Cannabis medisch

Er zijn grote verschillen in de kennis over het medicinale gebruik van cannabis en cannabinoïden bij verschillende ziekten. Voor misselijkheid en braken, geassocieerd met kankerchemotherapie, anorexia en cachexia bij HIV/AIDS, chronische, vooral neuropatische pijn, spasticiteit bij multiple sclerose en ruggemergschade, zijn er sterke bewijzen van medicinale voordelen. Voor veel andere indicaties zoals epilepsie, jeuk en depressie, zijn er minder gegevens beschikbaar. Nochtans, wetenschappelijk bewijs voor een specifieke indicatie geeft niet noodzakelijk het huidig therapeutisch potentieel bij een bepaalde ziekte weer.

Klinische studies met afgezonderde cannabinoïden of met komplete plantpreparaten (gerookte cannabis, cannabisextracten) volgen dikwijls op de positieve anekdotische ervaringen van patiënten die ruwe cannabisprodukten gebruiken. De antibraak, eetlustverwekkende en kalmerende effecten, de pijnstillende werking en therapeutisch gebruik bij Tourette's syndroom, werden allemaal ontdekt op die manier.

Toevallige observaties hebben ook bijgedragen tot de ontdekking van therapeutisch bruikbare effecten. Dat bleek uit een studie met Alzheimer-patiënten waarbij een onderzoek naar de eetlustverwekkende effecten van THC een belangrijk onderdeel was. Niet enkel eetlust en gewichtstoename werden vastgesteld, ook het gestoorde gedrag tussen de patiënten onderling verminderde. De ontdekking van de dalende oogboldruk bij toediening van THC in het begin van de jaren 1970 was even verrassend. Mogelijk interessante aanwijzingen die niet wetenschappelijk werden onderzocht, zijn nochtans wijd verspreid binnen de moderne geneeskunde. Vermits de behandelingen met cannabis of cannabinoïden baat brengen, werden personen ondervraagd over hun therapeutisch gebruik van cannabis. Dit gebeurde via niet gestandaardiseerde interviews in het kader van overheidsstudies of studies van wetenschappelijke instituten (House of Lords Select Committee on Science and Technology in Groot Brittannië, Institute of Medicine in de VS), of als anoniem onderzoek met gestandaardiseerde vragenlijsten.

Misselijkheid en braken

De behandeling van nevenwerkingen van kankerchemotherapie is, wat de werking van de cannabinoïden aangaat, het best gedokumenteerd, namelijk met een 40-tal studies (THC, Nabilone, andere THC-vormen, cannabis). De meeste onderzoeken werden in de jaren 1980 uitgevoerd. THC moet relatief hoog gedoseerd worden zodat psychische nevenwerkingen vaker optreden. In een enkel onderzoek moet THC het afleggen tegen hoge doses metoclopramide. Er zijn geen vergelijkende studies verricht tussen THC en de moderne serotonine antagonisten. Enkele recente onderzoeken hebben aangetoond dat lage doses THC de werking van andere braakwerende middelen verbeteren als ze gelijktijdig worden toegediend. In de volksgeneeskunde zijn cannabinoïden populair en dikwijls gebruikt bij andere oorzaken van misselijkheid, inbegrepen AIDS en hepatitis.

Anorexia en cachexia

Het eetlustverwekkend effect van THC is al merkbaar bij een totale dagelijkse dosis van 5 mg. Indien nodig kan de dagelijkse dosis tot 20 mg verhoogd worden. Uit een langetermijnonderzoek bij 94 AIDS-patiënten blijkt dat het eerlustverwekkend effect van THC maanden blijft voortwerken, wat een bevestiging is van een eerder uitgevoerde studie van 6 weken. THC verdubbelde de eetlust in vergelijking met een placebo. De patiënten behielden een stabiel lichaamsgewicht gedurende de studieperiode van 7 maanden. Een positieve invloed op het lichaamsgewicht werd ook vastgesteld bij 15 Alzheimer-patiënten die daarvoor niet konden eten.

Spasticiteit

In veel klinische studies met THC, Nabilone en cannabis, toonde een gunstig effect aan op spasticiteit die veroorzaakt wordt door multiple sclerose en ruggemergschade. Andere symptomen die gunstig beïnvloed worden zijn pijn, paraesthesia, bevingen en ataxia. In enkele studies werd een verbeterde blaascontrole waargenomen. Er is ook anekdotisch bewijs van de voordelen van cannabis bij spasticiteit ten gevolge van hersenbeschadiging.

Bewegingsstoornissen

Er zijn een aantal positieve anekdotische rapporten over de therapeutische werking van cannabis bij het Tourette's syndroom, bij dystornia en tardive dyskinesia. Het gebruik bij Tourette's syndroom is recent onderzocht in klinische studies. Veel patiënten ervoeren een bescheiden verbetering hoewel anderen een behoorlijke verbetering of zelfs een volledige spiercontrole bereikten. Bij enkele ms-patiënten werden na THC-toediening antiatactische werkingen en een vermindering van het beven vastgesteld. Ondanks occasionele positieve rapporten werden geen objectieve resultaten bereikt bij de ziekte van Parkinson noch bij de ziekte van Huntington. Toch kunnen cannabisprodukten bruikbaar zijn voor de behandeling van bewegingsstoornissen die het gevolg zijn van L-Dopa medicatie bij de ziekte van Parkinson. De cannabis zal de basissymptomen van de ziekte van Parkinson niet verergeren.

Pijn

Uitgebreid klinisch onderzoek heeft de pijnstillende eigenschappen van cannabisproducten aangetoond. Bij de mogelijke toepassingen horen onder meer neuropatische pijn als gevolg van multiple sclerose, schade aan de plexus brachialis, HIV-besmetting, reumatische artritispijn, kankerpijn, hoofdpijn, menstruatiepijn, chronische darmontsteking en zenuwpijn.

Glaucoma

In 1971 werd tijdens een systematisch onderzoek naar de effecten bij gezonde cannabisgebruikers ontdekt dat cannabis de intraoculaire druk verlaagt. In de 12 daaropvolgende jaren werden talrijke studies verricht bij gezonde personen en bij glaucomapatiënten met cannabis en met verscheidene natuurlijke en synthetische cannabinoïden. cannabis verlaagt de oogboldruk met 25 tot 30 %, soms tot 50 %. Sommige niet-psychotrope cannabinoïden en in geringe mate andere bestanddelen dan cannabinoïden, veroorzaken mogelijk ook een verlaging van de oogboldruk.

Epilepsie

Het gebruik van cannabis bij epilepsie behoort historisch gezien tot de oudste toepassingen. Dierproeven leveren het bewijs van de anti-epileptische effecten van sommige cannabinoïden. De anti-epileptische werking van phenytoïne en diazepam werd door THC versterkt. Volgens een paar individuele rapporten uit de 20e eeuw blijken patiënten cannabis te gebruiken om hun anders oncontroleerbare aanvallen te kunnen beheersen. http://www.herbal-ahp.org/documents/press_releases/AHP%20Therapeutic%20Compendium-Cannabis%20Epilepsy%20and%20Seizures%20Scientific%20Review.pdf

Astma

Experimenten om het anti-astmatisch effect van THC of cannabis te onderzoeken dateren voornamelijk uit de jaren 1970. Het gaat in alle gevallen over diepgaande studies. De effecten van een cannabissigaret (2 % THC) of orale THC (15 mg) zijn ongeveer hetzelfde als deze die bereikt worden met therapeutische doses van de gebruikelijke bronchusverwijdende middelen (salbutamol, isoprenaline). Omdat inhaleren van cannabisprodukten de luchtwegen en de slijmvliezen kan irriteren krijgt de orale toediening of een alternatieve toedieningswijze de voorkeur. Slechts weinig patiënten ontwikkelen een bronchusvernauwing na inhaleren van THC.

Afhankelijkheid en ontwenningsverschijnselen

Volgens historische en moderne onderzoeksresultaten is cannabis een goede remedie om de ontwenningsverschijnselen tegen te gaan bij verslaving aan benzodiazepines, opiaten en alcohol. Omwille daarvan werd al eens gerefereerd naar cannabis als uitstapdrug. In die context zou cannabis zowel voor de vermindering van fysieke ontwenningsverschijnselen als van de stress die ontstaat door de onderbreking van het gebruik, een weldoende rol spelen.

Psychiatrische symptomen

Een verbetering van de gemoedstoestand bij de behandeling van reactieve depressie werd waargenomen in diverse klinische studies met THC. Er zijn bijkomende verslagen waarin gesteld wordt dat cannabinoïden voordeel bieden bij andere psychiatrische symptomen en ziekten, zoals slaapstoornissen, angstgevoelens, bipolaire stoornissen en endogene despressies. Verschillende auteurs hebben een andere mening uitgedrukt over psychiatrische syndromen in relatie met cannabis. Terwijl enkelen de nadruk leggen op de nevenwerkingen van cannabis, schuiven anderen de therapeutische mogelijkheden naar voor. Mogelijkerwijze zijn cannabisprodukten of weldoend of schadelijk, afhankelijk van persoon tot persoon. De behandelende arts en de patiënt moeten een open en kritisch onderhoud kunnen hebben hierover met een openheid voor beide mogelijkheden.

Autoimmuunziekten en infecties

Bij een aantal pijnlijke syndromen (bijvoorbeeld colitis ulzerosa, artritis) werken cannabisprodukten mogelijkerwijze niet enkel pijnstillend maar ook ontstekingswerend. Bijvoorbeeld, enkele patiënten die cannabis gebruiken meldden een daling in hun gebruik van steroïdale en nonsteroïdale ontstekingswerende drugs. Ook zijn er enkele verslagen over positieve effecten van cannabis zelfmedicatie bij allergieën. Het is niet duidelijk of cannabisprodukten een relevant effect hebben op oorzakelijke processen van autoimmuunziekten.

Diverse gemengde syndromen

Er zijn talrijke positieve rapporten over de medische toestand van patiënten die niet eenvoudig te klasseren zijn in bovenstaande categorieën zoals jeuk, hik, ADS (concentratiestoornissen), hoge bloeddruk, oorsuizingen, chronisch vermoeidheidssyndroom, rusteloze benen, en andere. Meerdere honderden mogelijke indicaties voor cannabis en THC werden beschreven door verschillende auteurs. Bijvoorbeeld 2,5 tot 5 mg THC hadden een goede werking tegen jeuk die ontstond door een leveraandoening bij drie patiënten. Een ander voorbeeld is de succesvolle behandeling van een chronische hik die zich ontwikkeld had na een chirurgische ingreep. Geen enkel geneesmiddel bracht soelaas, maar het roken van een cannabissigaret volstond voor een complete eliminatie van de symptomen.

Cannabisprodukten geven goede resultaten bij ziekten met meerdere indicaties die binnen het actiespectrum liggen van THC. Bijvoorbeeld in pijnlijke situaties ten gevolge van ontstekingen (bijv. artritis) of die samenvallen met verhoogde spierspanningen (bijv. menstruatiepijnen, rugschade) of bij ziekten waar misselijkheid en anorexia gepaard gaan met pijn, angst en depressie (bijv. AIDS, kanker en hepatitis C).



CANNABIS SOORTEN RIJK AAN CBD

Traditioneel is het THC-gehalte de enige indicator voor de kracht en kwaliteit van cannabis, maar dit is aan het veranderen nu de voordelen van de andere cannabinoïden, en met name CBD, wetenschappelijk worden erkend. THC is de cannabinoïde die grotendeels verantwoordelijk is voor de psychoactieve effecten van cannabis en is door recreatief gebruikers nog steeds de meest gewilde stof.  Om deze reden hebben de meeste kwekers de nadruk gelegd op het verhogen van de THC-niveaus, maar andere cannabinoïden, zoals CBD, zijn genegeerd.

Nu steeds meer wetenschappelijk bewijs de medicinale effecten van cannabis ondersteunt, zien we niet alleen een opleving van legaal en sociaal geaccepteerd gebruik van medicinale cannabis, maar ook een verschuiving in de focus op andere cannabinoïden. THC heeft aangetoond haar eigen medicinale kwaliteiten te bezitten, maar het is CBD die momenteel in het spotlicht staat vanwege de vele medicinale eigenschappen. Met name de afwezigheid van psychoactieve effecten maakt CBD aantrekkelijk voor vele toepassingen, waardoor het met succes aan kinderen is toegediend zonder een high te veroorzaken. Als een gevolg hiervan, produceren cannabis kwekers vele nieuwe soorten die een hoog niveau CBD bevatten.
Nu de mainstream media verhalen over CBD oppikt, zoals die van Charlotte, het kleine meisje die epilepsie heeft verslagen dankzij een CBD-rijke soort, verspreidt het bewustzijn over de krachtige medicinale kwaliteiten van deze cannabinoïde. De legalisatie van recreatieve en medicinale cannabis in diverse staten van de VS heeft CBD soorten meer beschikbaar gemaakt. Niet alle medicinaal gebruikers hebben echter geluk via een legale apotheek te kunnen kopen en illegale cannabis van de straat is niet geschikt voor medisch gebruik. Hierom nemen velen zelf het heft in handen en kweken hun eigen voorraad, waarvan zij hun eigen medicijnen maken, zoals tincturen en concentraten.

WAT WORDT ALS EEN CBD-RIJKE SOORT BESCHOUWD?
CBD is de afkorting voor cannabidiol, na THC de meest voorkomende en belangrijke cannabinoïde in cannabis. Wanneer je kijkt naar het cannabinoïden gehalte in een soort, is het heel normaal om een THC-niveau te vinden tussen de 12-20 procent, waarbij alles boven 20 als zeer sterk wordt beschouwd. Dit is niet het geval als we het hebben over CBD, het is zeldzaam om zulke hoge percentages te vinden: elk CBD-niveau van 4 procent of hoger wordt beschouwd als een CBD-rijke soort. Hoewel 1% CBD al beter is dan niets, zijn soorten met meer dan 18% de laatste jaren opgekomen, hoewel ze nog steeds moeilijk te vinden zijn. Commercieel beschikbare CBD-rijke soorten bevatten tussen de 8% - 12% CBD.
WAT DOET CBD?
In eerste instantie werd altijd gedacht dat CBD slechts fungeerde om de effecten van de THC te modereren en te temperen, waardoor kwekers een goede reden hadden dit te negeren. Nieuwe onderzoeken hebben echter aangetoond dat CBD in feite de meeste medicinale waarde heeft. Het is waar dat CBD de manier waarop THC op het lichaam inwerkt, verandert, maar niet direct op een negatieve manier. Het gaat een aantal ongewenste bijwerkingen tegen, die bij hogere doses THC kunnen optreden en het verlengt ook de effecten.
Op zichzelf heeft CBD aangetoond toepasbaar en nuttig te zijn voor diverse ziektes, aandoeningen en problemen. In onderzoek heeft CBD veelbelovende resultaten laten zien bij de behandeling van Multiple Sclerose, de ziekte van Chrohn, Alzheimer, Parkinson, Epilepsie en PTSS. CBD is ook een bestanddeel van cannabis die patiënten kan helpen omgaan met (chronische) pijn, spasmen en artritis.
Het is zinvol om nogmaals te vermelden dat CBD, in tegenstelling tot THC, niet psychoactief is. Daarom kunnen en worden tincturen en extracten ook gebruikt om kinderen te behandelen die lijden aan slopende aandoeningen, zoals het hierboven genoemde voorbeeld van Charlotte die een cannabis tinctuur gebruikt, gemaakt van een CBD-rijke soort met de toepasselijke naam "Charlotte's Web", om haar aanvallen te stoppen. Voordat ze cannabis gebruikte, kreeg Charlotte 1.200 aanvallen per maand; nu heeft ze er ongeveer 3 en ze vertoont gebalanceerd gedrag.
Verder heeft CBD geen negatieve bijwerkingen, is niet schadelijk voor lichaam of geest, is niet verslavend en een overdosis kan niet worden genomen.

 5 CBD-RIJKE SOORTEN
Van de volgende 5 soorten is aangetoond dat ze een zeer hoog CBD-gehalte hebben en deze zijn dus geschikt voor diegenen die graag hun eigen medicijn willen produceren en/of het zelf willen kweken. 

SHARK SHOCK
CBD Crew Shark ShockShark Shock is een van de geweldige creaties van de CBD Crew. De CBD Crew zijn cannabis kwekers die tegen de standaard ingaan. Ze hebben geen interesse in de massa marketing van THC-rijke soorten en hebben al hun energie gestoken om CBD-rijke, hoogwaardige, medicinale soorten te maken. Shark Shock is hierin geen uitzondering, het is een van de weinige soorten waar het CBD-gehalte de THC overstijgt. Met een gemiddeld THC-gehalte van 6,33% en een CBD-gehalte van maar liefst 7,28% is het een perfecte soort voor medicinaal gebruikers.
Mocht je ervoor kiezen het te vaporizen (roken wordt niet echt aangeraden), dan produceert Shark Shock een zoete, fruitige damp. Dankzij haar voornamelijk Indica erfgoed, blijft Shark Shock klein, heeft een snelle bloeiperiode van ongeveer 8 weken en kan ongeveer 400 gram/m2 opbrengen. Ze is een sterk, klein plantje en een aanwinst in de collectie van elke medicinale kweker.

CBD SKUNKHAZE
CBD Crew Skunk HazeCBD Skunkhaze is het resultaat van een samenwerkingsverband tussen de CBD Crew en de kwekers van Dutch CBD en een geweldige medicinale verbetering van een klassieke soort. CBD Skunkhaze is absoluut gekweekt met de medicinaal gebruiker in gedachten. Deze soort is gekweekt om de gewenste 1:1 ratio van CBD:THC te bereiken, wat resulteert in 5% THC en 5% CBD. Het gevolg is een milde en plezierige stone, maar nog belangrijker: Een krachtig medicijn om de vele aandoeningen te bestrijden waar CBD effect op heeft.
CBD Skunkhaze produceert een damp die zowel kruidig, fris, citrus-achtig als mintachtig is. Zoals de naam al suggereert, is CBD Skunkhaze een 50/50 Sativa/Indica hybride. Ze wordt groot, maar niet enorm en heeft een bloeiperiode van ongeveer 10 weken. Ze kan oogsten opleveren van ongeveer 450 gram/m2.

ROYAL HIGHNESS
Royal Queen Seeds - Royal HighnessRoyal Highness is het antwoord van Royal Queen Seeds op medicinale soorten. Hoewel het exacte THC- en CBD-gehalte onbekend is, geeft de kweker aan dat beiden erg hoog te noemen zijn en zowel wij hier bij Zamnesia als medicinale gebruikers zijn het hiermee eens. Ze produceert een zeer heldere mentale, gefocuste high, terwijl ze ook effectief werkt op de behandelde aandoeningen.
Bij het verstuiven, levert Royal Highness een uitgesproken, zoete smaak, met skunky ondertonen. Het is alweer een soort waar zelfs beginnende kwekers mee uit de voeten kunnen. Ze groeit als een Indica, klein en stevig van stuk en heeft een bloeiperiode van grofweg 8-9 weken.

CBD NORDLE
CBD Crew NordleEn alweer een soort, geproduceerd door de kwekers van CBD Crew. CBD Nordle brengt de grenzen van CBD naar het volgende niveau. Het beschikt over een maximaal getest CBD-gehalte van 8,97 procent, terwijl het THC-gehalte 6,43 procent bedraagt. Hier zijn ware kweek-kunsten aan het werk geweest en dit toont de bekwaamheid aan van de CBD Crew. Er zijn maar weinig soorten die een beter medicijn maken (de nadruk op deze soorten ligt op het medicijn en niet op de high). Je zal maar zelden een soort vinden met een hoger CBD-gehalte (hoewel we er zeker van zijn dat het de CBD Crew zal lukken).
Bij het vaporizen, zal CBD Nordle een sterke, kruidige smaak opwekken. De soort is zeer geschikt voor beginners en blijft klein van stuk, waarbij de vorm doet denken aan een kerstboom. CBD Nordle is een Indica dominante hybride die ongeveer 8-10 weken nodig heeft om te bloeien. Ze produceert tot wel 500 gram / m2.

CBD MEDI HAZE
CBD Crew Medi HazeCBD Medi Haze is een van de meest recente creaties van CBD Crew. Het is een Sativa dominante soort die is verrijkt met een bizar CBD-gehalte. Tests hebben aangetoond dat het CBD-gehalte in deze soort tot wel 8% kan bevatten! De THC haalt slechts 4! Het is wederom een verbazingwekkende kweekprestatie en perfect voor medicinaal gebruikers.
Mocht je CBD Medi Haze vaporizen, kan je rekenen op een pittige, mint-achtige smaak. Als een Sativa dominante soort, kan CBD Medi Haze vrij groot worden. Na haar bloeiperiode van 9-10 weken kan ze echter een oogst opbrengen van 450-550 gram/m2.
 


Cannabinoids

Cannabinoids are a group of 21-carbon–containing terpenophenolic compounds produced uniquely by Cannabis sativa and Cannabis indica species.[1,2] These plant-derived compounds may be referred to as phytocannabinoids. Although delta-9-tetrahydrocannabinol (THC) is the primary psychoactive ingredient, other known compounds with biologic activity are cannabinol, cannabidiol (CBD), cannabichromene, cannabigerol, tetrahydrocannabivarin, and delta-8-THC. CBD, in particular, is thought to have significant analgesic and anti-inflammatory activity without the psychoactive effect (high) of delta-9-THC.

Antitumor Effects
One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors.[3] During this 2-year study, groups of mice and rats were given various doses of THC by gavage. A dose-related decrease in the incidence of hepatic adenoma tumors and hepatocellular carcinoma was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were also noted in the rats. In another study, delta-9-THC, delta-8-THC, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo .[4] In addition, other tumors have been shown to be sensitive to cannabinoid-induced growth inhibition.[5-8]

Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of tumor angiogenesis invasion and metastasis.[9-12] One review summarizes the molecular mechanisms of action of cannabinoids as antitumor agents.[13] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. These compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats. Cannabinoids protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1 receptor.[14]

The effects of delta-9-THC and a synthetic agonist of the CB2 receptor were investigated in hepatocellular carcinoma (HCC).[15] Both agents reduced the viability of hepatocellular carcinoma cells in vitro and demonstrated antitumor effects in hepatocellular carcinoma subcutaneous xenografts in nude mice. The investigations documented that the anti-HCC effects are mediated by way of the CB2 receptor. Similar to findings in glioma cells, the cannabinoids were shown to trigger cell death through stimulation of an endoplasmic reticulum stress pathway that activates autophagy and promotes apoptosis. Other investigations have confirmed that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma [16] and breast cancer.[17]
An in vitro study of the effect of CBD on programmed cell death in breast cancer cell lines found that CBD induced programmed cell death, independent of the CB1, CB2, or vanilloid receptors. CBD inhibited the survival of both estrogen receptor–positive and estrogen receptor–negative breast cancer cell lines, inducing apoptosis in a concentration-dependent manner while having little effect on nontumorigenic, mammary cells.[18]

CBD has also been demonstrated to exert a chemopreventive effect in a mouse model of colon cancer.[19] In the experimental system, azoxymethane increased premalignant and malignant lesions in the mouse colon. Animals treated with azoxymethane and CBD concurrently were protected from developing premalignant and malignant lesions. In in vitro experiments involving colorectal cancer cell lines, the investigators found that CBD protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation.
Another investigation into the antitumor effects of CBD examined the role of intercellular adhesion molecule-1 (ICAM-1).[12] ICAM-1 expression has been reported to be negatively correlated with cancer metastasis. In lung cancer cell lines, CBD upregulated ICAM-1, leading to decreased cancer cell invasiveness.

In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines.[20] Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[21,22]
In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation.[23] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[24-27]

Appetite Stimulation
Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice.[28] Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.[29]

Analgesia
Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing.[30] CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[31,32]

Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesic opioids has been described.[33-35] One study reported that the efficacy of synthetic CB1- and CB2-receptor agonists were comparable with the efficacy of morphine in a murine model of tumor pain.[36]

Referenties
  • Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PUBMED Abstract]
  • Grotenhermen F, Russo E, eds.: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Binghamton, NY: The Haworth Press, 2002. 
  • National Toxicology Program .: NTP toxicology and carcinogenesis studies of 1-trans-delta(9)-tetrahydrocannabinol (CAS No. 1972-08-3) in F344 rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser 446 (): 1-317, 1996. [PUBMED Abstract]
  • Bifulco M, Laezza C, Pisanti S, et al.: Cannabinoids and cancer: pros and cons of an antitumour strategy. Br J Pharmacol 148 (2): 123-35, 2006. [PUBMED Abstract]
  • Sánchez C, de Ceballos ML, Gomez del Pulgar T, et al.: Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61 (15): 5784-9, 2001. [PUBMED Abstract]
  • McKallip RJ, Lombard C, Fisher M, et al.: Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100 (2): 627-34, 2002. [PUBMED Abstract]
  • Casanova ML, Blázquez C, Martínez-Palacio J, et al.: Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111 (1): 43-50, 2003. [PUBMED Abstract]
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  • Blázquez C, Casanova ML, Planas A, et al.: Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17 (3): 529-31, 2003. [PUBMED Abstract]
  • Vaccani A, Massi P, Colombo A, et al.: Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 144 (8): 1032-6, 2005. [PUBMED Abstract]
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  • Vara D, Salazar M, Olea-Herrero N, et al.: Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ 18 (7): 1099-111, 2011. [PUBMED Abstract]
  • Preet A, Qamri Z, Nasser MW, et al.: Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prev Res (Phila) 4 (1): 65-75, 2011. [PUBMED Abstract]
  • Nasser MW, Qamri Z, Deol YS, et al.: Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion. PLoS One 6 (9): e23901, 2011. [PUBMED Abstract]
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  • Preet A, Ganju RK, Groopman JE: Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene 27 (3): 339-46, 2008. [PUBMED Abstract]
  • Zhu LX, Sharma S, Stolina M, et al.: Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol 165 (1): 373-80, 2000. [PUBMED Abstract]
  • McKallip RJ, Nagarkatti M, Nagarkatti PS: Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol 174 (6): 3281-9, 2005. [PUBMED Abstract]
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  • Patsos HA, Hicks DJ, Greenhough A, et al.: Cannabinoids and cancer: potential for colorectal cancer therapy. Biochem Soc Trans 33 (Pt 4): 712-4, 2005. [PUBMED Abstract]
  • Liu WM, Fowler DW, Dalgleish AG: Cannabis-derived substances in cancer therapy--an emerging anti-inflammatory role for the cannabinoids. Curr Clin Pharmacol 5 (4): 281-7, 2010. [PUBMED Abstract]
  • Malfitano AM, Ciaglia E, Gangemi G, et al.: Update on the endocannabinoid system as an anticancer target. Expert Opin Ther Targets 15 (3): 297-308, 2011. [PUBMED Abstract]
  • Sarfaraz S, Adhami VM, Syed DN, et al.: Cannabinoids for cancer treatment: progress and promise. Cancer Res 68 (2): 339-42, 2008. [PUBMED Abstract]
  • Mechoulam R, Berry EM, Avraham Y, et al.: Endocannabinoids, feeding and suckling--from our perspective. Int J Obes (Lond) 30 (Suppl 1): S24-8, 2006. [PUBMED Abstract]
  • Fride E, Bregman T, Kirkham TC: Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) 230 (4): 225-34, 2005. [PUBMED Abstract]
  • Walker JM, Hohmann AG, Martin WJ, et al.: The neurobiology of cannabinoid analgesia. Life Sci 65 (6-7): 665-73, 1999. [PUBMED Abstract]
  • Meng ID, Manning BH, Martin WJ, et al.: An analgesia circuit activated by cannabinoids. Nature 395 (6700): 381-3, 1998. [PUBMED Abstract]
  • Walker JM, Huang SM, Strangman NM, et al.: Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci U S A 96 (21): 12198-203, 1999. [PUBMED Abstract]
  • Facci L, Dal Toso R, Romanello S, et al.: Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A 92 (8): 3376-80, 1995. [PUBMED Abstract]
  • Ibrahim MM, Porreca F, Lai J, et al.: CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A 102 (8): 3093-8, 2005. [PUBMED Abstract]
  • Richardson JD, Kilo S, Hargreaves KM: Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75 (1): 111-9, 1998. [PUBMED Abstract]
  • Khasabova IA, Gielissen J, Chandiramani A, et al.: CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain. Behav Pharmacol 22 (5-6): 607-16, 2011. [PUBMED Abstract]

Conclusions http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1617062/
Presented findings suggest that cannabinoids exert a number of effects depending on cell types, activation of signal transduction pathways, route of drug administration, timing of drug delivery and, last but not least, responsivity of tumour and normal cells.

Epidemiological studies reported inconsistent association between cannabis smoke and cancer, and administration of high oral doses of THC in rats or mice did not increase tumour incidences in a 2-year study (Chan et al., 1996). In animal models, cannabinoids exert a direct antiproliferative effect on tumours, but they could indirectly enhance tumour growth via inhibition of immunogenicity (for immunosuppressive effect of cannabinoids, see Klein, 2005). The typical immunosuppressive effect of THC is an unquestionable topic imposing caution in the dosage and administration timing of CB2-receptor-selective compounds (Klein et al., 2000; Salzet et al., 2000).

The immunosuppressive properties of plant-derived cannabinoids could enhance tumour cell proliferation (Zhu et al., 2000; McKallip et al., 2005) and accelerate cancer progression in patients, but the biological response to cannabinoids critically depends on drug concentration and cellular context (Hart et al., 2004). Nevertheless, different therapeutic strategies could be developed on the basis of peculiar characteristics expressed by several malignancies. Jones & Howl (2003) suggested as therapeutic target for tumour intervention some distinctive properties: (1) in cancer, such as malignant astrocytomas, gliomas, breast, thyroid, prostate, where cannabinoid receptor expression is enhanced, strategies aimed at raising levels of endocannabinoids could be a successfully treatment; (2) in colorectal carcinoma, the increased expression of endocannabinoids suggests that inhibitors of endocannabinoid metabolism could be used as therapeutic tools; (3) upregulation of CB2 receptor expression in malignant astrocytomas and gliomas and/or the increased CB2/CB1 ratio in tumours of immune origin could suggest the use of cannabinoid-based drugs devoid of psycotropic effects. Moreover, there is at present no obvious universal mechanism whereby cannabinoids affect cell viability and proliferation; furthermore, the immunosuppressive properties of cannabinoids or their effects on COX-2 expression, even if incompletely demonstrated to date, could represent cons evidence for medical use of cannabinoids, at least in lung carcinoma.

Indeed, cannabinoids have the advantage of being well tolerated in animal studies and they do not present the generalized toxic effects of most conventional chemotherapeutic agents (Guzman et al., 2003). Routes of cannabinoids administration have been recently studied. THC is rapidly absorbed after inhalation and its effects become apparent within minutes. Grotenhermen (2001) showed that THC oral administration was associated with slow onset of action and with accidental overdosage. In fact, maximum THC serum concentration measured after smoke intake (Huestis et al., 1992) is 2–3-fold higher than maximum serum concentration achievable with oral or rectal THC administration (Consroe et al., 1991; Brenneisen et al., 1996). The inhalation may have pharmacokinetic advantages, but it requires use of higher potency cannabinoids and strategy aimed at eliminating carcinogenic products combustion: for this purpose, Gieringer (2001) proposed the vaporization lacking the carcinogenic compounds formed during combustion. The trans-dermal route could be eligible for pain, nausea and vomiting treatment in chemotherapy patients giving a continuous steady dose (Stinchcomb et al., 2001).

In rats, THC and WIN-55,212-2 administered by infusion at the site of tumour showed a good efficacy, but so far, only preliminary results from one clinical study applying a strategy of local THC administration in patients with recurrent glioblastoma multiforme has been reported (Blazquez et al., 2004). Moreover, long-term effects of chronically administered cannabinoids have not been studied. To date, the prescription of cannabinoids is provided for medical conditions that are not adequately controlled by standard treatments, but considering their potentiality in clinical practise the Clinical Cannabinoid Group, chaired by Dr Peterwee, encourage properly conducted clinical trials to evaluate the further potential therapeutic uses of cannabinoids alone or in combination with other drugs.

Even if the use of cannabinoids in clinical practice needs further preclinical research, in order to confirme safety, efficacy, doses and administration protocols, the cannabinoids could provide unquestionable advantages compared to current antitumoural therapies: (1) cannabinoids selectively affect tumour cells more than their nontransformed counterparts that might even be protected from cell death; (2) systematically administered selective inhibitors of endocannabinoid degradation would be effective only in those tissues where endocannabinoid levels are pathologically altered, without any significant psychotropic or immunosuppressive activity; (3) selective CB1 agonists unable to cross the blood–brain barrier would be deprived of the immunosuppressive and psychotropic effects of cannabinoids and therefore could be efficaciously used as antineoplastic drugs in a large number of tumours, with the exception of glioma; (4) cannabinoids could represent an efficacious therapy in COX-2-expressing tumours that have become resistant to induction of apoptosis: acting as COX-2-substrates with no effect on the protective properties of COX-2-derived products, they could offer some advantage with respect to the NSAID in order to enhance the sensibility to conventional anticancer therapies.

Even if further in vivo research are required to clarify cannabinoids action in cancer and especially to test their effectiveness in patients, the cannabinoid system represent a promising target for cancer treatment.



Cannabis and Schizophrenia
by Lindsay Stafford Mader
HerbalGram. 2013; American Botanical Council

The proposition that cannabis causes schizophrenia has existed since at least the early days of the anti-marijuana movement in America, as illustrated in the 1936 film Reefer Madness, in which a character descends into psychosis after smoking a joint.1 The cannabis-schizophrenia connection intensified during the “War on Drugs,” which produced propaganda linking the herb to schizophrenia, as well as cancer and brain damage.2 Fast-forward more than seven decades since the film, and the academic and mainstream media continue to refer to cannabis’s ability to cause and increase the risk of developing this serious mental illness.3,4
The link between cannabis (Cannabis sativa, Cannabaceae) and schizophrenia, however, is much more complex and much less certain. Cannabis and the brain have an interesting and unique relationship, part of which remains a mystery to researchers even today. After more than two decades of scientific analysis, researchers know that the human body contains receptors that bind with tetrahydrocannabinol (THC) and other cannabinoids from the cannabis plant, and also has neurotransmitters that activate these receptors in much the same way. The body's receptors include the CB1 and CB2 receptors, and the endogenous cannabinoids, referred to as endocannabinoids, including anandamide and 2-AG.5,6


Although this intricate endocannabinoid system of receptors and neurotransmitters — as well as the exact role played by the cannabis plant — is not yet fully understood, it clearly is involved in numerous physiological and pathological processes that are essential to human health. As Ester Fride and Ethan Russo, MD, wrote in the neuropsychiatry chapter of the 2005 book Endocannabinoids: The Brain and Body’s Marijuana and Beyond (CRC Press), “Endocannabinoids serve a modulatory function in many neurochemical and psychopharmacological processes, and deficiencies or excesses in any of these may produce manifestations of psychopathology.”5
Even more perplexing to scientists is the severe brain disorder called schizophrenia, which affects about 24 million people worldwide — approximately one percent of the population. According to the PsychCentral mental health web resource, “In spite of advances in the understanding of its causes, course, and treatment, schizophrenia continues to confound both health professionals and the public. It is easier for the average person to cope with the idea of cancer than it is to understand the odd behavior, hallucinations, or strange ideas of the person with schizophrenia.”7

Medical researchers believe that schizophrenia is tied to a genetic link as incidence among those with afflicted family members is increased by about nine percent.8 It is also thought that schizophrenia might be caused by the malfunction of a gene that creates important brain chemicals, as well as possible environmental triggers, and/or an imbalance of the neurotransmitters dopamine and glutamate. Scans of schizophrenia patients’ brains have revealed that they have larger center-brain ventricles and less gray matter, and post-mortem brain analyses have shown differences in schizophrenics’ brain cell characteristics — perhaps occurring during abnormal fetal brain development. Schizophrenia presents itself through a variety of symptoms, including hallucinations, delusions, thought and movement disorders, monotonous voice, and motionless face when speaking (referred to as “positive” symptoms), as well as social withdrawal, inability to make decisions, lack of emotion and motivation, etc. (referred to as “negative” symptoms and “cognitive deficits”).

Research
While a fair amount of scientific research has examined the relationship between cannabis and schizophrenia, most of this consists of laboratory, animal, epidemiological, or post-mortem human studies. Recognizing the “tremendous amount” of preclinical research on cannabis and schizophrenia, Martin Lee — author of the 2012 book Smoke Signals: A Social History of Marijuana – Medical, Recreational, and Scientific — noted the ethical implications of studying cannabis in humans.
“You’re not going to get experiments in the United States where the federal government will approve a researcher or a scientist giving marijuana to a schizophrenic, but you could do a survey of schizophrenics,” said Lee (oral communication, March 15, 2013).

Healthy Populations
Cannabis is well known to cause physiological and psychological side effects in almost all people who use it, particularly varieties that contain higher levels of THC. Thus, the concept that cannabis causes negative mental experiences is not ridiculous; anecdotal reports of momentary post-cannabis psychosis and hallucinations have been shared for quite some time.2
While the psychological side effects of cannabis can be similar to the symptoms experienced by diagnosed schizophrenics — such as visual illusions, paranoia, mood alterations, and memory deficits9 — cannabis-produced symptoms typically disappear after three to five hours.10
Still, the allegation persists that cannabis can cause schizophrenia, a disease in which psychotic symptoms typically last throughout a patient’s life. When experts discuss this cannabis-schizophrenia relationship, they make sure to differentiate between cannabis’s impact on healthy populations and cannabis’s impact on diagnosed schizophrenic patients and individuals with risk factors for developing schizophrenia.9 This important detail is often not provided in media reports on the topic.
“I don’t think we should say cannabis induces schizophrenia, and so we should discourage people from using cannabis because they’ll become psychotics,” said Andrea Giuffrida, PhD, an associate professor of pharmacology at the University of Texas Health Science Center in San Antonio, who researches this topic (oral communication, March 25, 2013). “Maybe some of them have a higher risk, but not the entire population.”
Researchers and proponents of the argument that cannabis does not cause schizophrenia in the general population often cite epidemiological data that shows a significant increase in cannabis usage during the last several decades while the rates of schizophrenia have remained largely static. As stated by the authors of a recent article titled, “Cannabis and Psychosis: What Causes What?,” “Most people who use cannabis do not develop schizophrenia, and many people diagnosed with schizophrenia have never used cannabis.”9
“As marijuana usage has increased in culture in the last 50 years, you haven’t seen that increase in schizophrenia,” said Lee. “If it was causing schizophrenia, you would probably see an increase, so the causal thing is just not there.”

But according to psychiatrists Patricia Gerbarg, MD, who has a clinical practice in New York City, and Richard Brown, MD, a professor at Columbia University, the lack of correlation could be explained in other ways. “For example,” they said, “improvements in prenatal nutrition and healthcare are more likely to lower the incidence of schizophrenia…. Also, there may appear to be a lack of increase in schizophrenia because of a lack of increase in the diagnosis of schizophrenia, which could be due to the many changes in diagnostic categories since the 1970s. Many cases that would previously have been diagnosed as schizophrenia, would now be diagnosed as Asperger’s or bipolar disorder” (email, March 16, 2013).
Some epidemiological surveys have shown that schizophrenic patients abuse cannabis more than any other illegal drug and also have cannabis usage rates higher than healthy population rates, which has been used as an argument that cannabis possibly causes or increases the chance of developing schizophrenia in otherwise healthy populations.11 But according to Dr. Giuffrida, this is just a correlation, which, he points out, cannot establish causality. He additionally noted the hypothesis that schizophrenic patients might use cannabis more because they are attempting to self-medicate.
“Whether they smoke more because they are schizophrenic or they are schizophrenic because they smoke more cannabis, we don’t know the direction of the connection,” he explained.

Further, a Swedish survey published in 1987 of almost 50,000 male participants conducted over the course of 15 years found that those who self-reported heavy cannabis use were 50 times more likely to be diagnosed with schizophrenia.12 But when these findings were reanalyzed and adjusted to account for other risk factors, the increased likelihood dropped to 6.7 times, and many of the participants who reported cannabis use also reported the use of other drugs that have the ability to precipitate psychosis.13
In examining the connection between cannabis and schizophrenia, researchers also study brain morphology. In a 2012 paper in the European Archives of Psychiatry and Clinical Neuroscience, a team of researchers from Germany and England analyzed 16 neuroimaging studies. The authors concluded that there is “no convincing evidence” that cannabis-related brain alterations happen before the onset of schizophrenia.11 In fact, essentially none of the changes seen in the brains of schizophrenic patients using cannabis were observed in healthy individuals who used cannabis.
Some journals and other sources report that young people are especially vulnerable for developing cannabis-induced schizophrenia. A large-scale survey conducted in 2005 by Henquet et al. suggested that ingesting cannabis at a young age (14 to 24 years) was associated with an increased chance of developing psychotic symptoms,14,15 but this data did not analyze the risk of developing full schizophrenia, and those with predisposed risks for psychosis were more likely to develop psychotic symptoms. According to an expert peer reviewer of this article, while extra caution is always advised in adolescents, there is still no evidence that permanent, schizophrenia-related de novo damage is done to young, healthy individuals.
“The work of Henquet is very interesting,” added Dr. Giuffrida, “but the assessment of cannabis use is based on an interview and consequently is not as precise as a study where cannabis is administered in a controlled fashion. I do believe we need more experiments before establishing a causal relation between cannabis exposure and schizophrenia development in the healthy population.”

At-Risk and Diagnosed Populations
Most researchers agree that because schizophrenia likely is brought on by a variety of “component causes,” one of which could include cannabis use, a healthy person with no risk factors is very unlikely to develop the disease from cannabis use alone.9,11,14 The situation is different, however, for individuals with predisposed risks.
Those at risk for developing schizophrenia include individuals with schizophrenic family members or those who exhibit symptoms of the prodromal stage (a precursor to a more full set of symptoms or disease), which typically consist of increased isolation and decreased motivation and appear a year before true schizophrenia symptoms.11 Interestingly, recent research suggests that a mutation in the AKT1 gene also might put an individual at increased risk for developing cannabis-associated schizophrenia.16 These at-risk groups are cautioned against using cannabis as epidemiological evidence and survey data show that they have worse psychotic-disorder outcomes when cannabis is a factor.15
The aforementioned 2012 brain morphology literature review by Malchow et al. found just three studies on high-risk individuals, in which an “additional effect of cannabis use on brain structure” was suggested.11 These studies found that cannabis use was associated with a bilateral volume loss of the thalamus, a region of the brain that integrates and processes sensory and cognitive functions; increased thinning of the cortex, the largest region of the brain; and an increased volume of the brain’s fluid-filled cavities known as ventricles. (The latter of these studies, however, analyzed cannabis and alcohol in high-risk subjects.)

The review authors conclude that there is “some weak evidence that cannabis abuse could affect brain structures in high-risk subjects, but replication of these findings is needed. The results of the identified neuroimaging studies are heterogeneous and inconclusive,” for various reasons, including differing definitions of regional volume boundaries and differing volume extraction methods (when measuring content of the brain), as well as differing MRI techniques.11
For patients who have been diagnosed with schizophrenia, the implications for using cannabis are somewhat better understood. Although few human clinical trials on cannabis and schizophrenics have been performed, epidemiological data and survey evidence indicate — and most experts agree — that ingesting cannabis can aggravate schizophrenia symptoms and/or increase their frequency.13 The few human studies found cannabis products (i.e., hashish, THC) to exacerbate symptoms, although these were temporary effects. According to Endocannabinoid’s neuropsychiatry chapter, “Taken together, most studies confirm the vulnerability hypothesis for cannabis use and schizophrenia. Thus, schizophrenia patients should probably not use cannabis because a psychotic episode can be induced in someone with a preexisting disorder and, indeed, increased hospitalization rates and symptom exacerbation have been demonstrated.”5

Malchow et al. noted that most brain imaging studies on cannabis and schizophrenia examined individuals with first-episode or recent-onset schizophrenia.11 Some of this research suggested that schizophrenic patients who used cannabis had subtle brain abnormalities, increased ventricle volumes, thinning of various cortical regions, decreased gray and white matter volume, and “altered brain structure in particular regions … with a high density of CB1 receptors.” The authors noted, however, that anti-psychotic medication has been strongly associated with reduced gray matter and that many of the studies included “comorbid patients consuming other substances than cannabis, for example, amphetamines, cocaine, and sometimes alcohol, making it difficult to focus on the effect of cannabis alone.”
“The results of these neuroimaging studies are again heterogeneous and remain inconclusive,” they wrote.

Researchers are beginning to understand that the connection between cannabis and schizophrenic individuals might lie in the human body’s mysterious and powerful endocannabinoid system. According to the authors of a 2008 article in Expert Review of Neurotherapeutics, “There are several lines of evidence suggesting that, at least in a subgroup of patients, alterations in the endocannabinoid system may contribute to the pathogenesis of schizophrenia.”15
Human studies have shown schizophrenics to have increased levels of anandamide and endocannabinoid-like molecules such as palmitylethanolamide, and these patients with higher levels of anandamide typically experience fewer psychotic symptoms.15 Additionally, frequent cannabis usage was found to decrease cerebral spinal fluid levels of anandamide, suggesting a possible explanation for why some schizophrenic patients sometimes have negative experiences after ingesting cannabis. Authors of additional studies have found a possible connection between lower levels of the endocannabinoid 2-AG and schizophrenia progression, as well as impaired endocannabinoid signaling associated with acute psychotic episodes.

“My preferred hypothesis is that frequent and intense cannabis smoking [reduces] an endogenous protective mechanism, mediated by anandamide, resulting in an increased risk for precipitation of psychosis,” said Daniele Piomelli, PhD, PharmD, a professor of anatomy and neurobiology at the University of California at Irvine (email, March 22, 2013). “Please note that anandamide is not the only endocannabinoid present in the brain and that this theory does not rule out the possibility that other endocannabinoids (e.g., 2-AG) might be pro-psychotic.”
In explaining why cannabis and endocannabinoids might not act in the same way, Dr. Giuffrida pointed to the different pharmacologic profiles of THC and anandamide. “For example, when you smoke cannabis and take in THC, you activate all the cannabinoid receptors in the brain. But when you elevate anandamide, the elevation does not happen all over the brain but happens in specific brain areas.”

Interestingly, the CB1 receptor is expressed in high levels in the prefrontal cortex — the region of the brain responsible for cognitive and emotional functions and thought to be the “primary dysfunctional area” in schizophrenia — as well as in other brain areas relevant to schizophrenia, such as the basal ganglia, hippocampus, and the anterior cingulate cortex.8,15 Some post-mortem studies have found schizophrenic patients’ brains to have even-further increased binding levels of the CB1 receptor.
“But again,” said Dr. Giuffrida, “whether this is a contributing factor to develop schizophrenia is unknown at this time.”
Dr. Giuffrida reiterated that cannabis can sometimes help certain schizophrenia symptoms, which might explain why some patients might self-medicate with the herb.
“We know that, in schizophrenic patients, cannabis intake can make positive symptoms worse. But, on the other side, there is some work showing that the cannabinoids have a beneficial effect on the negative symptoms of schizophrenia, so they make people interact more with each other. But what happens with marijuana, especially if you are a psychotic individual, the more you use cannabis, the worse your symptoms become over time. So it can be helpful in the beginning, but definitely not in the long run.”

Therapeutic Role of CBD

While THC, the compound in cannabis responsible for the euphoric “high,” is known to increase the severity of psychotic symptoms in schizophrenia patients, another cannabinoid in cannabis — the non-psychoactive cannabidiol (CBD) — has been shown to be therapeutic for schizophrenia symptoms.

Based on CBD’s known anti-anxiety activity, researchers conducted a small pilot study on CBD in 42 patients with paranoid schizophrenia in 2012. This Phase II, double-blind, four-week trial compared CBD treatment with the antipsychotic drug amisulpride and found that CBD improved symptoms as well as the pharmaceutical — and that it produced fewer negative side effects.17
“It’s a small study so we have to see if the data is replicated in larger groups of people,” said Dr. Giuffrida, noting that CBD “is definitely one of the most exciting areas in the cannabinoid field.” He explained that although CBD’s activity within the brain is not yet completely understood, this compound is pharmacologically different from THC in that it does not bind to the CB1 receptor in the brain, whereas THC does. Additionally, he said some animal and human studies show that CBD boosts levels of the endocannabinoid anandamide, and elevated anandamide seems to have a beneficial effect on schizophrenia.
“These results suggest that the inhibition of anandamide activation may contribute to the anti-psychotic effect of cannabidiol,” said Dr. Giuffrida, “which possibly represents a completely new mechanism of treatment for schizophrenia.”

Conclusion
While CBD presents an exciting possibility as a novel schizophrenia treatment, additional research must be conducted to validate early studies. Likewise, more human research on cannabis’s impact on schizophrenia would greatly broaden scientists’ and medical professionals’ understanding of this interesting and complex relationship. Based on the available evidence — which includes epidemiological studies, surveys, brain morphology analyses, and a few human studies — most experts accept that cannabis intake could have negative impact on individuals who have schizophrenia and that those vulnerable to developing schizophrenia can have psychotic episodes if they ingest high doses of cannabis.
“So there definitely is something there,” said Dr. Guiffrida. “However, this is probably one of the components that may contribute to schizophrenia. It is not the cause of schizophrenia. And so I don’t think we have yet enough evidence to say that cannabis causes schizophrenia, and this is particularly true for the healthy population.”

References

1. George A. Hirliman Productions. Reefer Madness [film]. Director, Louis Gasnier. 1936.
2. Lee M. Smoke Signals: A Social History of Marijuana—Medical, Recreational, and Scientific. New York, NY: Scribner; 2012.
3. Collingwood J. Cannabis may cause schizophrenia-like brain changes. PsychCentral. Available at: http://psychcentral.com/lib/2012/cannabis-may-cause-schizophrenia-like-brain-changes/. Accessed March 18, 2013.
4. Schwarz A. Drowned in a stream of prescriptions. New York Times. February 2, 2013. Available at: www.nytimes.com/2013/02/03/us/concerns-about-adhd-practices-and-amphetamine-addiction.html?pagewanted=all&_r=0. Accessed March 18, 2013.
5. Onaivi E, Sugiura T, Marzo V, eds. Endocannabinoids: The Brain and Body’s Marijuana and Beyond. Boca Raton, FL: CRC Press; 2005.
6. Sulak D. Introduction to the endocannabinoid system. NORML website. Available at: http://norml.org/library/item/introduction-to-the-endocannabinoid-system. Accessed April 2, 2013.
7. Bengston M. Schizophrenia and psychosis. PsychCentral. Reviewed June 17, 2012. Available at: http://psychcentral.com/disorders/schizophrenia/. Accessed March 18, 2013.
8. What causes schizophrenia? National Institute of Mental Health website. Available at: www.nimh.nih.gov/health/publications/schizophrenia/what-causes-schizophrenia.shtml. Accessed March 18, 2013.
9. Castle DJ. Cannabis and psychosis: what causes what? F1000 Med Rep. 2013;5:1.
10. Cannabis/Marijuana (∆ 9 -Tetrahydrocannabinol, THC). Drugs and Human Performance Fact Sheets. National Highway Traffic Safety Administration website. Available at: www.nhtsa.gov/People/injury/research/job185drugs/cannabis.htm. Accessed April 2, 2013.
11. Malchow B, Hasan A, Fusar-Poli P, Schmitt A, Falkai P, Wobrock T. Cannabis abuse and brain morphology in schizophrenia: a review of the available evidence. Eur Arch Psychiatry Clin Neurosci. 2013;263(1):3-13.
12. Andreasson S, Allebeck P, Engstrom A, Rydberg U. Cannabis and schizophrenia: a longitudinal study of Swedish conscripts. Lancet. 1987;2(8574):1483-1486.
13. Sewell RA, Skosnik PD, Garcia-Sosa I, Ranganathan M, D’Souza DC. Behavioral, cognitive and psychophysiological effects of cannabinoids: relevance to psychosis and schizophrenia. Revista Brasilerira de Psiquiatria. 2010;32:Suppl 1.
14. D’Souza D, Sewell RA, Ranganathan M. Cannabis and psychosis/schizophrenia: human studies. Eur Arch Psychiatry Clin Neurosci. 2009;259(7):413-431.
15. Müller-Vahl KR, Emrich HM. Cannabis and schizophrenia: towards a cannabinoid hypothesis of schizophrenia. Expert Rev Neurother. 2008 Jul;8(7):1037-1048.
16. Di Forti, Iyegbe C, Sallis H, et al. Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biological Psychiatry. 2010;72(10):811-816.
17. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012 Mar 20;2:e94.



The Biochemical System Controlling the Effects of Cannabis: 

In every human there are complex biological systems working to keep physiological functions in order. When these biochemical systems are functioning optimally, they maintain optimal mood, help maintain appropriate levels of immunity, proper digestion, regular sleep, brain function, etc. The housekeeping properties of these systems have an important role in modulating health and disease. One of these systems is the endocannabinoid system (ECS). The system is built out of G protein-coupled receptors called (CB1 and CB2 “receptors”) and the “endocannabinoids” that bind to them. The ECS maintains normal cerebral and physiological function.1

Human clinical trials and animal studies show that stimulating this biochemical system can have both highly beneficial health effects and few negative side effects.2,3 Basic research experiments with genetically modified mice, which are created without CB1 or CB2 receptors, have shown that without this biochemical system, the animals (and presumably, humans) would probably die at birth.4-7 Studies in both humans and animals demonstrate that blocking this biochemical system can result in dreadful consequences, including, but not limited to, depression, stress, nausea, vomiting, diarrhea, anxiety, and even increased tendency for suicide.8-11 The only antagonist drug ever to be marketed to humans that blocked the cannabinoid receptors — Acomplia® (rimonabant; Sanofi-Aventis; Paris, France) — was quickly withdrawn from the market due to its negative health consequences.12

How Medical Cannabis Works

Cannabis (Cannabis sativa, Cannabaceae; common name marijuana, among others) has been used for centuries to treat neurological and neurodegenerative disorders such as epilepsy or spastic disorders. The medieval Arab writer Ibn al-Badri documented the use of hashish or a cannabis concentrate to cure a neurodegenerative disorder (probably epilepsy) afflicting the son of the chamberlain of the Caliphate Council in Baghdad.2 Centuries later, Western physicians, including W.B. O’Shaughnessy and other British neurologists of the 19th century, confirmed the benefits of cannabis concentrates (hashish, hash oil, and tinctures) in the treatment of spasticity, convulsions, and related neurodegenerative disorders.13,14 However, it was not until the discovery of the ECS in 1994 that scientists could explain these observations.
The progression of diseases such as multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease), and other neurodegenerative diseases is affected by neuroinflammation and neurodegeneration (brain cell death).15 Cannabis can have a positive effect on these and related disorders in a number of ways. Tetrahydrocannabinol (THC) from the cannabis plant stimulates CB2 receptors, which decreases neuroinflammation by inhibiting the movement, growth, and activity of immune cells. Basically, the stimulation of the ECS by constituents from the cannabis plant results in decreasing the migration and activation of the immune cells that maintain the environment of neurodegenerative disorders, thereby disrupting the signals that sustain inflammation and cell death.16

Another important aspect of neurodegenerative disorders is the irreversible death of neurons leading to progressive dysfunction. Excessive glutamate receptor activity is known to cause neuronal cell death by damaging cells and creating reactive oxygen species (ROS). The CB1 receptors found in the brain have a direct effect on neurons by limiting glutamate release when stimulated at the presynaptic nerve terminals. (Glutamate is a key neurotransmitter, derived from glutamic acid, an amino acid.) Cannabis compounds are also potent antioxidants, reducing oxidative damage and blocking the activities of inflammatory signaling molecules like TNFα (tumor necrosis factor-alpha). Stimulation of the ECS also has pro-survival effects on brain cells.17,18

At the present time, the evidence of the ECS as an appropriate target to treat neurodegenerative and other diseases does not come solely from the limited approved studies on marijuana from the U.S. National Institute on Drug Abuse (NIDA). The information comes from a wealth of new information about stimulating this biological system and the mechanisms explaining the central role of this system in health. The ECS is inherent to proper human functioning; in fact, every physiological system that has ever been studied is positively modulated by it.19 Recent reports suggest that cannabis, cannabis extracts, and mixtures of the plant’s active ingredients are useful for treating epilepsy (i.e., Dravet syndrome), traumatic brain injury, cancers, post-traumatic stress disorder (PTSD), human immunodeficiency virus (HIV), wasting, glaucoma, Crohn’s disease, multiple sclerosis, autism, and other diseases and symptoms.20

Since the isolation and structure elucidation of the main ingredient found in cannabis (THC) in the 1960s, several research groups have explored THC and other cannabinoids for therapeutic effects (e.g., anti-epileptic effects, palliative care) in adults and children.21-23 Also since the elucidation of THC’s structure, over 100 other plant cannabinoids have been documented.24-29 The efficacy of THC can be increased with other phytocannabinoids and plant compounds such as cannabidiol (CBD) and various terpenes, respectively.30-34 THC and CBD are both psychoactive but have very different therapeutic mechanisms of action; THC directly stimulates CB1 and CB2 receptors, while CBD appears to interact with receptors of other important neurotransmitters, serotonin and adenosine.33,35 When the distinct mechanisms of THC and CBD are combined, they can trigger an enhancement of activity. For example, experimentally derived combinations of THC and CBD have been documented to synergistically inhibit cancer cell growth in Petri dish experiments on human grade IV glioma cells by increasing activity in a specific molecular pathway when co-applied.34 When a 1:1 combination is used clinically, it proves effective at treating multiple sclerosis without causing intoxication.36-38

In mammals, the ECS is modulated during disease or injury; for example, CB2 receptor density is increased during inflammation or bone injury.39-42 This upregulation or modulation during disease or injury is associated with increases in both levels of endocannabinoids and the expression of the cannabinoid receptors on the cell membrane.1,43,44 Modulation of the ECS may be an attempt by the body to reduce or abolish unwanted effects or to slow the progression of various disorders. There is evidence supporting a modulation of this biochemical system in a number of disease models.2 Additionally, a number of genetic mutations and polymorphisms of the ECS (e.g., CB1 and/or CB2 receptor mutations) in the human genome are associated with diseases in human populations, such as anorexia, bulimia, migraines, chronic pain, gastrointestinal disorders, mental disorders, alcoholism, and other treatment-resistant conditions.45-50 A mutation or fault in the ECS that may underlie a disease or condition has been coined as the Clinical Endocannabinoid Deficiency Syndrome.47

Conclusion

In addition to anecdotal reports and more than 30,000 basic scientific studies with cannabinoids, there are also over 100 published clinical studies that have looked at the effect of a variety of cannabis-based medicines (including inhaled whole-plant material, oral THC capsules, and cannabis extracts) on the treatment of a wide range of disorders.3,36,51
The data generated from these clinical trials suggest that cannabis and its various preparations interact with the ECS to result in improvements in spasticity, muscle spasms, pain, sleep quality, tremors, appetite, and the patient’s general condition.3,51 Most of these clinical trials have focused on either THC as the primary therapeutic ingredient or a 1:1 ratio of THC to CBD, but there is a paucity of clinical studies examining pure CBD for a therapeutic outcome.
Animal and human research also demonstrates a potential for synergizing or enhancing certain therapeutic effects when cannabinoids and/or terpenes are applied in an appropriate combination. The therapeutic rationale for combining THC and CBD, and other cannabis plant components in fixed ratios, can result in a decrease in unwanted side effects and an enhancement of therapeutic benefits.33,37

Jahan Marcu, PhD, is currently the senior scientist at Americans for Safe Access and chief auditor for Patient Focused Certification, an oversight program that audits cannabis operations. Dr. Marcu is the director of research and development at Green Standard Diagnostics, Inc. He is also on the board of directors of the International Association for Cannabinoid Medicines. He received his PhD for significant contributions to the study of the structure and function of the cannabinoid receptors. He is also an author of the American Herbal Pharmacopoeia's cannabis monograph. Dr. Marcu is a recipient of the Billy Martin research award from the International Cannabinoid Research Society.

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