Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5515_Библиотеки_им_академика_М_И_Перельмана.pdf
Cannabis Use Disorder
A primer on cannabis addiction by researchers Jason P. Connor, Daniel Stjepanović,
Bernard Le Foll, Eva Hoch, Alan J. Budney, and Wayne D. Hall points out that cannabis
dependency is best broadly defined as the inability to stop consuming cannabis even
when it is causing physical or psychological harm. In their terminology this is called
cannabis use disorder (CUD). Connor and colleagues observe that “in 2018, the United
Nations estimated that 192 million persons or 3.9% of the global adult population had
used cannabis in the previous year.… Approximately 9.9% of individuals who reported
cannabis use in the past year were daily or near-daily users.… According to the most
recent global estimate 22.1 million persons met diagnostic criteria for Cannabis Use
Disorder in 2016 (289.7 cases per 100,000 people).”
Cannabis use disorder has become a major subject for study among medical
professionals and human geneticists. Over the span of one recent year (2021–2022), at
least twenty publications examined the genetic data on cannabis use disorder, many
trying to pinpoint any human genes that might be associated with cannabis dependency.
These publications generally shared the same conclusion: there is indeed a genetic basis
for cannabis use disorder. The major method they adopted was the GWAS approach
described in chapter 13, which uses the variation of the population being examined and
a case-and-control experimental design to pinpoint regions of the genome that are
associated with the cases. In the case of cannabis use disorder, entire genome sequences
for large numbers of humans and the metadata on individuals’ usage patterns were
employed.
Prior to 2020 several GWAS studies were performed on cannabis use disorder
with tantalizing results but also with caveats. One of the bad raps on these earlier
studies was the sample sizes, which used slightly over 2,000 cases. For GWAS,
increasing sample size often increases the accuracy of the inferences made. In 2020 a
publication with over 200 authors presented results of an extremely large GWAS study
of cannabis use disorder and related disorders. These researchers used data from
363,884 controls and 43,380 cases. Previous to this study, the sample sizes were only
about a tenth of this size.
Many human traits have highly complex genetic architectures. For instance, height
is apparently controlled by hundreds of genes in our genome. Nearly 300 genetic loci
have been tabbed as associated with schizophrenia (which is probably several different
disorders). One might expect cannabis use disorder to be rather complex too.
Surprisingly, though, the cannabis use disorder GWAS revealed fewer than ten
associated genetic loci. Of these only two passed muster when more stringent criteria
were used to identify the best associations. These two loci are CHRNA2 (as well as a
gene called EPHX2, which is linked to or in very close proximity to CHRNA2 in the
genome) and FOXP2. The former (CHRNA2) showed a strong association with CUD in
previous studies and has a cellular role as a gated ion channel protein. Its activity has
also been strongly implicated in nicotine abuse. The connection of CHRNA2 to
cannabis use disorder is tantalizing, since both nicotine abuse and cannabis use disorder
involve ingestion by smoking. Equally tantalizing is that CHRNA2 has also been shown
to be one of the many genes associated with different forms of schizophrenia. As noted
earlier, schizophrenia in those predisposed to the disorder can be triggered by
marijuana ingestion.
The FOXP2 gene codes for a protein that is a transcription factor. It is one of those
genes that is involved in many human traits. It appears that it is important in regulating
the expression of many different genes. Surprisingly, it has been associated with other
behavioral traits such as age at first sexual intercourse, generalized risk tolerance, and
educational attainment. Some of the cellular roles of FOXP2 also point to a
neurological role, as it has been shown to be essential to synaptic plasticity. Its ubiquity
in gene regulation makes it difficult to be more precise about its role at the cellular
level in cannabis use disorder.
While the GWAS studies are intriguing and point to interesting genes, pinpointing
exact causal roles is still beyond the reach of researchers. But there are potential
remedies for cannabis use disorder. The first and most obvious is abstinence, but
relapse into cannabis use disorder is common among those with the disorder when they
find themselves in the presence of the substance or when in stressful situations.
Cannabis use disorder involves many regions of the brain (CB1 receptors are
particularly plentiful in the brain), and so targeting a specific brain region for treatment
is tricky. Cannabis use disorder withdrawal symptoms can be treated with drugs such as
dronabinol, nabilone or nabiximols. Finally, the pathway to anandamide synthesis can
offer treatments. The idea here is to displace THC from the neural system with the
natural endogenous neurotransmitter anandamide. Increased anandamide can reset
neurotransmission patterns and alleviate the symptoms of withdrawal.
Overuse of any psychoactive substance such as alcohol or marijuana is something
to be aware and wary of. As toxicologist Andrew Monte puts it, “Cannabis is not the
root of all evil, nor is it the cure for all diseases.… You’ve got to understand what the
good is and what the bad is, and then make a balanced decision.” Grinspoon and
Bakalar were correct in pointing out that cannabis offers a treasure trove of medicinals.
But any drug or treatment needs to be balanced with its side effects. In many ways
modern marijuana use has sidestepped a lot of the reckoning concerning the side effects.
But legalizing it has brought cannabis into the limelight, where it can now be scrutinized
and understood better. Balance is everything.
17
Contemporary Cannabis Culture in Nine
Graphs
Marijuana has been infused into our contemporary culture in such an extreme way that
this book can only minimally touch on its current effects. Because our future use of the
plant and its compounds will be affected by changing social, political, cultural, and
philosophical attitudes, we need to consider some of the trends that cannabis culture has
experienced in the past few decades and might in the future. I will consider the trends in
attitudes toward legalization, marijuana potency, recreational and medicinal use in the
United States, stock indices, spending on US research, use by age, global distribution of
cannabis, and cannabis’s influence on our entertainment.
Legalization
The most recognizable changes in attitudes toward marijuana followed its legalization
in California in 1996. Figure 17.1 summarizes the results of Pew Research Center polls
taken from 1969 to 2020. I show only the years 1996 to 2020; this graph depicts the
overall trend of increasing support for legalization (white for legalization and dark gray
against it). The other lines in the graph (black and light gray) are data from Gallup polls
taken from 1996 to 2020 involving people’s attitudes to gay marriage. The lines overlap
considerably, with the crossover point coinciding nearly perfectly in the two surveys.
Are attitudes to legal gay marriage driving attitudes to cannabis legalization or vice
versa, or is there no relationship at all?
Figure 17.1. Survey results from 1996 to 2020. The first survey question was, “Should pot be legal?” White
= no, light gray = yes. The second survey question was, “Should same-sex marriages be recognized as
legal?” Dark gray = no, black = yes. Marijuana poll from Pew Research Center; same-sex marriage poll
from Gallup.
The key word for understanding graphs such as this one is “trend.” Its definition is
“a general direction in which something is developing or changing.” Epidemiologists
use it to summarize the changing dynamics of a disease that spreads in populations.
Interpretations of a trend can serve as a basis for hypothesis testing and future research,
and can suggest ways to deal with the overall trajectory of a phenomenon. A trend in
itself won’t test a hypothesis, though. It can only suggest the presence of something, and
further study is necessary to determine the causation of the phenomenon. The first lesson
from this cannabis graph is that it is a simple representation of real data. These kinds of
graphs are persuasive because they are based on real data, as opposed to graphs that
simulate outcomes.
The second observation is that there are four lines and hence four trajectories. A
trajectory is not a trend, but rather a visual representation of the course of a measured
variable over age or time that leads one to see a trend. Assessing the trajectories of
different categories is an important step toward perceiving a trend and understanding its
nuances. Once the trajectories are plotted, a trend might or might not be evident. If there
is no trend, that’s not so bad, because the analysis tells you something important: there
are no changes in the Y variable with time, and that could be critical information. But
fig. 17.1 shows a continuous trend to more acceptance of legal pot over time. Likewise
for attitudes to gay marriage: there is a continuous and positive attitude to legal
recognition of same-sex marriage.
The trends in the graph can now be stated as, “The attitude toward legalizing pot
changed from mostly negative to mostly positive from 1996 to 2020. Likewise, the
attitude toward the legal aspects of gay marriage changed from mostly negative to
mostly positive from 1996 to 2020.” Even with these more clearly stated trends, we
still cannot say anything about gay marriage attitudes having a causal relationship with
attitudes to legalizing pot. We can only say that it appears that trends in positive
response to legal pot are correlated with the attitudes of people toward gay marriage.
Gay marriage may not (and most probably does not) have anything at all to do with pot
smoking; we can’t say anything about causation.
How would we go about demonstrating, for example, that attitudes to pot caused
the trends of attitudes to gay marriage (or vice versa) in the graph? This endeavor
would involve posing a hypothesis and testing it. The hypothesis would be something
like the null hypothesis (typically the null hypothesis is written as H0) = Attitudes to
legalization of pot are directly responsible for increases in positive attitudes to gay
marriage. An adequate test of this hypothesis would no doubt lead to its rejection. But
the way science works is that rejected hypotheses can help advance us. When a
hypothesis is rejected, we move on to a more restrictive or specialized hypothesis that
can be tested to find an explanation for the correlation.
In subsequent studies one might interview people with a cleverly designed survey
that strives to understand the sociological reasons why, at a particular point in time in
the 2010s, people’s attitudes to pot and gay marriage reversed. Maybe politics was
involved; maybe religion; maybe it was Barack Obama’s presidency; or maybe it was
something else a creative social scientist can pinpoint. But any causation will remain a
mystery until a hypothesis is tested. Using the scientific method, we can whittle down
the possibilities and find better explanations for phenomena we see in both nature and
culture.
Is Cannabis Becoming More Potent?
It is commonly believed that cannabis products are getting stronger and stronger as time
goes on. What can we discover about that perception? Fortunately, agencies such as the
FDA and DEA keep track of THC and CBD concentrations in confiscated marijuana.
Figure 17.2 presents data from 1995 to 2018 compiled by the DEA. Specialized
equipment (gas chromatography and mass spectrometry) is needed to accurately
determine the THCA content of a sample, and these determinations are often highly
accurate, but sometimes not. Nick Jikomes and Michael Zoorob have compiled data
from over 300,000 analytical tests in Washington State to gauge the accuracy of THC
and CBD concentration estimations. Their results “documented systematic differences
in the cannabinoid content reported by different laboratories, relative stability in
cannabinoid levels of commercial flower and concentrates over time, and differences
between popular commercial strains.” In general, THC levels can be illuminating, and
there is no reason to doubt the overall trends demonstrated by figure 17.2. The results
come from a single lab with the same standards (DEA). Measurements at different time
points were taken, and only well-defined commercial strains were used.
The results demonstrated a fourfold increase in THC concentration from 1996 to
present. The increase was somewhat linear over the three decades of the surveys. On
the other hand, CBD concentration appears to have dipped over the years, even though
the concentration measures in 1995 and 2018 were nearly the same. CBD concentration
doubled between 1995 and 2002, but consistently dropped to a low 0.14 percent in
2017.
This trend for increase in potency is not just a US phenomenon. Seizure of illicit
European marijuana and subsequent THC analysis have shown the same overall trend of
increased potency in Europe.
My marijuana was nothing like my daughter’s, who was born in 1996. What does
this increase in potency indicate? One possible reason for the sharp increase is demand
for a more potent psychoactive product. For a long time, there has been no regulation of
THC content in illicitly grown marijuana, and growers could amp it up as much as
possible. For recreational reasons (a better, more powerful high) growers did the
breeding that increased the THC content. Another likely factor could be economics.
According to pharmacologist Mahmoud A. ElSohly, “the higher the THC content is, the
more expensive the product.” Demand for more expensive pot was strong enough to
induce growers to increase the THC in their strains. This purely economic reason brings
us to our next set of graphs addressing the economics of marijuana.
Figure 17.2. Proportions of THC and CBD content over the years since legalization began. Adapted from
Chandra et al. (2019).
Marijuana as a Booming Business
There are many indicators for a healthy business. The first we examine here for the
cannabis industry concerns patents. This indicator is similar yet distinctly different from
the clinical trial indicators discussed in chapter 14. Patent analysts Joseph Wyse and
Gilad Luria have provided an extensive review of cannabis patents as of 2021. They
suggest that product development in the cannabis industry has three major areas:
upstream agritech, midstream chemistry/analytics, and downstream medical
applications (table 17.1). Each of these areas produces different challenges for patent
development of medical cannabis products.
Patenting cultivars is another question. To date about 300 different cannabis strains
have been patented, which means over 300 cultivars have been deemed distinct enough
to warrant intellectual property rights protection. We can expect a deluge of patent
applications as the legalization ramifications have more effect on cannabis farming and
breeding. In addition, experimental strains produced by gene editing might also swell
the number of patent applications in the cannabis industry. Wyse and Luria show that
there was a significant peak for 2018 in the number of patent filings for all three stages
of cannabis product development. They reasonably conclude that patent filing growth is
related to legalization and the economic lure of the cannabis industry. The economic
siren is what this section’s graphs are all about.
Table 17.1. UPSTREAM, MIDSTREAM, AND DOWNSTREAM DEVELOPMENTS IN THE MEDICAL
CANNABIS INDUSTRY
Upstream Improved strains
Genetic modification
Plant material assessment
Harvesting technology
Postharvesting processing
Midstream Extractions
Purification methods
Separation methods
Downstream Disease treatments
Medical devices
Compositions
Formulations
Dosage forms
It is undeniable that marijuana has become a booming business since its
legalization in many US states and in other countries. The signs of its health as a
business included increased sales and employment. Figure 17.3 summarizes global
medicinal sales, global adult use sales, and job availability in the marijuana industry in
the United States. The trend lines are all increasing, with jobs going from under 100,000
in 2017 to almost 500,000 in 2023. Simulations of job availability in 2024 and 2025
project another 100,000 or so workers in the cannabis arena. Sales are also trending
upward, showing a tenfold increase in sales of medicinal marijuana and a twenty-fivefold increase in sales for adult use.
Figure 17.3. Summary of trends from 2017 to 2022 and simulated to 2024. The top line represents global
adult use in billions of US dollars; the middle line represents global medical use in billions of US dollars; the
bottom line shows the number of US jobs in the cannabis sector in hundreds of thousands. Adapted from
ElSohly et al. (2021).
Another indicator of business health is the number of jobs added each year. Figure
17.3 shows the increase in jobs from 2017 to 2021 in the United States was about
100,000 new openings. The state-by-state increases are equally interesting—Florida
led the way with over 9,000 new jobs, followed by Nevada, Washington, Arizona, and
Colorado, all of which had between 4,000 and 7,000 jobs open. Pennsylvania, New
York, New Jersey, Illinois, Alaska, Maryland, and Oklahoma were all doing quite well
too, with between 1,500 and 3,000 new jobs created in the cannabis industry per state.
Because each state has different population sizes, a better indicator of what these
numbers mean would be the percentage of job gains in each state. This metric suggests
that Pennsylvania (with a 4,200 percent increase in jobs) and Florida with (a 700
percent increase in cannabis jobs) are experiencing especially rapid growth of the
cannabis industry work force. Another aspect of economic health concerns how much
tax revenue governments take in from their regulation efforts. This variable is also
trending upward.
Since legalization, the US stock market has seen many cannabis-based companies
become publicly available. There are over 5,000 indices characterizing the stock
market, the most popular of which are the S&P 500, Dow Jones Industrial Average, and
Nasdaq Composite. For cannabis there are about ten indices that can be used to
compare and contrast stock performance. New Cannabis Ventures (see For Further
Reading) lists four indices and provides plots for stock performance by day and
compressible options to view trends over ten years. Figure 17.4 shows a ten-year
projection of the Global Cannabis Stock Index, based on the performance of publicly
available cannabis entities. Other indices based on different assumptions and criteria
will show different patterns, but the graph in figure 17.4 can suggest how the stock
market influences our attitudes to cannabis and vice versa. One should always inspect
the scales on the y-axis of a graph. What might look like a smooth period of stock
performance between 2018 and 2023 in figure 17.4 (albeit a little jagged) can on a
different scale appear wildly unstable. The caveat is that the timeframe examined here
is over a decade, and the price of stocks ranged from $1,000 to a little under $10. There
was a huge peak in 2014, when stock prices started at about a little under $100 and
skyrocketed to $1,000. These prices persisted for about a year and then dropped
precipitously to about $50 by 2016. This pattern is what stock market experts would
call volatile.
Figure 17.4. Price fluctuations in the Global Cannabis Stock Index from 2014 to 2023. Data from the Global
Cannabis Stock Index.
Over the last eight years, though, the average stock price has stayed somewhat
stable but bounced between a little under $200 down to about $10. Again, scale is
important here. What I am calling a relatively stable period might look to others like a
fairly volatile period. If stock was bought in 2016 and sold in 2018 a trader might make
as much on average as $100 per share sold. On the day I sat down to write this chapter
the Global Cannabis Stock Index was down to ten dollars per share. Other indexes had
a bit higher average stock prices but in general as the figure shows there is a slow
gradual decrease in stock price since 2021.
The dips and peaks can be correlated with specific events that impacted the value
of cannabis stock. For instance, that blip up in 2018 coincides with the legalization of
recreational cannabis in California (January 1, 2018) and also caused by legalization in
Canada a few months later (October 17, 2018). The dip around 2020 is more than likely
the result of California increasing its tax markup on cannabis from 60 percent to 80