O’Shaughnessy’s • Summer 2010 —29—

By O’Shaughnessy’s News ServiceThe International Cannabinoid Re-

search Society (ICRS) held its 2009meeting last July at a golf-oriented re-sort outside Chicago. Some 250 scien-tists employed mainly by academic in-stitutions and drug companies attended—a slight fall-off from previous years,attributable to the recession (universitiesare limiting their travel allotments) andthe advent of other conferences devotedto the cannabinoids.

There was a corresponding rise in reg-istrants from California’s medical can-nabis movement/industry. UC Berkeleysociologist Amanda Reiman gave a pa-per on cannabis as an alternative to al-cohol, based on a survey taken at theBerkeley Patients Group (BPG). KristenPeskuski presented a poster describingher regimen of raw cannabis as a treat-ment for multiple medical problems.William Courtney, MD, had a poster pro-posing an alternative nomenclature forthe endocannabinoid system.

Courtney was one of six pro-cannabisMDs who attended from California.There was a large BPG contingent, andobservers from the Farmacy, a Los An-geles dispensary chain, which has sinceexpanded to Colorado, and General Hy-droponics, the Sebastopol-based plantnutrient manufacturer. Starr Hergen-rather sold specially designed hempshirts commemorating the conference.

The ICRSThe ICRS was founded in 1991 by a

group of scientists —mainly pharma-cologists— who had been followingeach other’s work in journals and hold-ing rump sessions at various confer-ences. As befit its members’ reliance onfunding from the National Institute onDrug Abuse (NIDA), the first ICRS con-ference was a “satellite meeting” of theCollege on Problems of Drug Depen-dence.

At annual meetings in the years thatfollowed, the discovery of the body’s en-dogenous cannabinoids, anandamide and2-AG, was reported, as were other break-throughs in the emerging field of can-nabinoid science.

The “C” in ICRS originally stood for“Cannabis.” But in 1995, because so fewmembers were actually conducting re-search with the plant, a vote was takento change the C-word to “Cannabinoid,”which refers to chemicals from threesources —extracted from the plant, syn-thesized in the lab, or produced by thebody.

Conferences such as the ICRS meet-

ing enable researchers to report their lat-est findings and to network. Speakershave 15 minutes to summarize their stud-ies and answer questions. Giving a talkat a conference is equivalent to publish-ing a paper in a peer-reviewed journalbecause the content has been evaluated

toms with mice unable to produce FAAH(known as “FAAH knockout mice”).The offspring had fewer Beta amyloiddeposits in the cortex, hippocampus andthalamus, leading the investigators to“postulate that FAAH ablation and sub-sequent enhancement of the endocan-

proach could be used for treating mari-juana addiction. Compounds that inhibitFABPs could produce an effect similarto nicotine patches for smokers or metha-done for opiate replacement. This line ofresearch may also be important for othertypes of addiction, such as chronic alco-hol abuse, which also affects AEA lev-els.”

And to think this bureaucrat is thegreat-daughter of Leon Trotsky!

Add drug targets: MAGLThe enzyme that degrades the body’s

other known cannabinoid, 2-AG, hasbeen identified as Monoacylglycerol Li-pase (MAGL). MAGL offers the drugdevelopers another target in their questto achieve the beneficial effects of can-nabis. Jonathan Z. Long of the ScrippsResearch Institute in La Jolla gave a pa-per on a MAGL inhibitor, JZL184,which raises 2-AG levels eight-fold andreduces pain in mice while having noeffect on anandamide levels.

For some the highlight of ICRS 2009was a report by a Belgian-French teamled by Geoffray Labarl on the X-raystructure of MAGL. The exact, atom-by-atom depiction of the MAGL mol-ecule will facilitate development of moreselective MAGL inhibitors.

Rimonabant: the dream dies hardSanofi-Aventis, the world’s fifth larg-

est pharmaceutical company, has spentmore than a billion Euros trying to mar-ket a drug that blocks (“antagonizes”) theCB1 receptor. Synthesized in the early1990s by pharmacologist Gerard Le Fur,the antagonist compound was called SR(for “Sanofi Recherche”) 1716A, andsold to labs investigating the function ofthe receptor.

It was soon determined that blockingthe CB1 receptor suppresses appetite,among other things, so Sanofi redefinedSR1716A as a therapeutic drug andgeared up to test it for weight-loss andsmoking cessation. They would call it“Rimonabant” in some countries and“Acomplia” in others.

At the ICRS meeting in 2004 Sanofiscientists reported that Rimonabant hadproven safe and effective as a weight-loss drug in clinical trials involving13,000 patients. The company launcheda pre-market campaign notifying doctorsabout a disorder called “Metabolic Syn-drome,” a cluster of risk factors for dia-betes that Sanofi defined as a diseaseunto itself —a disease that could betreated by blocking the CB1 receptor!

In this period Sanofi became the num-ber-one financial backer of the ICRS, andmany cannabinoid researchers got grantsfrom Sanofi and/or the National Instituteon Drug Abuse to study the potential ofantagonist drugs. John McPartland wasone of the few ICRS scientists to openlyquestion the safety of Rimonabant. Jef-frey Hergenrather and other Californiadoctors warned that blocking CB1 wouldalmost certainly result in serious adverseeffects.

“The consequences of interfering withthe cannabinoid receptor system have notbeen evaluated in normal human physi-ology,” Hergenrather was quoted inO’Shaughnessy’s (Fall 2004). He sug-gested that before Sanofi marketedRimonabant, “It would be ethical to de-sign longitudinal studies to assess the

Researchers Share Findings at ICRS Meeting in Chicago—Input From Users of the “Crude Plant” is Increasing

Sanofi Keeps Hope Alive for Cannabinoid Antagonist Drug

continued on next page

KRISTEN P ESKUSKI , who was told shecouldn’t bear children, with baby Zahila.

Larry Brooke of General Hydroponics, a Californiaplant-nutrient maker, with Mahmoud ElSohly, America’sonly legal cannabis grower (under federal law). ElSohlysupervises a garden at the University of Mississippi. Hehas a contract with the National Institute on Drug Abuse.

(isolthizolyidene amides and thiophenebisamide derivatives) that bind only tothe CB2 receptors, which are scant in thebrain and central nervous system (CNS).These compounds “are anticipated tominimize CB1-mediated CNS events,such as sedation, euphoria, and appetitestimulation that have plagued the clini-cal utility and development of non-se-lective cannabinoid agonists for manag-ing pain...”

The approach at several labshas been to target FAAH, theenzyme that breaks downanandamide.

The approach at several labs has beento target FAAH, the enzyme that breaksdown anandamide (a compound made inthe body that activates receptors alsoactivated by plant cannabinoids such asTHC). The less FAAH breaking downanandamide, the more anandamide avail-able to activate the cannabinoid recep-tors. (See “Enzymes and the Endocan-nabinoid System” by Martin Lee,O’Shaughnessy’s Summer 2009). It ishoped that FAAH inhibition will lead topain relief and other desired effects un-accompanied by “euphoria.”

At the Chicago meeting, investigatorsled by Kay Ahn of Pfizer announced thediscovery and characterization of PF-3845, a FAAH inhibitor 10-to-20 timesmore potent than its predecessors. PF-3845 “displays remarkable in vivo se-lectivity for FAAH... and raises brainanandamide levels for up to 24 hours,resulting in profound cannabinoid recep-tor-dependent anti-hyperalgesic effects...PF-3845 has excellent pharmacokineticproperties, including high oralbioavailability.” Maybe Pfizer can mar-ket it someday as “Faah-out.” As in“Faah out your pain with...”

A Spanish group led by LourdesRuiz-Valdepenas (plus the ubiquitousBenjamin Cravatt from Scripps ResearchInstitute) crossed a strain of mice bredto exhibit Alzheimer’s Disease symp-

nabinoid tone may delay the develop-ment of amyloid pathology in the ani-mal model of AD.”

Patricia Reggio and colleagues at theUNC Greensboro are investigating howanandamide, after binding at a CB1 re-ceptor on a cell membrane, gets trans-ported to the FAAH enzyme locatedwithin the cell’s endoplasmic reticulum(ER). Anandamide is lipid (fatty), andslipslides along the membrane onto thereceptor. But the cell’s internal environ-ment is watery —so how doesanandamide proceed to the ER?

The answer, published earlier in 2009by Martin Kaczocha, Sherrye Glaser andDale Deutsch of Stonybrook University,is a “transporter molecule” known as afatty acid binding protein. Reggio’s teamhas “begun to study, in atomic detail, thebinding mechanism of anandamide toFABP.”

Kaczocha et al found that inhibitionof two fatty acid binding proteinsdoubled the time it took for anandamideto break down within the cell. “Inhibit-ing FABPs could potentially raise thelevels of AEA in the brain’s synapses,”says Dale Deutsch. “Naturally occur-ring AEA levels have been shown to curbpain without the negative side effects,such as motor coordination problems, ofmolecules like THC that can also bindthe cannabinoid receptor.”

NIDA reported the finding by theStonybrook team in a press release head-lined “NIDA research could lead to bet-ter treatment for pain and marijuana ad-diction.”

Here’s the factual part: “Researchershad long suspected that endocan-nabinoids needed a specific transporterthat would ferry them to the locationwhere they are broken down. This studysuccessfully identified a couple of pre-viously known fatty acid binding pro-teins (FABPs) as capable of carrying theendocannabinoid anandamide (alsoknown as AEA) from the cell membrane,through the cell interior, to the locationwhere it is destroyed.

Here’s the propaganda from Dr. NoraVolkow, the director of NIDA: “This ap-

and deemed worthy by fel-low scientists (appointedby the conference organiz-ers). A poster is considereda slightly less prestigiousformat, but posters oftendescribe the progress ofsignificant studies.

Drug DevelopmentICRS scientists, in gen-

eral, accept the constraintsof marijuana prohibitionand seek to develop drugsthat deliver the medicalbenefits of the herb with-out any psychoactive ef-fect. They employ round-about strategies.

For example, at theChicago meeting a teamfrom Abbott Laboratoriesdescribed the develop-ment of compounds

—30— O’Shaughnessy’s • Summer 2010

consequences of interfering with the can-nabinoid system.”

On behalf of the Society of CannabisClinicians, Tod Mikuriya, MD, wrote aletter to the U.S. Food and Drug Admin-istration advising against approval. Tothe FDA’s credit, a panel of physicianswould unanimously turn down Sanofi’sapplication 2007. (Their decision was in-fluenced by the recently revealed fataleffects of Vioxx. )

Scientists at the MD Ander-son Cancer Center reportedthat mice treated with Rimona-bant developed potentially can-cerous colorectal polyps at ahigher rate than controls.

In October 2008 the European Medi-cines Agency ordered Sanofi-Aventis tostop selling Rimonabant. (Also thatmonth Merck abruptly canceled fiveclinical trials of a cannabinoid-blockercalled Taranabant.) Data from ongoingclinical trials showed that Rimonabantusers suffer depression, anxiety, insom-nia and aggressive impulses at twice therate of subjects given placebo. In onestudy there were five suicides amongRimonabant users compared to only oneamong subjects on placebo.

Although Rimonabant was ostensiblyremoved from the market because of itsadverse psychiatric effects, one studyconducted by scientists at the MD Ander-son Cancer Center found that the drugcaused mice to develop potentially can-cerous colorectal polyps at a higher ratethan controls. We do not know of otherpublished data on adverse effects involv-ing cancer, seizures, and other illnessesthat the cannabinoid system plays a rolein suppressing.

Given Rimonabant’s withdrawalfrom the market, it was surprising that ablock of four talks at ICRS 2009 wasdevoted to the therapeutic potential ofcannabinoid-receptor blockers for treat-ing metabolic syndrome and cirrhosis ofthe liver. Antagonist drugs of the nextgeneration will be designed, it was ex-plained by George Kunos and others, tonot cross the blood-brain barrier. Thusthey will exert their effects only on re-ceptors in the body’s “periphery,” andthey will not induce suicidal ideation orother changes of mood.

Several speakers mentioned thatRimonabant had been withdrawn due toadverse psychiatric effects —as if theMD Anderson Cancer Center study hadno significance! Drs. Hergenrather andMcPartland shook their heads just asthey had at the ICRS conference in 2004when the antagonist dream was unveiledby scientists funded by Sanofi andNIDA.

No sooner does White Man discoverthe function of the body’s cannabinoidsignaling system than he dreams of howto block it! It’s incredible —but true.

Huntington’s DiseaseMichele Glass and colleagues at the

University of Auckland School of Medi-cal Sciences have been studying cannab-inoid receptors and in a mouse model ofHuntington’s Disease. She noted that theonset of Huntington’s can be delayeddramatically by providing the mousewith an interesting (“enriched”) environ-ment, which raises anandamide levels.

Activation of CB1 receptors may beprotective in HD, but the mechanism isnot yet understood.

A Substitute for Alcohol Amanda Reiman described the study

she conducted between August and Oc-tober 2008 at the Berkeley Patients

into. Some people kind of scowled asthey walked by, as if we didn’t belongthere. But most people were interestedand took some of our literature. A few

been following a line of ‘truth’ thatmaybe isn’t so true. I understand thatcompletely. Because when you rely ongrants for your livelihood and you studysomething for the government you know

ICRS Meeting from previous page

scription drug intake. “Fewer adverseside effects” was the primary reason forchoosing cannabis as an alternative, fol-lowed by “better symptom manage-ment.” Some 12% used cannabis be-cause it has “greater social acceptance”than alcohol. (Today, Berkeley, tomor-row the world!)

“Three hundred and fifty is a largesample compared to typical clinical sam-ples,” Reiman observed in a post-con-ference interview. “I think that’s one rea-son my data was taken seriously.”

Reiman helped staff the BPG table.“There was a really wide range of reac-tions to us,” she reported. “We had EdRosenthal’s Big Book of Buds right thereon the table so there was no questionabout the kind of botanicals we were

Group. She surveyed 350patients ages 18 to 81, about2/3 male and White. Of the180 respondents currentlydrinking alcohol, 40% re-ported using cannabis tolimit their drinking; 26%used it as a substitute forhard (illicit) drugs; and65.8% used it to reduce pre-

took it almost in a giddy way,as if it was somethingnaughty.

“Samir Ross from the Uni-versity of Mississippi told methat he really liked my pre-sentation and that he was veryinterested in what I was do-ing. He took a copy of theentire report. He was look-

ing at the Big Book of Buds and asked‘Is this real?’ And Debby [Goldsberry,director of BPG] said, ‘Oh yes, those aredifferent varieties of cannabis that wehave in California.’

“He asked about the THC percent inour strains, and Debby said, ‘Our highgrade could range from 18 to 25 percent.What’s your high grade?’ And he said,‘Eleven to 12 percent.’ He was justblown away. He offered to help us onthe chemistry if we ever needed help.

“The first day at breakfast a youngwoman asked, ‘Why would you use can-nabis as a substitute when cannabis it-self is harmful?’ I got that question froma couple of scientists. And I would ex-plain the idea of harm reduction. Nobodyseemed to be close-minded but they had

“People seemed very open tothinking about things in a dif-ferent way and a little enviousthat we could enroll so manysubjects in our study.”

The Inadvertent Inventor of “Spice”Dr. John W. Huffman

John W. Huffman, a foundingmember of the ICRS who runs a lab atClemson University, is a mild-man-nered pharmacologist who does notuse cannabis medicinally or otherwise.(His drug of choice is alcohol.) Thetalks Huffman gives at ICRS meetingsare far removed from the clinicalrealm. In Chicago, for example, his pa-per was called “Structure-Activity Re-lationships at the CB1 and CBS Re-ceptors for 1-Alkyl-3(1-Napthoyl-4And 8-Halogen Substituted) Indoles.”

But Huffman has become some-thing of a counter-culture hero, thanksto his development in 1995 of a syn-thetic cannabinoid that he dubbedJWH-018. In 2008 some bootleggersconcocted a batch which theysprinkled on various herbs and mar-keted as an intoxicant known as“Spice.” (“K2” and other knock-offsof Spice have since proliferated.)

At the 2009 ICRS meetingHuffman seemed bemused by hisunsought celebrity. He recalled, “Thecompound was made by an under-graduate named Michele Phillips aspart of a program to look at structure-activity relationships in can-nabimimetic indoles. The structurewas finally published in 1997 or 98 ina paper by Jenny Wiley from VirginiaCommonwealth. It was just anothersomewhat potent research tool...

“In early December 2008 I had anemail from a blogger in Germany whoincluded a pdf file of a paper from DieSpiegel. I read enough German that Iwas able to gather that people wereadding our compound to herbs and ithad become ‘Spice Gold.’ People weresmoking it.

“Subsequently I had email from awoman at the University of Colognein their forensic chemistry department,she wanted a copy of the mass spec,which I was able to send her. And ulti-mately I was able to send her a sample. “I have heard from some otherpeople in Germany, including the

lowed to go on or has somebodycracked down?

JWH: I have no idea. I think thewebsite has been taken down.

O’S: Are you entitled to royalties?JWH: No, because we never pat-

ented it. Alex Makryanis patented it buthis patent is not valid because we re-ported the compound at the 1997 ICRSmeeting, and then Jenny published thepaper in ‘98 and Alex’s patent was filedin 2000. If you want to patent some-thing in the U.S., you have one yearafter you publish it to patent it.

O’S: Were any of the emails of spe-cial interest?

JWH: I had one interesting one thatI responded to. It was obviously fromsomebody with a synonym, using a Ya-hoo address. Apparently they werebootlegging it at night at a pharmaceu-tical company somewhere. The Englishwas perfect so I assumed it was the UKor Ireland. They had made a variationof JWH018. It was actually a varia-tion on one of our petyl acetyl indoles.

“We have nothing aboutthe nature of the metabolites.I am sure some of them arecarcinogenic.”

They picked the most po-tent one. And then theystuck the Winthrop-Makryannis side chain onit, and it’s very potent. Ap-parently they’ve done somereal pharmacology with it.These guys are good.

O’S: What’s their goal?To get another psychoactivecompound?

JWH: I think the goal is to get an-other psychoactive compound that isnot illegal. Because Spice is now ille-gal all over Europe...

I have universally told people: “Donot use this stuff. (Whispering) If youwant to get high, use marijuana.”

JOHN W. HUFFMAN

continued on next page

the line because they have to feed theirfamilies and do what they need to do toget by. It’s understandable.

“But overall people seemed veryopen to thinking about things in a dif-ferent way and a little envious that wecould enroll so many subjects in ourstudy.”

Cannabinoids Kill Cancer CellsJahan Marcu personifies the merging

interests of the medical marijuana move-

that you have tophrase things acertain way to getfunded. You haveto toe the line.And I don’t blameanyone for toeing

AMANDA REIMAN

Luftswaffe. They don’t want their pilotsgetting high on Spice Gold and I can’tblame them.

O’Shaughnessy’s: Where did it sur-face first?

JWH: Apparently, it was first in Aus-tria. Then Germany. Then it was declaredillegal in Germany. I also heard fromsomebody in Japan. And of course I haveheard from the DEA —from their sci-ence people, not the enforcement people.They just wanted to confirm the physi-cal properties because some of the stuffthat winds up in the smoked product ispretty impure.

O’S: How do people obtain JWH-018?

JWH: It is sold by a Korean companyas a plant growth stimulant.

O’S: Could it possibly be a plantgrowth stimulant?

JWH: I very much doubt it. But that’sa good excuse. I have seen websiteswhere it’s been advertised. When I firstheard from this German lady, my wifeGoogled JWH018 and there were like26 hits. That was in December. Last timeI googled it was in early May and therewere 26,000. It has certainly become alegendary, infamous compound.

O’S: What effects do people report?JWH: I don’t know. They seem to like

it.O’S: And burning it

doesn’t destroy the potency?JWH: No. It’s a very

simple compound —a two-step synthesis by somebodywho knows what they’re do-ing... The advice that I havegiven all of these people —including the two zillionemails I’ve gotten about howdo I take this stuff— is, ‘You shouldn’t.You’re stupid if you do because we havenothing about the pharmacokinetics, wehave nothing about toxicity, we havenothing about the nature of the metabo-lites. I am sure some of them are carci-nogenic.

O’S: Is the Korean distributor al-

O’Shaughnessy’s • Summer 2010 —31—

ICRS Meeting from previous page

Accutane is one of the deadliest drugsin the aptly named “armamenture” ofWestern medicine. Could a cannabis-based medicine be safer and more effec-tive in treating acne? At the 2009 ICRSmeeting, Tamas Biro gave an intriguingtalk entitled “Cannabidiol as a NovelAnti-Acne Agent? CBD Inhibits LipidSynthesis and induces Cell Death inHuman Sebaceous Gland-DerivedSebocytes.”

Acne involves the overproduction ofsebum, a lipid (oily substance) excretedby the sebaceous glands to create water-proofing of the skin. Conversely, lipidproduction is too low in dry-skin condi-tions such as seborrhea, eczema and itch-ing (which can lead to inflammation). Ithas been learned in recent years that thesebaceous glands and hair follicles(which also produce oil) haveendocannabinoid receptors, as do thesurface keratinocytes.

At his lab at the University ofDebrecen (Hungary) Department ofPhysiology, University of Debrecen,Biro works with a line of cells derivedfrom human sebaceous glands. Apply-ing endocannabinoids to the cells, heobserved, results in the CB2 receptorsdramatically “upregulating” lipid pro-duction. Blocking the endocannabinoidswith an antagonist drug dramaticallysuppresses lipid production. Biro won-dered, “If the endocannabinoids are soimportant for the work of the sebaceousglands, how would phytocannabinoidsaffect that process?”

Biro started with CBD rather thanTHC for several reasons, he explainedin an interview. “CBD is not banned inHungary —there’s no restrictions on itsuse, you can buy it from Sigma and othersources. Because it’s non-psychoactive,if we turn up a potential good drug, itwill be much easier to market withCBD.” Moreover, CBD had been shownby Audra Stinchcomb at the Universityof Kentucky College of Pharmacy topenetrate the skin readily through atransdermal patch.

Biro and colleagues applied CBD tocells that had been treated withanandamide, expecting that CBD wouldfurther stimulate lipid synthesis. “To oursurprise,” he recounted, “Anandamide inthe presence of CBD was unable to pro-

duce a lipid synthesis! CBD does exactlythe opposite of the endocannabinoids. Itdoes not stimulate but inhibits lipid syn-thesis, especially if the lipid synthesiswas previously upregulated, as for ex-ample in acne. It was very surprising,”he reiterated, “that a phytocannabinoidcould prevent the action of theendocannabinoids.”

Biro has been investigating themechanism by which CBD works. Hisdata show that CBD “does not target the‘classical’ CB receptors but rather cer-tain ion channels expressed on thesebocytes. When activated by CBD,these channels open and permit the in-flux of calcium to the cells which, in turn,inhibit lipid synthesis. We are workingto elucidate the exact mechanism.

“Acne can also be considered as an

vehicle should be the easiest possible,”he said. “Think about the psychology ofit. If you’re a teenager you don’t want toput creams on your face, you want a clearsolution.

“There will be no trouble getting vol-unteers for clinical trials. Acne is not alife-threatening disease, but the impair-ment of quality of life is tremendous. Youdo not want to socialize. You close thedoor. It’s your face! And the scars canestablish an extreme cosmetic problem.The current medications are variably ef-fective —topical gels combined withoral antibiotics and even hormone drugsfor severe cases.”

The average US incidence of acne is10%. “Very difficult to say the actualcause,” Biro says. “ They call it a ‘mul-tifactorial’ disease. Genetic background

CBD? He said it had not been studied,but was on his to-do list for 2010.

At the ICRS meeting in Chicago Biromet several other researchers interestedin testing various cannabis-plant com-pounds. “We think CBG [cannabigerol]might have an effect [on lipid produc-tion],” he said. “Once you’ve found thatthere’s something in the plant, why notsee if there’s other things in the plant thatmight be effective?”

CBD, he hastened to add, “is veryefficient —actually, in our model sys-tem, it was much more efficient than theVitamin A derivatives like Accutane. Offurther importance, CBD was univer-sally inhibitive of lipid synthesis. It wasable to inhibit not only the actions ofendocannabinoids but also the effects ofother inflammatory mediators such assteroid hormones that stimulate fat pro-duction in these cells.

“Another important result: we foundthat low concentrations of CBD werevery effective in inhibiting lipid synthe-sis but did not affect the viability of cells.This was also in contrast to the effectsof Vitamin A derivatives which inhibitthe fat production of sebocytes by kill-ing them.”

We asked Biro what happens to thenormal cells surrounding the zit? Hesaid, “We found that at the right non-toxic concentration, CBD doesn’t sup-press basal lipid synthesis in normalcells. Why bother those guys that areokay? It would create dry skin. Dry skinand itching —that’s also impairment ofquality of life. At the right concentrationyou get only the cells that are pathologi-cally increased.”

We also asked about baldness. “Cur-rently, there is no effective treatmentagainst hair loss,” said Biro. “However,as we published before, THC and theendocannabinoid anandamide applied tocultured hair follicles were found to in-hibit hair growth, most probably via theactivation of CB1 in the hair follicle. Ingood accord with these data, a singleanimal study has shown that orally ad-ministered CB1 antagonists acceleratedhair growth in mice. Perhaps somedaya version of Rimonabant can be devel-oped to promote hair growth.”

Cannabidiol as a Treatment for Acne?

ment and the cannabinoid research es-tablishment. While Marcu was doinggraduate work at California PacificMedical Center Research Institute in SanFrancisco, his mentors included re-searchers Sean McAllister and MaryAbood —and he was romantically in-volved with Alex Franco, an organizerfor Americans for Safe Access. Marcuand Franco are now married and livingin Philadelphia, where he is doing re-search in the lab run by Abood (whomoved from CPMC to Temple Univer-sity Medical School.)

Marcu’s poster at the ICRS meeting—which won the highest award givento grad students— was based on researchbegun with McAllister. It showed that acombination of THC and CBD is muchmore efficient at killing cells from an ag-gressive brain cancer, glioblastomamultiforme, than either cannabinoid onits own. Marcu got the idea to test can-nabinoids in combination because theplant itself deploys them in combination,and he entitled his poster “Plant Wisdom:CBD Synergizes with THC to Inhibit

Marcu measured the efficacy of THCand THC acid, CBD and CBD acid, can-nabinol and cannabichrome. Then hestarted testing various combinations —“and that’s when we started seeing sur-prising results,” he recounts. “Doses thatliterally did not kill a statistically sig-nificant amount of cancer cells were sud-denly obliterating everything in the petridish in three days.”

The most efficient combinationturned out to be a 4-to-1 ratio of THC toCBD. Whether that THC-to-CBD ratiois optimal only in the case of one par-ticular cell line, or holds true in treatingother glioblastomas, or other cancers, re-mains to be studied.

Marcu, McAllister et al also deter-mined that cannabinoids in combinationkill cancer cells by a different pathwaythan cannabinoids acting solo. Marcu’sanalogy for the layman: “Instead ofchoking the victim, ‘you hold his armswhile I punch him in the stomach.’”

Individually or in combination, can-nabinoids kill cancer cells by inducingapoptosis —“programmed cell death.”

WILLIAM COURTNEY (LEFT) AND JAHAN MARCU

GBM Proliferation and Survival.”Marcu explains, “Looking at chro-

matograms of plant samples, I noticedthat certain cannabinoid ratios wereshowing up frequently. THC to CBD ina 10-to-1 ratio was very common. So Ithought a 10-to-1 ratio would be moreeffective than either compound alone.Sean McAllister suggested that we startby testing the cannabinoids individually,and that’s what we did —starting withthe precursor compound CBG— to seehow well they killed cancer cells in thepetri dish.”

Cannabinoids in combination induceapoptosis earlier in the cancer cell’s lifecycle —which is good news, given thegoal of preventing metastasis.

The cells go through three phases: ini-tial growth, synthesis of DNA, division.“Cancer cells grow and divide, grow anddivide, and soak up all the nutrientsaround them,” says Marcu. “You wantto inhibit them in the growth phases, ifpossible. And that’s what the combina-tion of cannabinoids does, we found.”

Marcu was outside smoking a ciga-rette when his first prize was announcedat the ICRS awards banquet. “I havesince tried to quit,” he says ruefully.Marcu applauds the work of AntonioLuchini, the grad student whose presen-tation took second place. Luchinishowed that inhibiting FAAH can reducethe cocaine reward response.

And the nicotine reward response?New Hope in the War on Zits

SKIN IN CROSS-SECTION: The sebaceous glands, which have endocannabinoidreceptors, produce sebum that lubricates the skin and hair.

inflammatory disease in which the skinwithin the zit is highly inflamed. Weknow from the literature that CBD hasanti-inflammatory properties but it hadnever been tested on the skin cells. If itreally works as an anti-inflammatory,then we would be getting two birds withone stone.

“Acne is a human-specific disease.We don’t have too much fur. Animalswith fur may not need the oily cover forthe surface of their skin because theydon’t have uncovered skin. No hair —only around the paw and the genitaliaregion, the nose, the very tips... Seba-ceous cells from animals may operatedifferently than human ones. So there isno good animal model for acne.”

Biro applies CBD in a methanol-etha-nol solution. He is considering how bestto formulate it for acne patients. “The

plays a role, hormones —that’s why wesee acne starting with adolescents as theyenter puberty. There can be local inflam-matory factors —some specific patho-gens, the Propionibacteria that can ac-cumulate and cause inflammation...”

Diet? “A fat-rich diet (chocolate is fat-rich) and extremely spicy foods —if theother factors are present. Some say evensmoking can aggravate... Stress is animportant factor. We say not only theeyes but the skin is the mirror of our souland our spirit.” Dermatologists study-ing the interaction of brain and skin, Birosays, “have found real mediators com-ing from the nervous system and actingon the skin cells.”

We asked Biro about the possibleanti-acne effects of THC —does THCstimulate lipid production in the skin,like anandamide, or decrease it, like

Cannabinoids in combina-tion kill cancer cells by a dif-ferent pathway than cannab-inoids acting solo.