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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5515_Библиотеки_им_академика_М_И_Перельмана.pdf
until you remove the grip on your nose. Once you do open your nose, you’ll immediately
get a waft of cherry or strawberry odor that makes you think you are tasting those fruity
tastes (as artificial as they might be). Odor assists taste to produce our perception of
flavor in our brains.
Taste and smell work through the binding of chemical compounds to tiny molecules
embedded in the membranes of some of the cells in your mouth and nose, respectively.
The small molecules that make it to your tongue and nose are all different sizes and
shapes. Cannabis has not only cannabinoids but also many other molecules such as
terpenoids, which are rather small (but in the same size range as THCA and CBDA).
The terpene molecules and the cells in your olfactory system act like cards and card
readers, respectively, to get the information to your brain about the odors and tastes.
Part of the small molecules that do the sensing poke out of the cells to the outside, and
some of the molecules poke into the inside of these smell and taste cells. Terpenes (and
other molecules—see fig. 8.1) interact with small membrane-bound proteins on the cell
surface. These proteins are called receptors, and a chemical signal is produced that is
turned into an electric potential; this electrical signal is sent to your brain, where it is
interpreted as a particular odor or taste.
Your taste-sensing cells detect five basic kinds of taste—sweet, salty, sour, bitter,
and umami—and this means that you have five basic kinds of molecular receptors for
taste in your gustatory system. Your olfactory system, on the other hand, has hundreds of
these membrane-bound proteins, and because these receptors can act in a combinatory
fashion, millions if not billions of different odors can be detected by the typical human
olfactory system. The system is so fine-tuned that molecules that look almost identical to
one another in three dimensions can be discerned as different, because the angles that
the molecules’ carbon atoms align with each other are different from terpene to terpene.
Figure 8.2 illustrates four terpenes with identical chemical formulas (C10H16) and with
very similar (but not identical) three-dimensional structures. Although your gustatory
system might not detect a difference in taste of these four terpenes (they mostly have
citrusy tastes), your olfactory system will detect the slight structural differences of these
molecules and interpret them in your brain as different odors (specifically turpentine,
herbal, herbal/citrusy, and citrusy). These olfactory signals will also impact the overall
sensation of taste.
Taste and smell interact to give us an overall sensation and mental picture for the
foods, beverages, and drugs we ingest. Figure 8.3 shows four terpenes that do not have
the same chemical makeup (are not isomers) as the ones shown in figures 8.1 and 8.2.
Their chemical formulas are shown in parentheses after the names (nerolidol, linalool,
alpha-humulene, and beta-caryophyllene) of each terpene. The overall shapes of these
terpenes are notably different, making the receptors they trigger quite different and in
turn the tastes they evince quite distinct. When combined with the different odors for
these four terpenes, a plethora of combinations of smells and tastes is created.
Figure 8.1. Terpenes inhaled in a hit of marijuana. All the terpenes shown here have the chemical formula
C10H16. Despite having the same chemical formula, they all have substantially different three-dimensional
structures. When two chemicals have the same chemical formula but different three-dimensional shapes,
they are called isomers.
It is possible that some individuals can taste more or less intensely than others.
Perhaps you are one who abhors spicy food or hoppy beer. Or you could be someone
who rarely if ever is put off by the taste of the food you are eating. But almost everyone
has the same five kinds of taste receptors, so it can’t be that someone sensitive to bitter
or spicy food or tolerant of all kinds of foods has more or fewer of the receptors. Then
how do some people end up tasting more intensely or less sensitively than others?
Figure 8.2. Four terpenes with identical chemical formulas and similar two-dimensional shapes. The central
carbon ring is depicted as flat on the surface of the page and shows how the two methyl groups (CH3) on
the left side of the molecule are arranged differently in the four terpenes. The methyl group is twisted into
different orientations in the four terpenes. All these terpenes share a chemical formula of C10H16 and are
isomers of each other, as well as isomers of the molecules in the previous figure.
One old notion about how we taste held that different areas of the tongue were
responsible for different tastes. For instance, the tip of the tongue was thought to be the
area where we tasted sweet, while the back of the tongue toward our gullet is where we
supposedly tasted the five categories of the gustatory experience. But our tongues are
covered with a field of small mushroom-shaped structures called fungiform papillae—
normally about 10,000 of them at birth. Each papilla has cells with all five of the
different kinds of receptors embedded in the membranes of each cell. Hence each
papilla (also called a taste bud) has the capacity to sense all five major categories of
taste. Thus the idea that there is regional control of tastes by the tongue flies out the
window. As with our hearing, we lose some of the papillae as we age, and by doing so
lose some of our taste.
These small structures are bathed with molecules from the food we ingest, and
these molecules find places to attach to the receptors embedded in the cell membranes
of our taste buds. When bound to a molecule such as salt, the receptors in the taste bud
cell membranes will produce a cascade of reactions in the cell that soon sends a signal
to the brain. It isn’t the kinds of receptors that enable some people to taste more
intensely than others; it’s the number of the papillae that imparts the capacity to taste
intensely (or hardly at all). An intense taster is also called a supertaster or hypertaster,
and a person who can stand any taste is called a subtaster or hypotaster. A person in
between is considered a normal taster. A supertaster will have more than thirty or so
papillae in a circular area with a one-centimeter diameter; a subtaster will have fewer
than ten; and normal taster will be in between.
Figure 8.3. Four terpenes that are not isomers of the previous nine. In other words, they do not have the
chemical formula C10H16. On the other hand, beta-caryophyllene and alpha-humulene are isomers of each
other. These larger terpenes take different three-dimensional shapes.
A typical population in the United States will include about one-quarter
supertasters, one-quarter subtasters, and half normal tasters. Although THC has little to
no taste, CBD tastes quite bitter. Supertasting will definitely influence the taste of CBD
and make it seem overly bitter. The taste sensations of CBD in normal tasters and
subtasters are more than likely not intense, even when the CBD is concentrated into oils.
But it always tastes better to mask the taste of a bitter compound (like CBD) with
something sweet when ingesting it. If you are a supertaster, you might need more
masking of the bitter taste than other people when ingesting it.
On to the Lungs
We may have lost track of our THC molecule with this diversion into taste. But it is still
wafting along with all the terpenes previously mentioned and many other molecules.
Cannabis is known to make an enormous number of chemical compounds, and will be
volatile in inhaled smoke. A weird phenomenon occurs when THC interacts with the
cells in your mouth. When THC first hits the mouth, it interacts with the gustatory
receptors and then wafts into the nose to interact with the odorant receptors. You will
get a bud smell and a floral taste. But THC also will interact with the salivary cells in
your mouth and produce the odd-sounding physical state of xerostomia. This state is
caused because THC shuts down the production of saliva, causing what is otherwise
known as cottonmouth. Saliva is as efficient as any mouthwash in cleansing the mouth of
food particles and bacteria that will cause odors and result in bad breath. In addition to
causing cottonmouth, marijuana smoke will leave residues of plant toxins, tar, and an
array of other stinky molecules. “Weed breath” is thus amazingly unpleasant both for the
breather and the person being breathed on.
But let’s say our single THC molecule makes it past the receptors in the mouth and
doesn’t interact with the salivary cells or contribute to xerostomia. What happens next?
It enters the upper airway and, oddly, has two impacts that are somewhat opposite of
each other. The THC and other molecules in the hit you took can cause coughing,
wheezing, and sputum production. These adverse effects occur because THC and other
molecules are irritants, and the cells in the upper airway recognize them as such. But
once the THC interacts with the cells a little longer, it activates upper airway hyperresponsiveness, anti-inflammatory activity, and antitussive activity (cough suppression).
Our THC molecule thus gets past the lining of the upper airway and travels to the lungs.
Our lungs are an architectural wonder. They are made of three lobe-like structures
on the left and two on the right. Tubes large and small are distributed throughout the
organ, with the major feeding of the marijuana smoke occurring through a large tubelike
structure called a bronchus (one on the left and one on the right). These primary bronchi
then branch into hundreds of smaller tubes or secondary bronchi, which then branch into
even smaller tubes or bronchioles. At the end of the bronchioles are microscopically
small sacs, the alveoli. The alveoli are important in the primary function of the lung,
because they are where gas exchange occurs; oxygen is pushed into the bloodstream,
and carbon dioxide is pulled out by exhaling. Gas exchange enables oxygen to travel
throughout the body in the bloodstream, with some of it going to the brain. Our lucky
THC molecule makes it to a small alveolus at the tip of a bronchiole (fig. 8.4), which
absorbs it and allows the THC to jump the alveolar barrier (because it is a small
molecule) and enter the bloodstream. Once in the bloodstream the THC molecule
travels rapidly to other organs. The THC molecule will make it to the brain rather
quickly, where it jumps the blood–brain barrier and enters our nervous system. I have
dedicated chapter 9 to its further psychoactive journey, but will take the molecule
through your stomach here.
Figure 8.4. Drawing of a healthy lung showing primary and secondary bronchi and bronchioles.
The Stomach
We are now onto our second THC molecule, which comes from a food such as ingested
white chocolate that has been laced with ground decarboxylated bud. The chocolate
tastes sweet, and the sweetness and vanilla taste mask most of the somewhat bitter
herbaceous taste that THC will impart to the gustatory and olfactory systems. In the
mouth our second THC molecule is confronted with the massive mechanical disruption
of the teeth. While maceration occurs, the salivary glands start to produce enzymes.
Amylases and lipases are two enzymes in the saliva, but these enzymes will avoid the
THC molecule and instead degrade the sugars and long-chain carbohydrates of the
white chocolate, making the THC molecules more available later in the process. Past
the tongue, the macerated material containing our THC molecule gets to the esophagus.
The esophagus is a tubelike organ with two jobs—to get food to the stomach and to
keep stomach acids from getting out. It accomplishes the first by muscle movements
called peristalsis, and the latter by a sphincter that resides at the junction of the
esophagus and stomach.
In the stomach the THC molecule is bombarded with acids and digestive enzymes.
But our lucky molecule reaches the bloodstream before these enzymes have an impact
on it, by being absorbed by the cells of the stomach. Once absorption occurs, the
molecule will pass into the bloodstream easily. Even if it passes through the pyloric
valve (the valve that connects the stomach to the small intestine), it will more than
likely be absorbed by the small intestine and transferred to the blood, or it will get
absorbed in the small intestine and shuttled onto the liver. If it makes it past the small
intestine it will end up in the kidneys and eventually in your urine or will be eliminated
in your feces. A surprising amount makes it to both of these exits, which is why if you
are using cannabis and are tested for drugs, you will most likely lose out to cannabis.
After passing through the stomach, our second THC molecule will probably travel
first to the liver. The liver functions as a detoxification device for whatever you have
ingested. There our THC molecule might encounter a protein called cytochrome P450
and other cytochrome enzymes called CYP2C9 and CYP3A4, which detoxify most of
the molecules such as THC. But let’s posit that our lucky THC molecule avoids
detoxification by these CYP molecules. If so, other liver enzymes will transform some
of the remaining THC into slightly modified forms of THC. The THC that gets into our
bodies by inhalation or ingestion is called delta-9-THC. The THCs that are metabolized
from delta-9-THC in the liver are delta-11-OH-THC and delta-11-COOH-THC (fig.
8.5). The former is more psychoactive than delta-9-THC, and the latter is not
psychoactive at all. These molecules are moved to the circulatory system, where they
flow about the body much in the same way that our inhaled THC molecule did, reaching
many organ systems. Our second THC molecule makes it to the arteries of the brain,
where it jumps the blood–brain barrier and enters our nervous system. Its brethren
delta-11-OH-THC molecule gets there too simultaneously. For now we will simply
state that the THC molecules which make it to the brain will interact with the
cannabinoid receptors there.
Figure 8.5. The top figure shows the route of metabolism when delta-9-THC is inhaled into the lungs. The
thickness of the arrows indicates the relative abundance of that molecule being transmitted from one organ
system to the next. The bottom figure shows the route of metabolism for ingested delta-9-THC. The
molecule is transported to the stomach, where it is absorbed and sent on to the liver. In the liver there are
major chemical transformations of delta-9-THC to 11-OH-THC and 11-COOH-THC. These molecules are
then transported to the heart and on to the brain. The pathway through the stomach therefore transmits
mostly the highly psychoactive 11-OH-THC and smaller amounts of nonpsychoactive 11-COOH-THC and
moderately psychoactive delta-9-THC.
The dynamics of THC delivered to our bodies by ingestion differ from the
dynamics of THC delivered by inhalation. First, with inhalation the THC bypasses the
liver and can go directly to the brain. With ingestion, the pathway goes through the liver,
and this takes more time, which is why when cannabis is inhaled the psychoactive
effects are immediate. It is also why when you ingest cannabis you need to wait for it to
take effect. A second dynamic is that the more psychoactively powerful delta-11-OHTHC is in tenfold higher concentrations when ingested relative to inhaling. A final
dynamic common to both ingestion and inhaling is that THC can also bind up in fat
tissue, where it can lie dormant for several days. Eventually the THC is released slowly
back into the bloodstream from these fat deposits. This slow release is why if you are
tested for THC in your system a week after your last toke, you might still be positive for
cannabis consumption.
So far I have not discussed CBD’s journey through the body. But because it is about
the same size and shape as THC, what I have described about the movement of THC is
generally true for CBD. The only difference is the way that receptors interact with the
two molecules in the brain and elsewhere. The most impactful destination of CBD
molecules is also not necessarily the brain at all.
What about the Skin?
CBD will enter the body when smoked and when eaten, the same way as does THC.
The primary destination for THC is the brain. When smoked, it enters the bloodstream
via the lungs, and when eaten by means of the stomach and liver. In the long run, some
CBD will make it to the brain the same way THC does, but the cannabinoid receptors
are not the only places where it ends up. Instead, it seeks out other kinds of receptors in
the brain such as adenosine receptors, serotonin receptors, and vanilloid receptors.
Adenosine receptors are involved in the expression of anxiety. Serotonin receptors,
when activated, have an antidepressant effect. Vanilloid receptors are involved in
inflammation and pain reception. But there is another way to enter the body for which
CBD seems to be well suited—topical application. Because some of the medicinal uses
of CBD are for localized parts of the body, it makes sense to apply it near the injured or
painful site and not by treatment to the entire body. So how does topical application of
CBD work? Let’s start by considering how organisms distinguish between what is
inside them and what is external.
Bacteria, archaea, and single-celled eukaryotes (cells with a nucleus) all have
cellular membranes delimiting their insides from the outside. Different cells have
different functions, and such functions are best carried out separate from other cells;
keeping these functions on the inside of cells does the trick quite well. To accomplish
this, cells have membranes and also have evolved ways of regulating what kind of
communications can be made between cells. Cell clusters that have developed this way
of communicating are usually called tissues—including neural tissue, stomach tissue,
and skin tissue. Multicellular organisms such as humans also have a need for keeping
the inside from the outside on an organismal level.
Scientists have only recently learned about the evolution of skin. Obviously singlecelled organisms lack skin, so researchers need to look for protoskin, or the origin of
skin in multicellular organisms. Plants have skin, but it’s not the same kind of skin
animals have. It is composed of a single cell layer covered with a waxy polymer that
separates the internal organs and other parts of the plant from the outside world.
Although human skin is different from bird or lizard skin, most mammalian skin is
similar to ours, except that we are much less hairy than most mammals. But the cells that
make up the skin, the various layers of skin, and the kinds of molecules floating around
in the cells of the different layers of skin are similar to those of other mammals.
Skin is our first line of defense in making sure we keep the outside from getting
inside (and good things from getting out). In addition to the mechanical exclusion of bad
things, like bacteria or toxic molecules, skin is an immunologically active tissue. There
are three major layers: epidermis, dermis, and an area that is collectively called the
subcutaneous area (fig. 8.6). The epidermis is made up of specialized cells called
keratinocytes because they have abundant amounts of a protein called keratin. Keratin is
a “jack of all trades” fibrous protein and amazingly versatile. It is used by vertebrates
in all kinds of structures like hair, fingernails and toenails, feathers, horns, claws,
scales, and hooves. Its role in the cells of these tissues is structural, and in fact the
protein provides tensile strength to the cell and hence to the tissue. The epidermal
keratinocytes form sublayers, of which the most important for topical application is
called the stratum corneum. Imagine a brick wall with mortar that is used to seal the
spaces between the bricks. In the stratum corneum the cells (also called corneocytes)
are the bricks, and a lipid matrix serves as the mortar to create a rather efficient barrier
against the outside world. Just below the stratum corneum is a structure called the basal
lamina, which also is fibrous and makes an effective buffer from outside to in. The rest
of the cells of the epidermis contain many active proteins and receptors, which could be
the destinations for our CBD molecule. Immune cells are also present in this part of the
epidermis.