in severe, enduring Anorexia nervosa: a randomized controlled trial. Int. J. Eat. Disord. 47, 18–23.

Ball, S., Vickery, J., Hobart, J., Wright, D., Green, C., Shearer, J., Nunn, A., Gomez Cano, M., MacManus, D., Miller, D., et al. (2015). The cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis. Health Technol. Assess. Winch. Engl. 19, 1–188.

Blake, D.R., Robson, P., Ho, M., Jubb, R.W., and McCabe, C.S. (2006). Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid Arthritis. Rheumatology 45, 50–52.

Camilleri, M., Kolar, G.J., Vazquez-Roque, M.I., Carlson, P., Burton, D.D., and Zinsmeister, A.R. (2013). cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G553-560.

Centonze, D., Mori, F., Koch, G., Buttari, F., Codecà, C., Rossi, S., Cencioni, M.T., Bari, M., Fiore, S., Bernardi, G., et al. (2009). Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis. Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol. 30, 531–534.

Davis, J.P., and Ramsey, H.H. (1949). Anti-epileptic action of marijuana-active substances. Federation Proceedings, vol. 8, p284. Maa, E., and Figi, P. (2014). The case for medical marijuana in Epilepsy. Epilepsia 55, 783–786.

Das, R.K., Kamboj, S.K., Ramadas, M., Yogan, K., Gupta, V., Redman, E., Curran, H.V., and Morgan, C.J.A. (2013). Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology (Berl.) 226, 781–792.

Ellis, R.J., Toperoff, W., Vaida, F., van den Brande, G., Gonzales, J., Gouaux, B., Bentley, H., and Atkinson, J.H. (2009). Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 34, 672–680.

England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental Stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358.

Esfandyari, T., Camilleri, M., Busciglio, I., Burton, D., Baxter, K., and Zinsmeister, A.R. (2007). Effects of a cannabinoid receptor agonist on colonic motor and sensory functions in humans: a randomized, placebo-controlled study. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G137-145.

Flachenecker, P., Henze, T., and Zettl, U.K. (2014). Nabiximols (THC/CBD oromucosal spray, Sativex®) in clinical practice--results of a multicenter, non-interventional study (MOVE 2) in patients with multiple sclerosis spasticity. Eur. Neurol. 71, 271–279.

Guzmán, M., Duarte, M.J., Blázquez, C., Ravina, J., Rosa, M.C., Galve-Roperh, I., Sánchez, C., Velasco, G., and González-Feria, L. (2006). A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent Glioblastoma multiforme. Br. J. cancer 95, 197–203.

Haroutiunian, S., Rosen, G., Shouval, R., and Davidson, E. (2008). Open-label, add-on study of tetrahydrocannabinol for chronic nonmalignant pain. J. pain Palliat. Care Pharmacother. 22, 213–217.

Hinds, N.M., Ullrich, K., and Smid, S.D. (2006). cannabinoid 1 (CB1) receptors coupled to cholinergic motorneurones inhibit neurogenic circular muscle contractility in the human colon. Br. J. Pharmacol. 148, 191–199.

Holdcroft, A., Maze, M., Doré, C., Tebbs, S., and Thompson, S. (2006). A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology 104, 1040–1046.

Jansma, J.M., van Hell, H.H., Vanderschuren, L.J.M.J., Bossong, M.G., Jager, G., Kahn, R.S., and Ramsey, N.F. (2013). THC reduces the anticipatory nucleus accumbens response to reward in subjects with a nicotine Addiction. Transl. Psychiatry 3, e234.

Johnson, J.R., Lossignol, D., Burnell-Nugent, M., and Fallon, M.T. (2013). An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J. pain Symptom Manage. 46, 207–218.

Kluger, B., Triolo, P., Jones, W., and Jankovic, J. (2015). The therapeutic potential of cannabinoids for movement disorders. Mov. Disord. Off. J. Mov. Disord. Soc.

Koppel, B.S., Brust, J.C.M., Fife, T., Bronstein, J., Youssof, S., Gronseth, G., and Gloss, D. (2014). Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders Report of the Guideline Development Subcommittee of the American Academy of. Neurology 82, 1556–1563.

Lahat, A., Lang, A., and Ben-Horin, S. (2012). Impact of cannabis treatment on the quality of life, weight and clinical disease activity in inflammatory bowel disease patients: a pilot prospective study. Digestion 85, 1–8.

Lotan, I., Treves, T.A., Roditi, Y., and Djaldetti, R. (2014). Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clin. Neuropharmacol. 37, 41–44.

Maa, E., and Figi, P. (2014). The case for medical marijuana in Epilepsy. Epilepsia 55, 783–786.

Milloy, M.-J., Marshall, B., Kerr, T., Richardson, L., Hogg, R., Guillemi, S., Montaner, J.S.G., and Wood, E. (2014). High-intensity cannabis use associated with lower plasma human immunodeficiency virus-1 RNA viral load among recently infected people who use injection drugs. Drug Alcohol Rev.

Müller-Vahl, K.R., Kolbe, H., and Dengler, R. (1997). [Gilles de la Tourette syndrome. Effect of nicotine, alcohol and marihuana on clinical symptoms]. Nervenarzt 68, 985–989.

Müller-Vahl, K.R., Schneider, U., Prevedel, H., Theloe, K., Kolbe, H., Daldrup, T., and Emrich, H.M. (2003). Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J. Clin. Psychiatry 64, 459–465.

Naef, M., Curatolo, M., Petersen-Felix, S., Arendt-Nielsen, L., Zbinden, A., and Brenneisen, R. (2003). The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions: pain 105, 79–88.

Naftali, T., Bar-Lev Schleider, L., Dotan, I., Lansky, E.P., Sklerovsky Benjaminov, F., and Konikoff, F.M. (2013). Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 11, 1276–1280.e1.

Pickering, E.E., Semple, S.J., Nazir, M.S., Murphy, K., Snow, T.M., Cummin, A.R., Moosavi, S.H., Guz, A., and Holdcroft, A. (2011). cannabinoid effects on ventilation and breathlessness: a pilot study of efficacy and safety. Chron. Respir. Dis. 8, 109–118.

Rabinak, C.A., Angstadt, M., Sripada, C.S., Abelson, J.L., Liberzon, I., Milad, M.R., and Phan, K.L. (2013). cannabinoid facilitation of fear extinction memory recall in humans. Neuropharmacology 64, 396–402

Ravikoff Allegretti, J., Courtwright, A., Lucci, M., Korzenik, J.R., and Levine, J. (2013). Marijuana use patterns among patients with inflammatory bowel disease. Inflamm. Bowel Dis. 19, 2809–2814.

Rhyne, D.N., Anderson, S.L., Gedde, M., and Borgelt, L.M. (2016). Effects of Medical Marijuana on Migraine Headache Frequency in an Adult Population. Pharmacotherapy.

Roberts, J.D., Gennings, C., and Shih, M. (2006). Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Eur. J. Pharmacol. 530, 54–58.

Rog, D.J., Nurmikko, T.J., and Young, C.A. (2007). Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin. Ther. 29, 2068–2079.

Rog, D.J., Nurmikko, T.J., Friede, T., and Young, C.A. (2005). Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 65, 812–819.

Schwarcz, G., Karajgi, B., and McCarthy, R. (2009). Synthetic Δ-9-Tetrahydrocannabinol (Dronabinol) Can Improve the Symptoms of Schizophrenia. J. Clin. Psychopharmacol. 29, 255–258.

Singh, Y., and Bali, C. (2013). Cannabis Extract Treatment for Terminal Acute Lymphoblastic Leukemia with a Philadelphia Chromosome Mutation. Case Rep. Oncol. 6, 585–592.

Storr, M., Yüce, B., and Göke, B. (2006). [Perspectives of cannabinoids in gastroenterology]. Z. Gastroenterol. 44, 185–191.

Taylor, G.H., and Schwaitzberg, S.D. (2015). The successful use of dronabinol for failure to thrive secondary to intestinal dysmotility. Int. J. Surg. Case Rep. 11, 121–123.

Venderová, K., Růzicka, E., Vorísek, V., and Visnovský, P. (2004). Survey on cannabis use in Parkinson’s disease: subjective improvement of motor symptoms. Mov. Disord. Off. J. Mov. Disord. Soc. 19, 1102–1106.

Wade, D.T., Makela, P.M., House, H., Bateman, C., and Robson, P. (2006). Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult. Scler. Houndmills Basingstoke Engl. 12, 639–645.

Wallace, M.S., Marcotte, T.D., Umlauf, A., Gouaux, B., and Atkinson, J.H. (2015). Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. J. pain Off. J. Am. pain Soc.

Ware, M.A., Wang, T., Shapiro, S., Robinson, A., Ducruet, T., Huynh, T., Gamsa, A., Bennett, G.J., and Collet, J.-P. (2010). Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ Can. Med. Assoc. J. J. Assoc. Medicale Can. 182, E694–E701.

Wilsey, B., Marcotte, T., Deutsch, R., Gouaux, B., Sakai, S., and Donaghe, H. (2013). Low-dose vaporized cannabis significantly improves neuropathic pain. J. pain Off. J. Am. pain Soc. 14, 136–148.

Wong, B.S., Camilleri, M., Busciglio, I., Carlson, P., Szarka, L.A., Burton, D., and Zinsmeister, A.R. (2011). Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology 141, 1638-1647.e1-7.

Wong, B.S., Camilleri, M., Eckert, D., Carlson, P., Ryks, M., Burton, D., and Zinsmeister, A.R. (2012). Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 24, 358-e169.

Zajicek, J.P., Hobart, J.C., Slade, A., Barnes, D., Mattison, P.G., and MUSEC Research Group (2012). multiple sclerosis and extract of cannabis: results of the MUSEC trial. J. Neurol. Neurosurg. Psychiatry 83, 1125–1132.

 

 

Enzymes: