Cannabis is More Than THC

Jahan Marcu4/22/2011

Hillig KW. Genetic evidence for speciation in Cannabis (Cannabaceae).

Genetic Resources and Crop Evolution. 2005;52:161-80.

Where did Cannabis come from?

A little more history…

Perfumed Garden,  as translated by Sir Richard Burton, Park St. Press: Rochester, VT, 1992, p. 26.

Shou-zhong, Y. 1997. The divine farmer's materia medica: A translation of the Shen Nong Ben Cao Jing. Boulder, CO: Blue Poppy Press.

Why do we care?• GPCRs – target for pharmacological

intervention - 1 and 2 adrenergic receptor; dopamine D2 antagonist

• Orphan receptors…

• Cannabinoid receptors -

• Amyotrophic Lateral Sclerosis (ALS)

• Cannabinoids ↓ cell proliferation, induce apotosis in human GBM cell lines (J Neurooncol, 2005)

• CBD reduces breast cancer tumor aggressiveness (Mol Cancer Ther, 2007)

• Cannabinoids - neuroprotective role against NMDA excitotoxicity (Mol Pharmacol 2006)

• Reduces progression of atherosclerosis (Nature 2005)• Schizophrenia

Timeline of Cannabis use and scientific advances

Archeological record ofhemp cord

Medical use in China

Religious use in India

Hashish use in the Arab world

Western world learns of

bioactivityMarijuana

Tax Act

Medical use

legalized in

CA and AZ

8000 BC 2000 BC2700 BC 1850’s1000 AD

1984 19881964

1937

1992 19941993 19951990

D9-THCisolated

Adenylyl cyclase

inhibition

Receptor binding

Receptor mapped

CB1

cloned

Anandamidefirst endogenous

ligandCB2

cloned

SR141716Afirst

antagonist

1998

Precipitatedwithdrawal

Receptor knock-out

mice

2005 2006

Sativex licensed

in Canada for MS

Rimonabantin Europe

and Canada for obesity

2-AGisolated

20052001

Retrograde signaling

GPR55

2009

Rimonabantwithdrawn

1996 1999

DronabinolSchedule III

1970

CSA

ECS in bone

Updated from Childers and Breivogel, Drug Alcohol Depend, 1998

Terminology• Variety: can be grown from seed• Cultivar: clonal propagation• Strain: a variety that is propagated for an improved

or unusual characteristic

What do we have in the U.S.?• Confusion: cultivars that are mislabeled as strains• Genetic testing can distinguish between a strain and a

cultivar• Example, Trainwreck, Bubakush, etc are cultivars from a THC

variety or strain • THC tunnel vision; where are the CBC, CBG, THCV, etc

varieties and strains?

+

Geranylphosphate: olivetolate geranyltransferase

CBCA synthaseTHCA synthase CBDA synthase

Biosynthetic Pathways of Pentyl Phytocannabinoids (Russo, after de Meijer et al., 2003)

Terpenoid synthasesEssential oils

OPP

geranyl pyrophosphate

HO

OH

COOH

cannabigerolic acid

O

OH

COOH

cannabichromenenic acid

O

OH

COOH

delta-9-tetrahydrocannabinolic acid

HO

OH

COOH

olivetolic acid (pentyl form)

OH

OH

COOH

cannabidiolic acid

CBD plants; what about CBG,CBC,etc?• Specific genes for CBD and

THC varieties and combos thereof (de Meijer et al.2003).

• CBG plants found in Europe (de Meijer et al.2005).

• Propyl Cannabis Strains (CBGV, THCV,CBDV)

• CBC varieties (Meijer et al.2008)

Meijer et al.2008

Phytocannabinoids: The Future

• CBD: rheumatoid arthritis, inflammatory bowel disease (TNF-α inhibition)

• THCV: metabolic syndrome (CB1 antagonism), epilepsy (CB1-mediated)

• CBDV: epilepsy, bone formation/healing• CBG: prostatic cancer (TRPM8 antagonism),

anxiety (AEA reuptake inhibition?), antibiotic (MRSA et al.)

• β-Caryophyllene: selective CB2 agonistCourtesy of E. Russo.

Plant Wisdom: Synergy and Enhancement

• Anticancer THC & CBD (Marcu et al. 2010)

• Efficiency THC & CBC (De Long et al. 2010)

May modulate activity in several ways:

1)CB receptor interactions2)Increase THC affinity3)Remodel G proteins4)Changes to BBB; alters pharmokinetics

“Generally, inhaled terpenoids cause sedation.”-McPartland

THC and Terpenoids

• Beta-Caryophyllene• Caryophyllene Oxide• Limonene• Linalool• Myrcene• Alpha-humulene• Nerolidol

Major Components

Conclusion

• A THC variety by any other name…• The THC variety of Cannabis is NOT the only type of

Cannabis • Many new varieties of medicine await discovery• Cannabis is not the only source of cannabinoids• Different ingredients can enhance and inhibit

different effects

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