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Cannabis
Medical “marijuana” has been around for some time, but since 1970, medicinal
use in the United States was prohibited by the Controlled Substances Act. It
has taken a strong push from multiple forces, but several clinical trials are
underway to test the efficacy in reducing anxiety, spasticity (in multiple
sclerosis), pain, memory loss (in Alzheimer’s), and nausea, as well as increasing
appetite. But smoking marijuana elevates risks of respiratory ailment.
“Sativex” is a newly developed mouth spray that is made from the cannabis leaf
extract. In 2010, Sativex became the first licensed medical marijuana in the
United Kingdom.
Cannabis is the scientific name of the plant often referred to as marijuana. Inside the cells of the
cannabis plant are huge numbers of similarly-shaped molecules called cannabinoids. Many
reputable sources will claim that one cannabinoid, 9-THC or delta-9 tetra-hydro-cannabinol is
THE psychoactive cannabinoid. Since more than 60 cannabinoids have been identified, and
since some are present in Cannabis sativa and not Cannabis indica (and the converse), it is
probably too simple to imagine that other cannabinoids lack mood-altering ability. Many of
these phytocannabinoids (plant made) bind to receptors in our bodies, brain, gut, immune
system, which also bind cannabinoids made by our own bodies – endocannabinoids. The study
of cannabis has grown since its “banning” in 1970. This research intensity could be attributed to
wider acceptance of the medicinal properties of this drug. The implications of cannabis-related
research are wide-ranging. Many feel that to allow for consideration of medicinal properties is
to also give acceptance to the intoxicating effect of cannabis. Any illegal drug carries with it the
baggage of its status.
Objectives
After successfully completing this lesson you will be able:
to understand what cannabis IS, where we find it, how we use it
to understand how cannabis works at the level of the molecule, the neuron, the brain, and behavior.
to be able to relate the properties of cannabis, and receptor locations, to medicinal marijuana.
to consider the power of set/setting and expectation on subjective drug effects.
to be able to weigh risks and benefits of this drug in a knowledgeable way that assists in wise decision
making.
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Before you begin!
Your ideas
Is medical marijuana legal? Careful!
What is the psycho-active ingredient in cannabis?
What are some consequences associated with using high doses of cannabis?
Previously learned material
What are two ways a neuron can become hyperpolarized?
What does the hippocampus do?
For opiates and amphetamines, we make endogenous versions. What are they called
What body system manages inflammation?
If a drug is unable to bind to the brain stem, what symptom will a user NOT have?
Lesson 24: Cannabis
Guiding Questions
1. What are cannabinoids, where are they found, what are some examples
2. What are CB receptors and where are they found (within the body and on a neuron)?
3. How do the localizations of these receptors influence symptoms, side effects, and medical
properties of cannabis? Conversely, what symptoms and side effects are NOT experienced due
to a lack of receptors in brain region(s)?
4. How do neurons regulate neurotransmitter release?
5. Why is the cannabis high so variable from user to user?
6. What are the politics of cannabis clinical trials?
Key Terms
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

Cannabinoid, 9-THC, anandamide, endocannabinoid, phytocannabinoid
CB1 and CB2
Retrograde signal
Activity One: Web Site Review
Please review the Web sites below and watch the associated videos:
1) A BBC-produced video on cannabis offers insight into why cannabis affects us.
Guiding questions
Why study drugs and drug responses in non-human animals?
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Cannabis
Why are sea squirts particularly useful when studying cannabis?
What are cannabinoid receptors, who has them, what purpose do they have?
http://www.youtube.com/watch?v=hpV6licCOMw
2) In the next video, pay attention both to the science and the scientists who describe their discoveries.
Guiding questions:
What is  9-THC and how was it discovered?
Briefly characterize the scientist who discovered  9-THC. How does he compare
to your stereotype image of a laboratory chemist?
Where are cannabis-binding (CB) receptors located?
Briefly characterize the scientist who discovered CB receptors. How does she
compare to your stereotype image of a laboratory biochemist?
What is anandamide? Where is it made and what does it influence (molecularly and
behaviorally?)
http://www.youtube.com/watch?v=NpH9C8-y708&feature=related
3) In last next video, the language after minute 3 becomes excessively technical. Keep in mind whether
endocannabinoids or anatgonists are being discussed as you view graphics after that point.
Guiding questions:
What are endocannabinoids?
What is CB 1? Where is it found?
What is a retrograde signal?
What happens when cannabinoids bind to the CB1 receptor on the PRE synaptic cell?
What are some functions of endocannabinoids?
What is the relationship between cannabinoids and food intake?
http://www.youtube.com/watch?v=qp633lcU9F8&feature=related
Activity Two: What Is Cannabis? Why do we use Cannabis?
What most refer to as marijuana, we will refer to as cannabis. Cannabis is the plant name, its Latin name
(we are Homo sapiens, dogs are Canis familiaris, “weed” is Cannabis sativa – although other species exist
such as Cannabis indica). The origins of the word “marijuana” suggest that this name was affixed to
Cannabis, in part, to assure that the American public would find the drug “foreign” and dangerous.
Cannabis can be obtained in many forms. There are many names under which cannabis is sold. All arise
from the plant Cannabis, a very hardy weed. Like the alkaloid “nicotine” found in tobacco leaves, many
focus their attention on 9-THC, “the” active alkaloid found in cannabis tissues. We will focus in this
ingredient too, but there are at least 60 related compounds in cannabis, and many have the potential to
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be euphoria-inducing and/or medicinal. Some also contend that it is the combination of cannabinoids
that accounts for the cannabis effect – that these individual components act best in combination. The
related cannabinoid molecules found in cannabis are referred to as phyto-cannabinoids (plant made).
The cannabis experience is extremely variable as you will see and similarly variable are the reasons for
using cannabis. Many users want to obtain a euphoric state. Others want to find inner calmness. Others
use cannabis to provide relief, either from emotional or physical ailment.
TEST OF CONTENT
9-THC can be synthesized and provided to patients in pill form. Consider previouslylearned course concepts. How would this pill-form differ from smoked cannabis?
Activity Three: How Is Cannabis Administered? How Much Cannabis is Used?
Cannabis is traditionally smoked (by pipe or rolled cigarette). Cannabis can also be used orally, often
combined with or baked into foods. The dynamics of the cannabis experience will vary depending upon
the method of delivery. It is generally true that eating cannabis slows and dilutes the onset of euphoria.
In some people, eaten cannabis alters the experience qualitatively (different symptoms).
The 9-THC content varies from product to product (portion of the plant used and variety of plant
used). One “hit” (inhalation) comes from burning 1/20th of a gram of cannabis. The 9-THC content in
that mass of cannabis averages at 5%. So if a person takes only one hit, she is consuming only 2.5
milligrams of 9-THC. An initial dose of medicinal Marinol is 2.5 grams. The entire marijuana cigarette
or joint (which also varies) corresponds to approximately 1 gram. So the effective dose of cannabis can
be between 2.5 milligrams and 2 grams (in some situations more, of course). The LETHAL dose of
cannabis is unknown. No human, nor experimental animal, has ever used enough cannabis to die of
overdose. There are no cannabinoid receptors in the brain stem, so this “take a breath” center is
unimpaired by cannabis.
TEST OF CONTENT
Compute the TI of cannabis based on the initial Marinol dose
Activity Four: Bioavailability of Cannabis
Recall from Lesson 9 in unit 2, 9-THC is metabolized by CYP3A11 into 8-THC.
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8-THC is itself psychoactive: some say it has even more activity than its precursor.
Both 9-THC and 8-THC are fat soluble. The half life of 9-THC is 24 hours. Fat soluble drugs are
hard to clear completely. That means they are also easy to detect in drug tests. Traces of the drug
remain in the body for a week or more depending upon the amount used. Typical “cheats” for drug
tests are generally ineffective. For instance, some products cause a would-be cheater to urinate
frequently, increasing drug output. But this cheat dilutes the urine and the fact that the urine is dilute
is detectable and will invalidate a drug test (and implicate the cheater). For a comprehensive news
story on drug test cheating, you might want to read
http://news.healingwell.com/index.php?p=news1&id=617831
TEST OF CONTENT
Some say 8-THC carries most of the intoxicating impact of the drug. If so, what
might explain why a particular person does not notice becoming intoxicated with the same
dose that intoxicates her friend?
She is unable to further metabolize the drug, accumulating 8-THC
She has a diminished ability to convert 9-THC thus 8-THC becomes available at
too slow a rate
Her CYP3A11 is too strong
She has a very high body fat composition
Activity Five: Where Do Cannabinoids Bind? Then What?
9-THC binds to two membrane bound proteins called CB1 and CB2 “CB” stands for cannabinoid
binding. One position of these receptors tells a story we have not yet addressed in this course. Rather
than just being localization to post-synaptic dendrites (or cell bodies), CB1 is also localized on the presynaptic cell.
Binding to the pre-synaptic cell helps it to regulate the release of neurotransmitter. When cannabinoids
bind, neurotransmitter release becomes much harder. Endogenous cannabinoids are released from the
post-synaptic cell and talk back to the pre-synaptic cells – a backward or retrograde signal.
CB receptors also influence a neuron at rest. When bound by cannabinoids, a message is sent to
potassium channels that makes them more leaky. Like opiates, increased potassium flow down its
concentration gradient (out of the cell) causes a neuron to become hyperpolarized and thus harder to
stimulate.
CB1 and CB2 have different distributions. CB2 is very restricted to cells of the immune system. Like a
neuron, immune cells bound by cannabinoids are less active (reduction of inflammation). CB1 receptors
are more wide-spread. They are found on neurons of the cerebrum and hippocampus and cells of the
gastrointestinal track. Neurons are hyperpolarized and therefore inhibited. Binding to gastrointestinal
cells results in stimulation of gut function and reduction of nausea. The gut is the only organ stimulated
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by cannabinoids, all others are inhibited. In some cases, the synthesis of agonists (and antagonists) that
bind to only one receptor type (CB1 or CB2) have been characterized. These enable researchers to
determine which effects are attributable to each receptor type.
While not direct, CB1-receptor binding leads indirectly to dopamine release in the nucleus accumbens.
As with opiates, hyperpolarization of CB1-bound neurons impairs neurons that inhibit dopamine
release. Inhibiting these inhibitions (double negative) enables dopamine to flow more freely.
TEST OF CONTENT
Rimonabant is a CB1 antagonist. Which symptom might it be helpful in treating?
Depression
Inflammation
Nausea
Traumatic memory formation
Obesity
Activity Six: Why Is Cannabis Addictive?
You will hear two radically different claims about whether or not cannabis is addictive. Those who say
“no” are referring to the fact that upon withdrawal, there are no systemic symptoms to make a user feel
physically sick. Those who say “yes” (cannabis is addictive) are referring to the craving that many users
experience when they stop using the drug. So both parties have a point. Because marijuana induces
dopamine release indirectly, production of euphoria is something a quitting user misses. In rare cases, a
user becomes dependent upon cannabis-stimulated dopamine release. Even less frequently, a user
cannot quit. To read more on this topic, and be directed to further resources, visit this blog briefly.
http://www.psychologytoday.com/blog/the-teenage-mind/201012/is-marijuana-addictive
There is glutamate reinforcement of cannabis use. But some have questioned whether the inhibition of
memory formation undoes the learning promoted by glutamate reinforcement.
Activity Seven: Does Cannabis do ANY Good?
Certainly the notion of medicinal marijuana is not new to you. It’s not new to science either. But upon
passage of the 1970’s controlled substances act, science had to take a break from testing the efficacy of
cannabinoids in health care. The trend since then shows increasing numbers of trials in successive years
since 1970 (see graph). These trials are analyzing some mental health conditions (anxiety, social phobia,
bipolar disorder) as well as physical conditions (spasticity from multiple sclerosis, dementia from
Alzheimer’s disease, pain, nausea, appetite loss, glaucoma, among others). Because medicines in the
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United States are harder to legitimize if they cause people to get high, medical marijuana advocates are
looking at different ways to provide cannabis-based therapies that are less likely to produce euphoria.
These approaches involve a number of alternate approaches:

Synthetic cannabinoids – in particular those specific to CB2 receptor (no binding in brain)
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Cannabinoid “stabilizers” – medicines that inhibit CYP3A11, prolonging the cannabinoid half life
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Oral cannabinoids – reducing respiratory illness and delaying the onset to diminish euphoria
Source of graph data http://www.cannabis-med.org/studies/study.php
All the “presumed” therapeutic uses of cannabinoids can be explained by the localizations of the CB
receptors. Binding to CB1 receptors in the spinal cord accounts for reduction in pain. Similarly, CB1
receptors in the gut account for cannabinoid’s anti-emetic (anti-nausea) effects and elevated appetite.
CB1 receptors throughout the brain, particularly in the limbic system, account for alterations in mood
related to anxiety and mania associated with bipolar disease. CB2 receptors exist on cells of the immune
system. When the immune system works too well, auto-immune disorders such as multiple sclerosis
result. Reducing immune function by CB2-bound cannabinoids helps to moderate the symptoms of
these conditions.
Three medicinal marijuana contradictions might occur to you.

If cannabinoids reduce immune function, why would one use it for HIV patients (who suffer
from immune deficiency)? While one must use it judiciously, the appetite stimulation can help
AIDS suffers who experience rapid loss of weight.
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Cannabis

The use of cannabinoids to treat dementia in Alzheimer’s patients contradicts the notion that
cannabinoids impair memory functions due to suppression of the hippocampus. While this is
true, it is also true that at least part of the reason for memory loss in Alzheimer’s can be
attributed to immune attack of the plaque build-up in the brain. Reducing the immune attack on
brain tissue can minimize cognitive declines.1
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Cannabis leads to bronchodilation – a widening of the bronchial openings which increases
airflow to the lungs. This can improve asthma symptoms. Generally the respiratory risks
associated with cannabis are too great for doctors to recommend cannabis as a treatment of
asthma.
Several studies underway are examining some impacts of very low doses of cannabis – the equivalent of
1/10th - 1/100th of a joint. These studies suggest that small doses can partially reverse atherosclerosis
(plaque build-up in arteries) and can result in increasing the birth of new neurons (neurogenesis) in the
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hippocampus3
Activity Eight: What are Cannabis’ Harmful Side Effects?
On the cardiovascular system, there are two impacts of cannabis. One is vasodilation (this leads to the
common occurrence of blood-shot eyes). Vasodilation can also lead to low blood pressure when
standing. The other is increased heart rate, known as tachycardia. The increased speed of contraction
can be quite steep, nearly doubling the pulse . Together, low blood pressure and increased heart rate,
can be interpreted by the sympathetic nervous system as a stress response, and can lead some users to
experience panic.
On the respiratory system, there are several impacts. From coughing to elevation of respiratory ailment
incidence, cannabis generally does not improve respiratory function. Ingredients within the burning
cannabis plant are also known to be carcinogenic. Correlation between cancer risk and cannabis
smoking have not been forthcoming for two reasons. One is that it is much harder to get people to speak
openly about their cannabis usage. The other is that quite a few cannabis smokers are also tobacco
smokers, complicating the analysis.
More concern has been focused on negative psychological impacts.

Inhibiting learning and neuronal stimulation generally impacts cognitive performance in
cannabis users. These impacts are generally restricted to the time a user is high. But if using is a
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PMID: 15728830
2
PMID: 15815632
3
PMID: 16224541
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frequent event, as it is in some students, then learning is interrupted frequently enough to impact
academic performance. One test of cognitive function (verbal recall) does show differences
between heavy users up to 7 days post use and non-users. But the same test shows no difference
28 days after use.4

Some describe an “amotivational syndrome” in cannabis users. And while loss of motivation and
cannabis use may be correlated, one cannot say that cannabis use CAUSES loss of motivation. It
is equally possible that the under-motivated person is drawn to using cannabis.

A variety of studies have been performed to determine if cannabis interferes with reaction time.
The results from these studies are inconclusive – both yes and no answers are found. There are
no data to demonstrate that cannabis intoxication is associated with motor vehicle accidents.
Nevertheless, it would be irresponsible to recommend cannabis-intoxicated individuals drive.
Some users testify that they are aware of impairment while driving and drive much more
carefully and slowly. Some electroencephalogram (EEG) studies support the notion that cannabis
users can perform the same tasks as non users, but they must work harder – employ more brain
activity – to accomplish these tasks compared to their non-intoxicated peers.5

A common concern about cannabis is that it causes a user to become psychotic. This notion arose
in 1936 with the movie “Reefer Madness” and persists in many circles. Examine the graph below
and decide if you think these data support the notion that cannabis causes psychosis.
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Harrison et al, Arch Gen Psych 2001, 58:909-915
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PMID: 17012692 16364685 16204329 15925403 15236825 14504418 12534429
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
Image citation???
There are some lesser symptoms that may “inconvenience” cannabis users. Stimulation of appetite and
gut function leads many users to increase snack food intake (“munchies”).
TEST OF CONTENT
Which statement is supported by the data shown in the graph?
Cannabis use is associated with more cases of psychosis (fewer people without
“negative symptoms”)
Cannabis use is associated with the same number of cases, but the age of onset
is younger.
There are more cannabis users in a population than non-users.
Activity Nine: Individual Experience May Vary
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Since CYP3A11, CB1, and CB2 are all proteins, encoded by genes, it stands to reason that some alleles of
these genes may influence a user’s experiences on cannabis.
Follow this link to a Powerpoint presentation describing the “active placebo” effect of cannabis. The
notion that one experiences what they EXPECT to experience suggests that set, setting, and expectation
are more influential than the drug itself.
Click http://uweoconnect.extn.washington.edu/public_cannabis_use/ link to open resource.
Activity Ten: Reading
Required Reading
Liska – Chapter 11, 11.1 – 11.5, 11.7 – 11.8
Internet
http://www.youtube.com/watch?v=hpV6licCOMw
http://www.youtube.com/watch?v=NpH9C8-y708&feature=related
http://www.youtube.com/watch?v=qp633lcU9F8&feature=related
Supplemental Reading
Liska – Chapter 11.6
Internet
http://www.erowid.org/plants/cannabis/cannabis_driving.shtml links to a variety of sources and studies
about cannabis intoxication and driving
http://www.erowid.org/plants/cannabis/cannabis_culture13.pdf (written by the author of Botany of
Desire, long and rich accounting of cannabis and forgetting)
http://www.psychologytoday.com/blog/the-teenage-mind/201012/is-marijuana-addictive (blog
discussing whether or not cannabis is addictive).
http://news.healingwell.com/index.php?p=news1&id=617831 (drug test cheating)
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