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ENDOGENOUS CANNABINOIDS, anandamide (AEA) and 2-arachidonoylglycerol SIGNALING PATHWAYS COUPLED TO THE CB1 CANNABINOID RECEPTOR
(2-AG), function as neurotransmitters. Synthetic cannabinoids have also been produced are outlined above. The CB1 cannabinoid receptor signals to a number of different
as pharmaceutical agents. Cannabinoids exert their effects by binding to specific Gi/o cellular pathways. These include (i) inhibition of the adenylyl cyclase (AC)-cyclic AMP-
protein-coupled receptors. protein kinase A (PKA) pathway; (ii) modulation of ion conductances, by inhibition of
has only been identified within the past creases neurotransmitter release. voltage-sensitive Ca2+ channels (VSCC) and activation of G protein-coupled inwardly-
rectifying K+ channels (GIRK); and (iii) activation of mitogen-activated protein kinase
20 years during which time an explosion The function of the endogenous can-
(MAPK) cascades. Other less established cannabinoid receptor effectors and the cross-
of knowledge has occurred.15-18 In the nabinoid system in the body is becom-
talk among the different pathways have been omitted for simplification.
mid-1980’s, researchers developed a ing more appreciated through advances
potent cannabinoid agonist to be used in in cannabinoid pharmacology. The iden- ity.13-20 Peak plasma concentrations oc- Canada in 1982, but only recently be-
research investigations. tification of the cannabinoid receptors cur after 1-6 hours and remain elevated came available in the US. Dronabinol
In 1986 it was discovered that can- has led to a host of agonists and antago- with a terminal half-life of 20-30 hours. was approved as an antiemetic to be used
nabinoids inhibited the accumulation of nists being synthesized. Utilizing these When consumed orally, delta-9-THC is in cancer chemotherapy in the US in
cyclic adenosine monophosphate tools, investigators are discovering that initially metabolized in the liver to 11- 1986.
(cAMP), suggesting the presence of a the system is likely to be important in OH-THC, also a potent psychoactive Numerous meta-analyses confirm the
receptor-mediated mechanism. By at- the modulation of pain and appetite, metabolite. utility of these THC-related agents in the
taching a radiolabel to the synthetic can- suckling in the newborn and the com- On the other hand, when smoked, the treatment of chemotherapy-induced nau-
nabinoid, the first cannabinoid receptor, plexities of memory. (Michael Pollan in cannabinoids are rapidly absorbed into sea and vomiting. Tramer et al. con-
CB1, was pharmacologically identified “The Botany of Desire” gives a particu- the bloodstream with a peak concentra- ducted a systematic review of 30 ran-
in the brain in 1988. larly entertaining description of the natu- tion in 2-10 minutes which rapidly de- domized comparisons of cannabis with
The CB1 receptor is coupled to Gi/o ral function of endocannabinoids in clines over the next 30 minutes. Smok- placebo or antiemetics from which di-
proteins. Its engagement inhibits memory.19) ing thus achieves a higher peak concen- chotomous data on efficacy and harm
adenylyl cyclase and voltage-gated cal- In addition to being utilized to learn tration with a shorter duration of effect. were available. 25 Oral nabilone, oral
cium channels, and stimulates rectifying more about the natural function of the Less of the psychoactive 11-OH-THC dronabinol, and intramuscular levonan-
potassium conductances and mitogen- endocannabinoid system, a number of metabolite is formed. tradol were tested. No smoked cannabis
activated protein kinase activity. these cannabinoid receptor agonists and Cannabinoids can interact with the trials were included. Thirteen hundred
By 1990, investigators had cloned the antagonists are being developed as po- hepatic cytochrome P450 enzyme sys- sixty-six patients were involved in the
CB1 receptor, identified its DNA se- tential pharmaceutical therapies. In the tem.21-22 Cannabidiol, for example, can systematic review. Cannabinoids were
quence and mapped its location in the meantime, dronabinol, nabilone inactivate CYP 3A4. After repeated found to be significantly more effective
brain, with the largest concentration be- (Cesamet(r), a synthetic cannabinoid) doses, some of the cannabinoids may antiemetics than prochlorperazine,
ing in the basal ganglia, cerebellum, hip- and cannabis are the currently available induce P450 isoforms. The effects are metoclopramide, chlorpromazine,
pocampus and cerebral cortex. cannabinoid therapies in the United predominantly related to the CYP1A2, thiethylperazine, haloperidol, domperi-
States. Levonantradol (Nantrodolum (r)) CYP2C and CYP3A isoforms. The po- done, or alizapride.
In 1993 a second cannab- is a synthetic cannabinoid administered tential for a cannabinoid interaction with In this analysis, the number needed
intramuscularly, not used as much clini- cytochrome P450 and, hence, possibly to treat (NNT) for complete control of
inoid receptor, CB2, was iden- cally since the oral agents became avail- metabolism of chemotherapeutic agents nausea was 6; the NNT for complete
tified outside the brain. able. has lead to a small amount of data on control of vomiting was 8. Cannabinoids
A whole cannabis extract (Sativex(r)) the possibility of botanical:drug interac- were not more effective in patients re-
In 1993 a second cannabinoid recep- delivered as an oro-mucosal spray with tions. ceiving very low or very high emetogen-
tor, CB2, was identified outside the varying combinations of THC and can- In one study, 24 cancer patients were ic chemotherapy. In crossover trials, pa-
brain. Originally detected in macroph- nabidiol is available in Canada and un- treated with intravenous irinotecan (600 tients preferred cannabinoids for future
ages and the marginal zone of the spleen, dergoing late phase testing in the US and mg, n = 12) or docetaxel (180 mg, n = chemotherapy cycles.
the highest concentration of CB2 recep- other countries. 12), followed three weeks later by the Tramer identified some “potentially
tors is located on the B lymphocytes and Through the receptors described same drugs concomitant with medicinal beneficial side effects” that occurred
natural killer cells, suggesting a possible above, cannabis delivered by way of in- cannabis taken as an herbal tea for 15 more often with cannabinoids, includ-
role in immunity. halation or orally can produce a host of consecutive days, starting 12 days be- ing the “high,” sedation or drowsiness,
The existence of cannabinoid recep- biologic effects. The Institute of Medi- fore the second treatment.23 The care- and euphoria. Less desirable side effects
tors has subsequently been demonstrated cine report makes the following general fully conducted pharmacokinetic analy- that occurred more frequently with can-
in animal species all the way down to conclusions about the biology of can- ses showed that cannabis administration nabinoids included dizziness, dysphoria
invertebrates. Are these receptors present nabis and cannabinoids:2 did not significantly influence exposure or depression, hallucinations, paranoia
in the body solely to complex with in- • Cannabinoids likely have a natural to and clearance of irinotecan or and hypotension.
gested phytocannabinoids? role in pain modulation, control of move- docetaxel. A later analysis by Ben Amar reported
The answer came in 1992 with the ment, and memory. that 15 controlled studies compared
identification of a brain constituent that • The natural role of cannabinoids in SYMPTOM MANAGEMENT nabilone to placebo or available anti-
binds to the cannabinoid receptor. immune systems is likely multifaceted emetic drugs.26 In 600 patients with a va-
Named “anandamide” from the Sanskrit and remains unclear. Antiemetic effect riety of malignant diagnoses, nabilone
word for bliss, the first endocannabinoid • The brain develops tolerance to can- The nausea and vomiting related to was found to be superior to prochlorpera-
had been discovered. Subsequently 2- nabinoids. cancer chemotherapy continues to be a zine, domperidone and alizapride, with
arachidonoylglycerol (2-AG) has also • Animal research has demonstrated significant clinical problem even in light patients clearly favoring the nabilone for
been confirmed as part of the body’s en- the potential for dependence, but this po- of the newer agents that have been added continuous use.
dogenous cannabinoid system. tential is observed under a narrower to our armamentarium since the 1970s Nabilone has also been shown to be
These endocanabinoids function as range of conditions than with benzodi- and 1980s when clinical trials of cannab- moderately effective in managing the
neurotransmitters. As the ligands for the azepines, opiates, cocaine, or nicotine. inoids were first conducted.24 nausea and vomiting associated with ra-
7-transmembrane domain cannabinoid • Withdrawal symptoms can be ob- In those days, phenothiazines and diation therapy and anesthesia after ab-
receptors, binding of the endocan- served in aminals but appear mild com- metoclopropramide were the main anti- dominal surgery.25-28 In the same meta-
nabinoid leads to G-protein activation pared with those of withdrawal from emetic agents used. Dronabinol (syn- analysis, Ben Amar reports that in 14
and the cascade of events transpires re- opiates of benzodiazepines. thetic THC) and nabilone (a synthetic studies of dronabinol involving 681 pa-
sulting in the opening of potassium chan- Pharmacology of Cannabis analog of THC) were both tested as novel tients, the cannabinoid antiemetic effect
nels which decreases cell firing and the When taken by mouth, there is a low oral agents in a number of controlled was equivalent or significantly greater
closure of calcium channels which de- (6-20%) and variable oral bioavailabil- clinical trials. Nabilone was approved in continued on next page
O’Shaughnessy’s • Summer 2009 —9—
smoked or inhaled cannabis is the sub- sion. Many providers would frown upon tory and physical examination should be On a more positive note, in a unani-
lingual preparation of whole plant ex- the use of a relatively benign smoked documented. The provider should ascer- mous vote, the Assembly of the Ameri-
tract.50, 61, 92 Sativex(r) was first approved psychotropic agent while freely writing tain that medical marijuana use is not can Psychiatric Association recently ap-
as a prescription medication in Canada prescriptions for pharmaceutical agents masking an acute or treatable progres- proved a strongly worded statement sup-
in 2005 for symptomatic relief of neu- with significantly greater cost, potential sive condition. A treatment plan should porting legal protection for patients us-
ropathic pain in multiple sclerosis and for addiction or abuse, and more nega- be formulated. A patient need not have ing medical marijuana with their doctor’s
subsequently as adjunctive therapy for tive societal impact overall. failed all standard interventions before recommendation.95 The APA action pa-
patients with cancer pain on other anal- The Medical Board of California in marijuana can be recommended. The per reiterates that “the threat of arrest by
gesic medications. The cannabis-based their July 2004 Action Report provides physician may have little guidelines in federal agents, however, still exists. Se-
medication is available in Spain, under- a model for how states with medical actually recommending a concrete dose riously ill patients living in these states
going regulatory review by the European marijuana legislation should advise phy- for the patient to use.94 with medical marijuana recommenda-
Union and is being evaluated in a Phase sicians.93 As there are so many variables asso- tions from their doctors should not be
II/III clinical trial in patients with can- “The intent of the board at this time ciated with effect, the physician and pa- subjected to the threat of punitive fed-
cer-related pain in the U.S.. is to reassure physicians that if they use tient should develop an individual self- eral prosecution for merely attempting
the same proper care in recommending titration dosing paradigm that allows the to alleviate the chronic pain, side effects,
GUIDELINES FOR PROVIDERS medical marijuana to their patients as patient to achieve the maximum benefit or symptoms associated with their con-
they would any other medication or treat- with tolerable side effects. Discussion of ditions or resulting from their overall
The Institute of Medicine is aware ment, their activity will be viewed by the potential side effects and obtaining ver- treatment regimens. ... [We] support pro-
that the development and acceptance of Medical Board just as any other appro- bal informed consent are desirable. Pe- tection for patients and physicians par-
smokeless marijuana delivery systems priate medical intervention.... If physi- riodic review of the treatment efficacy ticipating in state-approved medical
“may take years; in the meantime there cians use the same care in recommend- should be documented. Consultation marijuana programs.”
are patients with debilitating symptoms ing medical marijuana to patients as they should be obtained when necessary. It behooves the integrative oncologist
for whom smoked marijuana may pro- would recommending or approving any Proper record keeping that supports the to follow closely future studies of can-
vide relief.” So what is a provider to do? other medication or prescription drug decision to recommend the use of medi- nabinoids and cancer. It is likely that
Patients with cancer have a number treatment, they have nothing to fear from cal marijuana is advised. these agents will not only prove to be
of symptoms that may be responsive to the Medical Board.” Despite all these guidelines, the Medi- useful in symptom management and pal-
cannabinoid therapies. As enumerated, The Board recommends following the cal Board of California still reminds phy- liative care, but as anti-tumor agents as
these include nausea, vomiting, anor- accepted standards that would be used sicians that making a written recommen- well.
exia, pain, insomnia, anxiety and depres- in recommending any medication. A his- dation “could trigger a federal action.”
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—14— O’Shaughnessy’s • Summer 2009
to defend themselves– the integrity of He deemed it “completely implausible shown to promote apoptosis (damaged
the investigators... They actually pub- that smokers of only 365 joints of mari- cells die instead of reproducing) and to “no matter how much mari-
lished another paper in which they mim- juana have a risk for developing lung counter angiogenesis (the process by juana was smoked, the rate of
icked the design that we used for look- cancer similar to that of smokers of 7,000 which blood vessels are formed —a re-
ing at lung function.” tobacco cigarettes... Their small sample quirement of tumor growth). Other anti- decline was similar to nor-
Tashkin spoke from the stage of an size led to vastly inflated estimates... oxidants in cannabis may also be in- mal.” —Tashkin re COPD
airy redwood chapel designed by Julia They had said ‘it’s ideal to do the study volved in countering malignancy, said
Morgan. He is pink-cheeked, 70ish, in New Zealand because we have a much Tashkin. sured lung function of various cohorts
wears wire-rimmed spectacles. “For to- higher prevalence of marijuana smok- over eight years and found that tobacco-
bacco they found what you’d expect: a ing.’ But 88 percent of their controls had COPD only smokers had an accelerated rate of
higher risk for lung cancer and a clear never smoked marijuana, whereas 36% Much of Tashkin’s talk was devoted decline, but marijuana smokers –even if
dose-response relationship. A 24-fold of our controls (in Los Angeles) had to Chronic Obstructive Pulmonary Dis- they smoked tobacco as well– experi-
increase in the people who smoked the never smoked marijuana. Why did so ease, another condition prevalent among enced the same rate of decline as non-
most... What about marijuana? If they few of the controls smoke marijuana? tobacco smokers. Chronic bronchitis and smokers.
smoked a small or moderate amount Something fishy about that!” emphysema are two forms of COPD, “The more tobacco smoked, the
there was no increased risk, in fact Strong words for a UCLA School of which is the fourth-leading cause of greater the rate of decline,” said Tashkin.
slightly less than one. But if they were Medicine professor! death in the United States. Air pollution “In contrast, no matter how much mari-
in the upper third of the group, then their As to the highly promising implica- and tobacco smoke are known culprits. juana was smoked, the rate of decline
risk was six-fold... A rather surprising tion of his own study –that something in Inhaled pathogens cause an inflamma- was similar to normal.”
finding, and one has to be cautious about marijuana stops damaged cells from be- tory response, resulting in diminished Tashkin concluded that his and other
interpreting the results because of the coming malignant— Tashkin noted that lung function. COPD patients have in- studies “do not support the concept that
very small number of cases —fourteen— an anti-proliferative effect of THC has creasing difficulty clearing the airways regular smoking of marijuana leads to
and controls —four.” been observed in cell-culture systems as they get older. COPD.”
Tashkin said the New Zealanders and animal models of brain, breast, pros- Tashkin and colleagues at UCLA con- Breathe easier, everybody.
employed “statistical sleight of hand.” tate, and lung cancer. THC has been ducted a major study in which they mea-
A Sociologist Walks Into a Cannabis Club... having consistency in a life that was oth- them pay utility bills, and two patients forming relationships with other patients
At the 2008 Patients Out of Time Con-
ference sociologist Amanda Reiman de- erwise unpredictable; knowing that a visi- were extremely excited to relate their sto- for friendship and support. Participants
scribed a forthcoming study of the Ber- tor would come every Wednesday pro- ries of how BPG gave them Christmas mentioned that exposure to other patients
keley Patients Group. The BPG, founded vided this patient with comfort. trees when they could not afford them and with a range of ailments and circum-
in 1999, is one of the few dispensaries One patient mentioned that in addition how much that gesture meant to them. stances are therapeutic.
that allow medicating on-site —an ap- to medical help gained from the cannabis, Patients speak about the staff at BPG Participants who received medicine
proach Reiman calls “the social model.” the weekly hospice visits served as peer as if they are family and express such through Helping Hands reported that they
Reiman gave a written survey to 350 pa- counseling and allowed her time to vent gratitude for the personal interest that the learned of the program through word of
tients as they arrived at BPG, interviewed about her illness and the stresses of be- staff has taken in them, adding to their mouth and they felt that the criteria should
five members who received hospice de- ing ill. feelings of importance and self-worth. be clearer. Participants reported that most
livery services, and conducted a focus Patients who are also part of the low- Participants reported that they do not of their other medicines were covered
group with six participants. Excerpts of income “Helping Hands” program men- purchase cannabis every time they visit through Medi-Cal or Medicaid.
the study follow. tioned the huge financial burden that has BPG and stated that there are many times Suggestions
Every patient surveyed agreed that been lifted for them by having access to they visit just to receive services or so- Participants had several suggestions
there are benefits from BPG services be- high-grade medicine. cialize with other patients. for how BPG could be more service-ori-
yond the medication. All patients men- Other patients mentioned the help that Participants reported using a range of ented and patient-focused:
tioned the social support that they got they got from medical cannabis to deal services at BPG including acupuncture, 1. There should be a designated pa-
from visiting with other patients and re- with pain, eating and sleep issues. massage, renter’s assistance classes, and tient liaison that patients know they can
ceiving visitors through the hospice pro- One patient mentioned that, due to recreation activities such as open mic. go to with complaints, questions, sugges-
gram. Patients also mentioned the ben- periods of wasting, they would not be Access to free services allows patients tions. Participants felt that they did not
efits of having a community room where here if it were not for their medicine and to try out an alternative therapy to see if know who to approach about problems
they could relax and medicate in a safe BPG. they get relief from it before seeking it or suggestions. Perhaps a board could be
environment and speak with other pa- All patients mentioned the social sup- out as part of their permanent health care formed of staff and patients to discuss
tients. port that they get from other patients and regime. Many participants stated that the activities, services and issues related to
the staff at the dispensary. One patient services at BPG act as a bridge between BPG operations.
Most patients stressed the spoke about how services help her man- the times that they can receive health ser- 2. More arts and crafts.
age the stress of the struggle to stay vices elsewhere, either due to the cost of 3. Post the calendar where people can
importance of regular social healthy. She talked about the safe space the service or the cost of transportation. see it while they wait in line.
contact as being extremely ben- created at BPG where patients can open Patients report that losing BPG ser- 4. A way to inform folks when time is
eficial to their health. up and be vulnerable, which might be vices would disrupt their entire health almost up. Participants felt that some-
hard for some who must maintain a tough care treatment plan. For example, one times they were rushed out and that some-
exterior to get through their day. She also patient receives acupuncture both at BPG times a patient’s appearance affected how
Also mentioned were BPG programs
mentioned that coming to BPG helps get and at a clinic where she receives a more they were treated when their time was up.
such as acupressure and the different
patients out of the house and helps to intensive and longer treatment. She re- 5. Not enough chairs in the commu-
classes and speakers available to patients.
counteract the isolation that can come ported that she cannot afford these inten- nity room.
Most patients stressed the importance of
along with experiencing a chronic or ter- sive treatments regularly, so she uses the 6. There should be a designated
regular social contact as being extremely
minal illness. BPG treatments to supplement the more counter person for those with lots of ques-
beneficial to their health.
Another patient mentioned that hear- costly ones, as to not interrupt her treat- tions to speed up the line for those who
One patient described the benefits of
ing about other patients’ problems helps ment schedule. already know what they want.
him feel like he is not alone and that oth- Another participant reported that she
Amanda Reiman, MSW PhD, is an
ers are going through the same thing, lives near BPG and cannot afford the
academic coordinator/lecturer at the UC
which can be of great comfort. transportation to get to her more inten-
Berkeley School of Social Welfare.
One patient mentioned that BPG used sive treatments on a regular basis, so
to have a daily organic fruit and vegetable again, BPG is used to supplement these
delivery service that had to cease opera- treatments.
tions due to financial reasons. Other pa- Participants also reported getting peer
tients mentioned that BPG has helped support from other patients at BPG and
PATIENTS OUT OF TIME, ASILOMAR 2008: Al Byrne (who runs a tight meeting), Melanie Dreher, Laura Galli , Juan Sanchez-Ramos, Bill Britt, and MaryLynn Mathre.