Something Worth Toking About

Daniel Shneyer
05/09/2013








Table of Contents
Table of Contents
Table of Contents .......................................................................................................................................... 2
General Information ..................................................................................................................................... 3
Anatomy of the Plant ................................................................................................................................ 7
Taxonomy ................................................................................................................................................ 10
Basic Vocabulary ..................................................................................................................................... 12
The Phytocannabinoids ............................................................................................................................... 13
The Chemistry ......................................................................................................................................... 16
Metabolites & Drug Tests ....................................................................................................................... 21
Pharmacology ......................................................................................................................................... 24
THC ...................................................................................................................................................... 26
CBD ...................................................................................................................................................... 27
Others ................................................................................................................................................. 28
Our Endocannabinoids ................................................................................................................................ 30
Existing Synthetics....................................................................................................................................... 31
Sources ........................................................................................................................................................ 32



General Information
Marijuana is so much more than a recreational drug
[26]
. Some of its numerous uses are shown in the
diagram below:
Source: 420 Magazine

Marijuana has been the most commonly used illicit drug for many years now, with an estimated 18.1
million current users (80.5% of current illicit drug users). 64.3% of illicit drugs users used only marijuana
in the past month. The majority of marijuana users are under age 30
[13]
; the following is the prevalence
of daily use reported in 2011:




Age Percent Daily Users
19-20 6.6%
21-22 6.3%
23-24 6.9%
25-26 5.8%
27-28 4.6%
29-30 3.7%
Source: Monitoring the Future national survey results on drug use, 19752011: Volume II, College
students and adults ages 1950. Ann Arbor: Institute for Social Research, The University of Michigan, p.
35 and Table 4-5, p. 108.

There were 757,969 marijuana arrests in 2011, comprising 49.4% of all drug related arrests for that year.
The number of marijuana arrests is down from 858,408 arrests (the most ever in a single year) in 2009.
Of those 2011 arrests 87.5% of them were for possession alone
[13]
. It costs around $3 billion a year to
prosecute marijuana offenders
[25]
. Legalization and taxation of marijuana, under schedules similar in
structure to those regulating alcohol sales, are estimated to bring in tax revenues on the order of billions
of dollars
[6, 13, 24, 25]
. So long as marijuana is illegal it incurs this nation a deficit as opposed to a profit. The
benefits from legalization are not limited to sales of the product but also include benefits associated
with job creation and competition in the workplace. In my opinion (based on the assumptions used in
the economic models Ive read), most reported projective marijuana tax revenues are underestimates
for this reason.

Marijuana has been a part of human civilization for a long time; it has only been illegal for a relatively
miniscule portion of its existence. Its usage dates back as far as 2737 B.C. where it was described in a
Chinese medical reference. Its use spread from China to India, North Africa and eventually Europe by as
early as 500 A.D. The Spanish first introduced cannabis to America in 1545 and the first American
cannabis law was passed soon after in 1619. That law actually awarded bounties for hemp culture and
manufacture and imposed penalties on those who did not produce it
[3, 22]
.

Hemp was industrially produced until the psychoactive properties of some of its variants became
publicized in the early 1900s. During this time, the western states developed significant tensions
regarding the influx of Mexicans. Once the depression hit tensions between the small farmer and the
large farms that employed cheap Mexican labor hit a ceiling. Small farmers blamed marijuana
smoking Mexicans for the depression causing the state of California to pass the first state law outlawing
the preparations of hemp or loco weed in 1913. Further, Mormons who traveled to Mexico around
that time came back to Salt Lake City with marijuana; marijuana was outlawed in Utah soon after, in
1915. It is hypothesized that the churchs reaction to the returning Mormons may have contributed to
the waterfall of marijuana prohibition laws that followed suit after Utahs: Wyoming (1915), Texas
(1919), Iowa (1923), Nevada (1923), Oregon (1923), Washington (1923), Arkansas (1923), and Nebraska
(1927). These laws tended to be targeted specifically against the Mexican-American population
[14]
.

In 1930, Harry J. Anslinger was given control of the new Federal Bureau of Narcotics. He recognized that
his position was an amazing career opportunity (one in which he could define the problem and the
solution) and acknowledged that opiates and cocaine wouldnt be enough to help build his agency so he
latched on to marijuana and worked to make it federally illegal. His strategy drew upon the themes of
racism and violence. With the help of William Randolph Hearst owner of a huge timber based
newspaper chain Anslinger was able to draw the attention of the nation and make marijuana federally
illegal in 1937
[3, 14]
.

Currently, marijuana offenses account for most of the drug arrests in the United States and the number
has risen sharply in the past 20 years as is evident in the figure below
[21]
.

Not coincidentally, there were 5 privately run prisons in the United States in the late 1980s (20 years
ago) but by 2005 there were more than 260
[25]
. America holds 5% of the worlds population in its
prisons and the demand for prison space lured opportunistic investors into funding what have become
privatized prisons
[23]
. The scary part about privatizing prisons is it becomes a business interest to fill
them. As shown above in 2008 there were 750,000 marijuana prosecutions (5.3% of all arrests that
year), 80% of which were for possession alone
[13, 24]
; these numbers have risen since
[13]
. Its undeniable
that marijuana prosecutions add a steady supply of prisoners needed to sustain a privatized prison
system.

A lot of money and lives have been wasted away by the marijuana prohibition effort for no reason at all.
Doesnt marijuana kill people? According to FDA data obtained by a Freedom of Information Act (FOIA)
request marijuana was not once reported as a primary cause of death between January 1
st
1997 to June
30
th
2005
[22]
. Well, isnt marijuana a gateway drug? Only 1 in 104 marijuana users go on to use a harder
drug (cocaine, heroin, etc.)
[6]
. Thats a staggeringly low percentage considering that as long as marijuana
is illegal it will marketed to smokers and hard drug users alike. But wont people abuse marijuana if its
readily available? 8 of the 10 states that legalized medicinal marijuana in 2006 actually saw a decrease in
teen use from 1996 to 2006
[22]
. Fine, but all marijuana users must all be lazy, useless hippies. In
actuality, a multitude of prominent and highly successful figures including but not limited to Steven Jobs,
Ted Turner, Michael Phelps, members of the Beatles, Bill Clinton and Barack Obama have all admitted to
marijuana use
[24]
.

In fact, the cannabinoids in marijuana have been shown to have a multitude of prominent medical
benefits
[1, 2, 4, 6, 28]
; this should come as no surprise, considering its plethora of uses. Of course
pharmaceutical companies intend on finding a way to profit from this discovery. Its in their best
interests to isolate relevant cannabinoids and synthesize analogues so that they can patent and sell
them. This has already been done; Marinol (THC analogue) already exists on the market and Rimonabant
(CBD analogue) is readily used in research trials. 66 of the 483 chemical constituents known to exist in
cannabis are cannabinoids
[22]
; it is the mixture of cannabinoids that leads to a pleasant high experience.
Observational studies indicate that ingesting pure
9
-THC induces anxiety, an effect which is typically
mitigated by the presence of CBD
[27]
. Unfortunately, decrypting the particular functions of each
cannabinoid (and how those functions change with varying concentrations) will be a long and drawn out
task that will stretch over many years. It is not profitable for pharmaceutical companies to endorse
marijuana legalization (medical or recreational), especially because many of the known medical benefits
of marijuana could outcompete preexisting synthetic medications.

Negative consequences of marijuana use are surprisingly rare
[29]
. Marijuana smoke does contain 50-70%
more carcinogenic compounds than tobacco and 3-4 times the amount of tar
[30]
. On top of that
marijuana users hold all of that in their lungs for longer in an attempt to maximize the absorption of
9
-
THC into their blood streams. In lieu of this information numerous studies have attempted to link
chronic marijuana usage to various forms of cancer but, despite the efforts, the results remains
inconclusive
[54]
. A study of 79 lung cancer patients in New Zealand suggested that cannabis users are 5.7
times more likely to get lung cancer than non-users whereas a much larger study conducted in Los
Angeles with 2252 people failed to find a correlation between lung, head and neck cancers and
cannabis.


Anatomy of the Plant

Flowers: By definition, a flower is the reproductive structure found in flowering plants. Its function is to
affect reproduction, usually by providing a mechanism for the union of sperm with eggs. Marijuana bud
is a collection of individual flowers, each of which produces a seed when pollinated.
Flowers are surrounded by bracts as shown below. Bracts are modified leaves that surround a
flower (or cluster as is the case with marijuana) and serve to protect it and give it structure.

Stigmas: The stigma is the receptive tip of a flowering pistil. The stigma receives pollen at
pollination. In marijuana plants they typically start out looking milky white and turn amber-
brown upon maturation
[31, 32]
.
Calyx: By definition, calyxes are the sepals of a flower. Sepals are a husk or wrapping that form
the outer body of a flowering bud as shown below. The calyxes are covered in trichomes but in
smoked marijuana they are usually too small to see since most bud is sinsemilla.



For review, the following depiction of a typical angiosperms flowering bud is provided below:



So far, we have only looked at female flowering buds but males have flowering buds as well. Male
marijuana plants produce stamen when they flower as shown below:
Calyx
Calyx
Stigma
Stigma


Leaves: Leaves are not smoked and will generally give you a headache rather than get you high. This is
due to the relatively low concentration of resin on leaves as opposed to buds. Marijuana, like many
other plants, uses its leaves for photosynthesis and not for cannabinoid production
[32]
.
Stems: Stems form the base of the marijuana plant and give it structure. Stems do secrete some
cannabinoids as well but again will give the user a headache if smoked
[32]
.














Taxonomy
Despite the huge variety of marijuana available, almost all of them (over 99%) are derived from the
same plant species, cannabis sativa. C. Sativa has two main subspecies, known as Cannabis Sativa L. ssp.
Sativa and Cannabis Sativa L. ssp. Indica. The classification of Indica and sativa as the same species
has been hotly debated since the 1940s; we currently classify them as the same species and
differentiate them using subspecies because we believe Indica and sativa subspecies first differentiated
due to human selection
[33]
. Below is a pictorial comparison of Indica and sativa:

1. Cannabis Sativa: High
9
-THC, Low/No CBD
[34]

a. Sativa dominant strains produce greater concentrations of
9
-THC. Its leaves are
narrower and grow a lighter green color. The plant itself is tall and thin
[9]
.
i. Its less dense foliage and taller frame
[34]
allow for more air flow and sun
exposure around and between the branches resulting in healthier growth and
less risk of fungus in humid tropical conditions.
b. The geographic origin of cannabis is a rather difficult subject because the plant has been
used by humans since 2737 B.C. It is hypothesized that sativa came first and originated
in Central Asia North of the Himalayas predominantly south of 30
o
North latitude
[3, 14]
.
i. Today pure sativas are most likely found in tropical conditions.
2. Cannabis Indica: Equal THC/CBD OR Low THC, High CBD
[34]

a. Indica dominant strains produce greater concentrations of CBD. The leaves on Indica
dominant plants are broad and often grow a darker green. The plant itself is short and
dense; it tends to produce more side-branches and usually weigh more when mature
[9]
.
b. C. Indica was first classified in 1785 by evolutionary biologist Jean-Baptiste de Lamarck,
who received his samples from India (hence Indica). Although C. Indica is generally
agreed to have originated from Central Asia North as well, Afghanistan specifically
[9]
.
3. Cannabis Ruderalis: Low
9
-THC, High CBD
[35]

a. The shortest of the three subspecies, full grown C. Ruderalis extends only about 30 cm
to 80 cm high. It produces only a few branches and has wide, fat-bladed leaves (similar
to C. Indica)
[9]
.
i. Its branches usually produce 3 leaves as opposed to 5 or 7 as seen on sativa and
Indica strains
[9]
.

b. C. Ruderalis is tentatively described as the third type of cannabis, as botanists are
unsure whether it qualifies as a species in its own right. It is an uncultivated strain native
to Russia, Central Europe and Central Asia (more north) and is adapted to the harsher
environments found there
[9]
.
i. Ruderalis species are likely descended from Indica, which itself likely descended
from Sativa
[9]
.
c. C. Ruderalis is distinguishable by its capacity to flower according to the plants individual
age, independent of the photoperiod in which it is growing called auto-flowering
[9, 35]
.
i. Its adaptation to short, cool summers allows it to complete its life cycle in just
10 weeks (~16 weeks for sativa/Indica varieties)
[35]
.
ii. Its seeds detach easily and can survive more than one season in frozen ground
[35]
.
iii. The seeds can also survive their shells being cracked open; for some strains, this
may even aid the germination of the seeds
[9, 35]
.
Research at the University of Indiana and the Canadian Institute of Agriculture shows that using the
location where the strain was historically developed is the most reliable way to predict the strains
THC:CBD ratio
[36]
. A pictorial of the naturally occurring locations of Indica and sativa are shown below:

On the map above, lines from pole to pole (top to bottom) are lines of constant longitude (meridians).
The circles parallel to the equator are lines of constant latitude (parallels). The mesh formed by lines of
constant latitude and longitude is referred to as the graticule. Locations on the surface of the earth can
be reported by either specifying longitudinal and latitudinal angles of by specifying the latitude angle
with respect to the equatorial plane and the radius to that point.









30
o
North Latitude
Central Asia North
Basic Vocabulary
Cannabis: any plant that produces resin containing phytocannabinoids such as
9
-THC.
Resin: A sticky fluid secreted from the female plant for both reproduction and protection; resin
containing a mixture of cannabinoids and precursors builds up within the plants numerous
trichomes.

Hashish: A solid mass produced by compressing marijuana resin into a cake.

Hash Oil: The product of solvent extraction.

Tar: The sticky black crap that is produced as a byproduct of igniting the plant. It is a sticky
substance comprised of burnt oils, ash and carbon and contains very few cannabinoids.

Kif: Extremely well ground up weed.

The Phytocannabinoids
Phytocannabinoids: Cannabinoids that are produced from enzymes in a plant. Because cannabis is the
only plant genus which produces cannabinoids it has its own category
[1]
. All phytocannabinoids are
derived from their respective 2-carboxylic acids (2-COOH) via decarboxylation which itself is catalyzed
either by light or alkaline conditions
[40, 44]
.
All Phytocannabinoids are produced in the heads of trichomes
[7, 8]
. The word trichome comes from
the Greek expression for growth of hair. There are three types of trichomes:

1. Bulbous (yellow): This type is the smallest (15 to 30 ). They are comprised of 1-4 trichome
cells (3 make up the stalk and 1 makes up the head). The head cell secretes a resin
containing cannabinoids and related compounds
[7]
.
2. Capitate-Sessile (blue): This type is more numerous than bulbous glands and is called capitate
as an indication of their globular-shaped head. They are comprised of 1 stalk cell and 8 to 16
head cells all of which secrete the same resin. Their shape ends up being that of a convex
rosette due to the cannabinoid build up
[7]
.
3. Capitate-Stalked (red): This is the most abundant type of gland and also the largest, ranging
from 150 to 500 when their stalks reach full size. These glands appear during flowering and
form their densest cover on the female bracts (specialized leaves that cover the seeds). Male
flowers develop some stalked glands but they are smaller and less concentrated than on the
female
[7]
.

It is hypothesized that trichomes evolved both as a defense mechanism and as a pollination aid.
Cannabis is a wind pollinated plant so it is sensible for it to evolve sticky trichomes. Further, flowering
females which become pollinated have been observed to produce less trichomes due to seed
production. The cannabinoids themselves likely evolved as more of a defense mechanism seeing as
some of the chemicals in cannabis trichomes inhibit the growth of some types of fungus. The trichome
body also acts as a protective layer against offensive insects and makes a less palatable seasoning for
those animals which do attempt to eat it. The resin (secreted from the trichome heads) also acts as an
insulator, protecting the plant against extreme conditions (such as high wind or low humidity). The resin
could even act as a natural sunscreen, protecting against UV-B lights rays in particular since many
cannabinoids have been observed to react under UV-B radiation exposure
[7]
.


Below is a depiction of the general pathway showing how
9
-THC and other cannabinoids are produced
in the heads of the trichomes:

Phenols (produced in the organelle, vacuole, in red) and terpenes (produced in the organelle, plastid, in
blue) travel up the trichome stalk (in green) and combine inside the secretory cavity (or red, in yellow).
The solution within the secretory cavity produces cannabinoids upon the absorption of UV-B light
[7]
. To
review:
Phenols: Phenols are chemical compounds consisting of a hydroxyl group bonded directly to an
aromatic hydrocarbon ring. They are very similar to alcohols except that the carbon attached to
the hydroxyl functional group (OH) is saturated in alcohols (single bonds to three other atoms)
and unsaturated in phenols (carbon rings).

The phenol precursor to
9
-THC is olivetolic acid, which is also a fatty acid. A fatty acid is a
carboxylic acid (having at least one carboxyl group, COOH) with a long aliphatic (no carbon rings)
tail. For reference, fatty acids are important biochemically because they produce lots of ATP
when metabolized. Olivetol is already a rare compound, found naturally but only in certain
species of lichens (a composite fungus/plant symbiotic partnership which thrives in extreme
conditions). Cannabis plants produce a similar but unique compound, called olivetolic acid using
two enzymes: hexanoyl-CoA synthase and olivetolic acid cyclase (OAC) an enzyme which has
never been seen before in plants
[8, 37, 56]
.
o OAC and hexanoyl-CoA synthase have been used in the laboratory to coax yeast to
produce olivetolic acid. This could be a major step toward the development of methods
to biosynthesize cannabinoids with yeast or other microorganisms, which could be a
valuable alternative to chemical synthesis
[38]
.
Terpenes: Comprise a large diverse class of organic compounds, produced by a variety of plants
(particularly conifers). Terpenes are very odorous and thus are theorized to have protective
functions. They are the majority components of resin and of turpentine (fluid) produced from
resin
[39, 56]
. All terpenes are derived from units of isoprene, shown below:

Isoprene has the chemical formula C
5
H
8
but its structure is what distinguishes it (shown above).
It is more accurate to report its formula as CH
2
=C(CH
3
)CH=CH
2
. The Terpene precursor to
9
-THC
is Geranyl Pyrophosphate
[8, 37, 56]
.
































The Chemistry
Most of the compounds responsible for marijuanas characteristic aroma terpenes (cannabinoid
precursors) present in the resin. While smelling the aroma of weed can help validate that the product is
in fact marijuana, it is not correlated with its strength (THC:CBD ratio)
[8, 39]
. In the cannabis plant,
9
-THC
occurs mainly as THCA, which is biosynthesized from olivetolic acid as shown below
[1, 8, 37,

38, 56]
.

As discussed in the introductory section all cannabinoids are biosynthesized via a condensation reaction
between a phenol and terpene. CBG, CBD and
9
-THC are all biosynthesized from CBGA, as shown
above, via condensation of the particularly rare fatty acid olivetolic acid and the never before seen
terpene Geranyl Pyrophosphate (GPP)
[21, 56]
. It should be noted that
9
-THC is chemically synthesized
from CBD in labs
[8]
. When ignited, THCA is converted to
9
-THC via decarboxylation; as shown below,
this process happens spontaneously but it is expedited at higher temperatures
[12, 40, 44]
.


THC degrades to CBN from exposure to air. CBN is only very weakly psychoactive (approximately 10% of
the activity of
9
-THC
[41]
) and, much like CBD, interacts with
9
-THC attenuating its effects
[12, 40, 41]
.
When people speak of
9
-THC they usually speak of the compound delta 9-tetrahydrocannabinol. The
term tetra-hydro means four hydrogen atoms and the term delta 9 refers to the position of the
double bond on the upper aryl ring of the molecule as shown below
[42, 53]

The term cannabinol is the base word. The oxidation product of the main molecule (THC) was assigned
the base word because cannabinol (CBN) was the first phytocannabinoid to be obtained in pure form, in
1896. CBN was originally assumed to be the active psychotropic ingredient of cannabis until
9
-THC was
isolated in 1964
[41]
.

CBD is an isomer (same chemical formula, different molecular geometry) of
9
-THC and synthesized
directly from the same precursor using only one different enzyme, CBDA synthase
[12, 43]
. The chemical
formulas of CBD, CBN are shown below:

CBN CBD
CBN forms when
9
-THC undergoes a simple oxidation reaction, shedding the two hydrogen atoms
attached to its upper aryl ring (C ring in the image above)
[4]
. This reaction happens when
9
-THC is
metabolized in the body but it also happens when
9
-THC reacts with the oxygen in the air or when UV
radiation strikes the molecule. Some underground chemists have proposed submersing CBN in a
strongly acidic solution in hopes of forcing four hydrogen atoms back onto the CBN molecule. However,
this process could promote unknown side reactions and lead to unpredictable compounds with
unpredictable effects. In general, it is not worthwhile to convert CBN back into
9
-THC because its upper
aryl ring is very stable
[15]
.

CBD, on the other hand, is an isomer of
9
-THC. Isomers have the same molecular formula as their sister
molecules but attain different structures; further, isomers generally dont share similar properties with
their sister molecules. For example, CBD is NOT psychoactive whereas
9
-THC is
[2, 4, 12]
. The structural
difference is limited to the encircled parts of the depicted molecules as shown below:


There is already a patented method of converting
9
-THC into CBD. It involves boiling a solution of CBD
in a mixture comprised of an organic solvent and a Lewis acid. The solution is then poured into water
and extracted from it with ether. The ether solution is washed with water and dried with Na
2
SO
4
and
evaporated. Both 8 and
9
-THC were eluted from the resulting oil (
8
-THC was 64% of the crude
material). In fact, it is well known that
9
-THC is soluble in both alcohols and oils
[12]
.

Phytocannabinoids are often extracted from ground marijuana (i.e. hash, cannabutter, weed oil, butane
honey oil extraction, etc.) for increased potency. In fact freshly harvested buds from a mature marijuana
plant are on average 80% water and their metabolic processes will continue until their resources
(sugars, starches, nitrates and minerals) are extinguished. Typically, marijuana buds are dried and air
cured. Drying steadily reduces the moisture concentration to purify and prevent mold growth; curing
evenly redistributes the remaining moisture throughout a bud and promotes continued production of
THCA and CBDA. As the metabolic processes continue during curing, the conversion of cannabergerolic
acid (CBGA) into THCA and CBDA will continue and thereby increase the potency of the buds
[16]
.

Carboxyl groups are present on every phytocannabinoid produced by the cannabis plant
[40, 44]
. THCAs
carboxyl group makes it weakly water soluble and also psycho-inactive in humans
[45]
. Despite this fact, it
is well-documented that water curing buds actually increases the potency of the product by expediting
the activation of cellular enzymes and breakdown of cellular components such as chlorophyll
[46]
. Air
cured and water cured bud is shown in the image below:



This implies that the trichome body is itself not water soluble. It is generally a myth that wet weed
cannot be salvaged. Similarly, eating marijuana wont get you high because THCA hasnt been
decarboxylated (and wont be in your stomachs acidic conditions).

Decarboxylated phytocannabinoids (THC, CBD, CBN etc.) are nonpolar compounds; as such, they are
miscible in oil (also non-polar) but not water (polar). When simmered in oil, the elevated temperature
decarboxylates the carboxylic acid precursors which are subsequently trapped (dissolved) in the
surrounding oil. Simmering is key since some of the phytocannabinoids will vaporize when heated.
Marijuana is also miscible in alcohols (like ethanol)
[18]
. Ethanol, shown below, is a very polar molecule
due to its hydroxyl (OH) group but it also has a non-polar ethyl group (C
2
H
5
):

Ethanol is one example of a molecule capable of dissolving both polar and non-polar substances (soap is
another example). These molecules create what is known as colloids solutions where the solute is
indirectly dissolved into a solvent. Technically, marijuana dissolved by an alcohol creates what is known
Air Cured Bud Water Cured Bud
as an emulsion a colloid involving only liquids. The alcohol is the micelle (or surfactant with a
hydrophobic tail and hydrophilic head); the water is the aqueous solution and the phytocannabinoids
form the dispersed phase (yellow) in the image below:

The geometry of the micelle used will affect the extraction efficiency. For example,
9
-THC dissolves into
100 proof (US) alcohol at a 2.86 mg/mL clip but dissolves into Caprylic acid at a 40.47 mg/mL clip
[18]
.
Unfortunately, the significance of this number is not immediately intuitive because smoked marijuana
contains many other compounds (such as chlorophyll, cellulose and other cannabinoids). Nevertheless it
is possible to estimate how many bowl packs could be crammed into a shot of 100-proof vodka. A
bowl pack can be equivalent to anywhere from 0.1 g to 0.65 g depending on the size of the bowl and
the degree to which the weed is packed down
[49]
. In my experience, I find that I smoke an average of
about 0.25 g per bowl pack. There are approximately 30 mL in a fluid ounce (or a shot) so
approximately 85.8 mg of
9
-THC will saturate a shot of 100-proof vodka. Further, the average potency
of most recreational marijuana strains today is 1-5%
9
-THC per gram of dried marijuana
[47]
.

At this point caution should be thrown to the wind as there has been no standard methodology for
determining the potency of marijuana strains over the years. Many factors complicate the issue. For
instance, marijuana buds are largely comprised of water even after they are dried. This isnt a problem
if the sample is desiccated (completely dried) but the potency of bud today is almost always reported
without a supporting methodology leaving open the possibility of fudged results. Furthermore the
amount of oils the plant produces is not a constant fraction of its overall weight. The reported potency
will therefore depend on which part of the plant is sampled and how it is grown
[19]
. Lastly it is important
to remember this task is complicated by the presence of hundreds of other structurally similar
compounds
[41]
.

To be thorough, we will assume the sample uniformly contains 1%
9
-THC per gram of desiccated
marijuana. Therefore at least 7 bowl packs (1.72 g) of marijuana are needed to saturate a shot of 100-
proof vodka. Given the assumptions made, it should be noted that this result is actually an
underestimate. So we can conclude that it takes a lot of marijuana to saturate even a weak solvent.
Nevertheless other more hazardous extraction methods such as butane honey oil extraction (BHO) are
becoming more popular. Some will claim that other (non-ethanol based) extraction methods will
increase the potency of the product but we have just shown that this is likely to be a myth. That being
said, the rate of dissolution of
9
-THC into ethanol is small compared to better solvents. Many
recreational users report, through iteration, that it takes weeks (2-3) to dissolve
9
-THC into ethanol at
room temperature
[50]
. Thus using other solvents can result in a high grade product in a shorter amount
of time.
Metabolites & Drug Tests
The most common way of ingesting marijuana is smoking it. Smoking is also the most expedient way to
get
9
-THC and friends into the bloodstream. When marijuana smoke is inhaled, the mixture of
cannabinoids is absorbed by alveoli (tiny air sacs where gas exchange occurs) in the lungs
[51]
. After
smoking, venous blood levels of
9
-THC drop to 5-10% of their peak level within minutes. As discussed in
the chemistry section, marijuana resin can also be dissolved into a variety of solvents and ingested
orally. When digested
9
-THC enters enterohepatic circulation (circulation between the liver and
gastrointestinal track) and is slowly hydroxylated in the liver into 11-hydroxy-
9
-THC (11-OH-THC) an
equally as psychoactive as its precursor. This molecule is then further metabolized via oxidation into 11-
nor-9-carboxy-
9
-THC (9-COOH-
9
-THC or THC-COOH) which is no longer psychoactive
[47, 54, 55, 58]
. These
two metabolites are shown below:

9-COOH-
9
-THC is a glucuronide (an excretable form of a substance that cannot be used as an energy
source). Over time, it is expelled as the primary urine metabolite along with 18 or so other non-
conjugated metabolites. In total, more than 100
9
-THC metabolites including di- and tri-hydroxy
compounds, ketones, aldehydes and carboxylic acids have been identified
[58]
. In general, most absorbed
-
9
-THC is eliminated in feces (~65%
[47, 58]
) with the remainder eliminated in urine
[47, 55]
.

Smoked
9
-THC is metabolized the same way as when it is orally ingested. However, oral ingestion
delays the onset of action; as shown in the figure below, maximum cannabinoid blood levels are reached
1 to 6 hours after an oral dose as compared to 2 to 10 minutes after inhalation
[47, 51, 54, 55]
:


Concentration profile after oral ingestion Concentration profile after smoking

It should be noted that the disappearance of
9
-THC from blood is largely due its dissolution into other
tissues in the body rather than by metabolism
[55, 57]
. Further, the metabolism of
9
-THC is complicated
not only by the method of ingestion but also by the presence of other cannabinoids with which it may
interact (mainly CBD and CBN) and by the particular metabolic state of the user. The frequency of use,
dosage used, genetics of the user and rate of metabolism are among many user specific variables which
will also affect the detection time
[57]
. A solution of
9
-THC containing CBD and/or CBN will create more
psychoactive metabolites than a solution of
9
-THC alone because CBD and CBN competitively slow
9
-
THC metabolism in the liver
[55]
. Furthermore, 11-OH-THC induces slightly different psychoactive effects
as compared to
9
-THC contrasted primarily by a more rapid onset of generally more sedative effects
[58]
.

The terminal half-lives of THC-COOH and other inactive carboxy-metabolites range from 50 hours to 6
days or more and thus serve as markers of prior cannabis use in urine tests
[55]
. The most common test
for detecting marijuana or any drug is the immuno-assay. In this test urine is mixed with a solution
containing an antibody (tagged with a fluorescent dye or radioactive substance) specific to
9
-THC
metabolites (THC-COOH in particular)
[11, 59]
. There are also three other less common types of drug tests:

1. Blood Test: A blood test is a better detector of recent use since it measures the active presence
of
9
-THC in the system. Unfortunately, due to the invasiveness of the test, they are used less
frequently, typically for investigations and DUIs
[57]
.
2. Hair Test: This test measures the non-psychoactive residues that are internally absorbed into
hairs. Residue wont appear in hair until 7 to 10 days after use and cannot be washed out by
shampoos. Hair tests are more likely to detect regular than occasional marijuana use
[57]
.
3. Saliva Test: Saliva testing is a newer and less proven technology. In theory, the test is supposed
to detect recent use much like the blood test. Because this test is less invasive than blood or
urine tests the industry has been eager to develop it. The tests are not yet reliable though
[57]
.
Urine Test Blood Test Hair Test Saliva Test
Marijuana Single Use
[57]
1-7 days 12-24 hours Doubtful Not Validated
Marijuana Regular Use
[57]
7-100 days 2-7 days Months Not validated
Amphetamines
[57]
1-3 days 1-3 days Months Not validated
Psilocybin
[source]
< 1 day < 1 day < 1 day Not validated
LSD
[source]
A couple days A couple days A couple weeks Not validated

In America, an estimated 20 million workers are drug-tested annually at a cost of more than $1 billion
[11]
. We can thank Ronald Reagan for this; in 1986 he signed Executive Order 12564 which mandated
federal employees to be drug free on and off the job and spawned the emergence of suspicionless
drug testing in the private sector
[59]
. Detection of
9
-THC metabolites depends strongly on the type and
sensitivity of the test employed. The standard prescreening drug test is an enzyme multiplied
immunoassay test (EMIT) which tests for THC-COOH in urine. The cutoff concentration recommended by
the SAMHSA/NIDA for a positive result is 50 ng/mL. Most companies follow up the EMIT with a
confirmation test. This test detects THC-COOH using gas chromatography (GC-MS) and the
recommended cutoff is 15 ng/mL. Most companies also screen for common adulterants (chemicals
which alter the sample to yield a negative result) as well. Nevertheless, spiking a sample still remains a
viable option for beating the system as there is no shortage of new, alternative adulterants
[59, 60]
.

Aside from adulterants, there are several benchmarks assayed by urinalysis examiners to weed out
diluted samples. These include pH, color, specific gravity and the presence of Creatinine monohydrate.
The best way to pass a drug test is obviously to stop smoking weed at least 30 days before the test for
frequent users
[60]
but in the event that the user does not have enough time to sufficiently fast there
are other ways to pass as well. Online tutorials will include directions to take some combination of the
following supplements or will provide you with powdered urine (the fake dildo method):

Creatinine: A normal byproduct of muscle metabolism, Creatinine is present in urine within a
specific range. For this reason it is one of the benchmarks that drug companies test for to
ensure that the sample is not diluted
[59]
.
Vitamin B Complex: Doses of Vitamin B will help restore urine to its natural color. Riboflavin, or
vitamin B
2
, is the specific vitamin responsible for urines yellowish color
[59]
.
Diuretics: A diuretic is defined as any substance that increases urine output. Caffeine, cranberry
juice and most quick flush herbal teas are diuretics while water is not. Consuming diuretics
just prior to taking a urine test will dilute the concentration of drug metabolites but only
temporarily
[59]
.
Papain: Papain is an enzyme found in papaya fruit that is gaining popularity as an adulterant
after a recent study in The Journal of Forensic Toxicology reported that adding it to urine
reduces the presence of marijuana metabolites and is still undetected by drug tests
[61]
.















Pharmacology
There are many potential therapeutic uses for cannabinoids but not all of the documented effects of the
major cannabinoids are medicinal. Nevertheless, a summary of the potential and known medicinal
effects of the major cannabinoids are shown in the image below:

There are approximately 483 natural compounds found within the Cannabis Sativa plant. 66 of these
have been classified as cannabinoids or chemicals which are unique to the plant
[4]
. Cannabinoids are
compounds which act either directly or indirectly on the G-protein coupled receptors CB1 and/or CB2.
The former is present primarily in the central nervous system (brain) whereas the latter is present
primarily in the peripheral nervous system (limbs):

Source: Project CBD

In the brain CB
1
receptors are most abundant in the cerebellum (body movement and coordination),
hippocampus (learning and memory), cerebral cortex (higher cognitive functions), nucleus accumbens
(reward) and the basal ganglia (movement). Because CB
1
receptors are found mainly at the terminals of
central and peripheral neurons, it is likely that they modulate the release of other neurotransmitters. By
contrast, CB
2
receptors are present predominantly in immune cells both within and outside the CNS. The
functions of CB
2
receptors include modulation of cytokine release and immune cell migration.
[30, 41, 64, 65]

In most instances the reported pharmacological effects of the cannabinoids are speculative, primarily
because there is not yet enough evidence to say anything definitive. The plethora of functions that both
CB
1
and CB
2
receptors fulfill are not yet fully elucidated, especially because there are many other ligands
that may have significantly different pharmacological profiles that can interact with these receptors
[64]
.
Therefore in the following subsections we will explore studies that have been done but the scope of the
results will remain modest.






THC

9
-THC binds equally well to CB
1
and CB
2

receptors and behaves as a partial agonist at both. It is less
potent at CB
2
than at CB
1
receptors. The well-known psychotropic effects of
9
-THC are mediated by
activation of brain CB
1
receptors
[1, 2, 21, 41, 65]
.
9
-THC also has a closely related isomer
8
-THC but
8
-THC
surprisingly does not contribute significantly to the activity of the plant extract.
8
-THC is considered less
expensive to prepare and more stable than
9
-THC although it may be less active
[41, 42]
.
A small study (N=5) has shown that
9
-THC produces bronchodilatation in asthmatic and perfectly
healthy people. The researchers report that sufficient dosages are possible without overt psychoactive
effects and that all dosage levels caused bronchodilatation. To cause significant dilation a dosage in
excess of 10 mg must be consumed orally whereas dosage of 200 g was sufficient when inhaled
[62]
.
One could hypothesize that this effect could be reason why marijuana was not once reported as a
primary cause of death between January 1
st
1997 to June 30
th
2005
[22]
.
Another small study (N=9) found that
9
-THC could mitigate the proliferation of glioblastoma cells in
patients harboring actively growing recurrent tumors. The antiproliferative effects seem to be selective
for brain-tumor cells as the survival of normal brain cells and neurons is unaffected. It has previously
been shown that cannabinoids inhibit the growth and angiogenesis of gliomas in animal models but the
results of the present study did not exhibit statistical significance. From a pharmacological standpoint,

9
-THC is not the most appropriate CB
1
agonist for future antitumoral studies because of its high
hydrophobicity, relatively weak agonistic potency and ability to elicit CB
1
-mediated psychoactivity
[63]
.
When taken in high enough does to become psychoactive,
9
-THC can produce memory and learning
impairing effects;
9
-THC has also been shown to induce anxiousness as well
[27, 30]
. As
9
-THC enters the
brain it causes the user to feel a euphoric high by binding to the CB
1
receptors in the nucleus
accumbens an area of the brain that responds to food and drink via the release of dopamine
[30, 64]
.
Another common side effect of getting high is the red eyes. This occurs because
9
-THC reduces
intraocular pressure; coincidentally, abnormally high intraocular pressure is a key contributor to
glaucoma. It follows that marijuana could hypothetically be ingested in order to mitigate the symptoms
of the disease
[66]
.
CBD
[53]
CBD has very low affinity for CB
1
and CB
2
receptors. In fact it is an antagonist of CB
1
and CB
2
agonists.
Marijuana resin with less CBD has been shown to have increased psychological effects and incidence of
anxiety reactions. The anti-anxiety effects of CBD are hypothesized to lessen the psychotropic effects of

9
-THC. Although it is not clearly understood how it is hypothesized that it either involves action as a
serotonin receptor (5-HT
1A
) agonist, enhancement of adenosine signaling through inhibition of uptake or
inhibition of the GPR55 receptor
[21, 41, 27, 55]
.

CBD has been associated with many therapeutic applications but it is generally agreed upon to be
neuroprotective, analgesic, sedative, anti-emetic, anti-spasmodic, anti-proliferative (cancer cells) and
anti-inflammatory
[41, 58]
. The most exciting work being done with cannabinoids is in cancer research.
9
-
THC, CBG, CBC,
9
-THCA and CBDA have all been shown to exert anti-proliferative effects in a panel of
tumor cell lines including: breast cancer, prostate cancer, colorectal cancer, glioblastoma, leukemia and
thyroid cancer. These same molecules also have been shown to stimulate the activation of quiescent
stem cells present in bone marrow. However, CBD exhibited the highest efficacy followed by CBG and
CBC
[41]
. In fact, in 2011 the American Association for Cancer Research found that CBD actually causes
apoptosis in breast, Glioma and Leukemia cancer cells
[69]
. CBD may also prove beneficial in preventing
apoptotic signaling in neurons via restoration of Ca
2+
homeostasis
[41]
.
CBD is a potent antioxidant, exerting neuroprotective actions that might be relevant to the treatment of
neurodegenerative diseases including Alzheimers disease, Parkinsons disease and Huntingtons
disease. The effect of CBD on T-cells has been investigated in detail as well. It was found that CBD
exerted a generalized immunosuppressive effect. This is both a good and bad thing. Obviously a
suppressed immune system leads to an increased chance of sickness. That being said, CBDs exerts anti-
arthritic properties via a combination of immunosuppressive and anti-inflammatory effects
[41]
.





Others
Cannabinol (CBN)
[41]
Cannabinol (CBN)

Cannabinol (CBN) was first isolated in 1896 and represents the first natural cannabinoid to be obtained
in pure form. It was initially and incorrectly assumed to be the active psychotropic ingredient in
marijuana resin. However, it is a relatively minor constituent in fresh bud because it is the product of
9
-
THC oxidation. It is a weak CB
1
and partial CB
2
agonist with approximately 10% of the activity of
9
-THC.
Its potential therapeutic applications come in situations where cannabinoid receptors are up-regulated
[41]
.

Cannabichromene (CBC)


Cannabichromene (CBC) is a non-psychoactive compound that, together with
9
-THC, comprises the
majority of the cannabinoids in freshly harvested bud. CBC may cause hypothermia, sedation and
analgesia but it also exerts anti-inflammatory, antimicrobial and effects as well. In fact, CBC was shown
to be superior to the non-steroidal anti-inflammatory drug phenylbutazone in rats
[41]
.







Cannabigerol (CBG)

Cannabigerol (CBG) is a non-psychoactive compound that, in its carboxylated form (CBGA), is the
biosynthetic precursor to CBD and
9
-THC. It is known to exert anti-proliferative and antibacterial
activity and is a potent anandamide reuptake inhibitor in the low micro-molar range
[41]
.
















Our Endocannabinoids
Endogenous Cannabinoids: Cannabinoids that are produced within a human, another mammal, bird,
fish, reptile, etc. We will only be focusing on those that are produced within humans.

Because
9
-THC is a lipid compound, it was assumed that any possible endogenous cannabinoid
molecules would also be lipids. Thus, 28 years after the discovery of
9
-THC in 1964 anandamide (based
on the Sanskrit word ananda meaning supreme joy) was isolated in the brain (CB
1
agonist). 3 years
later a second compound, 2-arachidonoyl glycerol (2-AG), was isolated from peripheral tissues (CB
2

agonist)
[41]
. Their chemical structures are shown below:



For the time being, it is unclear whether there are more endogenous cannabinoids. Unlike most
neurotransmitters, anandamide and 2-AG are synthesized on demand rather than stored in vesicles.
Again, unlike most neurotransmitters, their action is not postsynaptic but rather mostly presynaptic
[41]
.
Contrary to
9
-THC which is metabolized over several hours / days and excreted, endocannabinoids are
rapidly removed by a membrane transport yet to be fully characterized
[64]
. What is known is that
anandamide is metabolized by the fatty acid amide hydrolase (FAAH) and 2-AG is metabolized
enzymatically both by FAAH and monoacyl hydrolases (MGLs). 2-AG is synthesized by diacylglycerol
lipases (DAGL) and anandamide by transferring arachidonic acid from lecithin to the free amine of
cephaline via an enzyme
[41, 64, 65, 67]
. These technical details are relevant because the endocannabinoid
system modulates a variety of brain functions including but not limited to: anxiety, reward, cognition,
depression, inflammation, neurogenesis and pain.

It is now generally accepted that there are certain disorders that modified endocannabinoid release
increases in particular tissues; by contrast, this upregulation in some instances leads to suppression of
unwanted symptoms and so is auto-protective. For example, there is evidence that endocannabinoid
release relieves multiple sclerosis and inflammatory pain whilst impairing fertility in certain women. As a
result, there is now enormous interest not only cannabinoid receptor agonists and antagonists but also
in compounds that can indirectly affect the activity of the endocannabinoid system
[65]
.

Distinguishing between the effects of anandamide and 2-AG has not always been straightforward but
biologists at Virginia Commonwealth University have found a way to suppress one whilst leaving the
other unaffected. In doing so they discovered that 2-AG modulates several behavioral processes
including analgesia, temperature regulation and movement
[68]
.
Existing Synthetics
Synthetic Cannabinoids: Synthetic cannabinoids are man-made compounds which are related in their
pharmacological functions to certain phytocannabinoids. There are many more synthetics cannabinoids
out there
[65]
. In this section we will explore the most prevalent synthetics.

Dronabinol & Nabilone
Dronabinol (Marinol ) is nothing more than man-made
9
-THC. It was approved in 1986 in the US as an
antiemetic and appetite stimulant for cancer patients who werent responding to traditional treatments.
Nabilone is the Canadian-made analog to
9
-THC. Nabilone was approved in Canada in 1982 for the
same uses as Dronabinol and is now also available in the US. Both drugs have been approved by the FDA
[54]
. The chemical structure of Nabilone is shown below:


Nabilone
[wiki image]

In a study of 454 patients with cancer, dronabinol capsules (oral administration) provided complete or
partial success in easing the nausea and vomiting of 68% of the patients. A different randomized,
double-blind, placebo-controlled, 6-week study involving 139 patients, dronabinol provided statistically
significant improvement in appetite and non-statistically significant trends toward improved body
weight and mood, and decreases in nausea
[55]
. The efficacy of nabilone was assessed by an analysis of
15 controlled studies. Among 600 cancer patients, nabilone was found to be superior to conventional
antiemetics such as prochlorperazine, domperidone and alizapride
[54]
.

Rimonabant
Developed by Sanofi-Aventis, Rimonabant is a selective CB
1
antagonist meant to suppress appetite (treat
obesity) by blocking endogenous cannabinoid binding to neuronal CB
1
receptors. It has been available in
Europe since 2006 for use as an adjunct to diet and exercise for obese or overweight patients. The drug
failed to secure FDA approval in the US and concerns have been growing that patients taking the drug
were at increased risk of psychiatric imbalances including suicide. Nevertheless its efficacy for its stated
purpose has been confirmed by a series of clinical studies involving over 6000 obese subjects. Two-year
data from the phase III multicenter Rimonabant In Obesity (RIO) trials showed that the positive results
seen after a year's treatment were sustained over the full two-year trial period
[70]
.
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When to harvest your marijuana buds!
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Conflicting cancer risks associated with cannabis use. Useful information about synthetics
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