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But think back to chapters 9 and 10, which discussed the biosynthetic pathways for
plant cannabinoid synthesis. These aren’t simple pathways. If an efficient bioreactor is
desired, the many steps in the synthesis of the cannabinoids all need to be a part of the
process. Nevertheless, considerable success has been attained in genetically
engineering THCA and CBDA bioreactors for commercial use. One sign of its potential
future growth is the number of patents submitted for accomplishing this method of
CBDA and THCA production.
14
Modern Medicinal Cannabis
I suffer occasional bouts of gout. It is an arthritic autoimmune disorder brought on by the
collection of urate crystals in some of your joints. It usually hits one of your big toes. It
is intensely painful, almost to the point that you might want to saw off your big toe. Men
are more susceptible to the disorder, first afflicting most of its victims in their thirties to
fifties. Diets rich in high-caloric, fatty foods are usually a cause of onset, along with
overconsumption of meats and shellfish. Imbibing too much beer or drinks with fructose
may trigger it too. Other factors such as weight, diabetes, kidney disorders, and high
blood pressure can trigger a flare-up. Gout can be slowed down by allopurinol, a
compound that breaks down uric acid; colchicine, a compound that ameliorates
inflammation; and corticosteroids such as prednisone, which also curtail inflammation.
All these have the possibility of problematic side effects, but they are federally
approved remedies.
I had read anecdotes about CBD and THC being effective at remedying the
symptoms of gout. Apparently CBD offers some relief. If a little THC is added to the
mix, then sleep becomes easier during a gout attack. (Usually gout is a real sleep killer,
because even the contact of sheets with the surface of your toes produces a severe
burning pain.) I contemplated trying this remedy for gout bouts, but one thing held me
back: CBD and THC are not FDA-approved remedies for gout (nor for many other
ailments). I could have done an “experiment of one” and tried CBD, but that is not
recommended when medicine is involved. And if I felt better, I wouldn’t be able to tell
whether it was due to the CBD/THC or some other factor that I wasn’t accounting for.
The temptation to use CBD as a gout remedy, however, stimulated me to examine more
deeply how cannabis medicinals are developed, tested, and approved.
A Sample Size of One
People have used cannabis for thousands of years as a remedy for one or another
malady. The medicinal applications in East and South Asia are especially well known
and wide-reaching. Many ancient medical texts from China outline the use of cannabis
as a treatment for several maladies. India has also been a longtime source of anecdotal
information about the medical uses of cannabis. It is this Indian knowledge that has
made the biggest impact on how westerners think about cannabis as a medicinal, much
of it thanks to one person—William Brooke (WB) O’Shaughnessy. He was an assistant
surgeon in the East India Company, stationed in the city of Kolkata (Calcutta).
Celebrated as the person who brought telegraph circuits to Kolkata at the Botanical
Gardens in Shibpur, he was also a forensic poison expert and had stopped a cholera
outbreak in Kolkata. Oddly, the original reason he went to India was because he could
not pass his medical exams in England.
O’Shaughnessy published the first clinically based paper on the effects of medical
marijuana in 1839, marking the birth of modern medical cannabis research. This paper
simply described the many ways that he had observed people in Kolkata preparing and
using cannabis as a medical agent. In some cases, he described his own administration
of cannabis extracts to patients with various medical anomalies. He used anecdotal
evidence to convey the range of medical effects of cannabis, thereby starting a long
history of medical trials to assess the efficacy and safety of drugs and treatments for
humans.
One report in his paper featured many of the aspects of a modern clinical trial. It
concerned a convulsive forty-day-old female infant. The convulsions suffered by this
poor, emaciated child were extreme and unrelenting, to the point that she could not sleep
or eat. After using every possible remedy he had at his disposal (warm baths, doses of
calomel, leeches, opium, and chalk), O’Shaughnessy decided that an alternate course of
action was needed. He convinced the parents that hemp administration might be a way
to treat their daughter, and they consented. A “single drop of spiritous tincture, equal to
one-twentieth part of a grain in weight was placed on the child’s tongue at 10 pm.”
When no immediate effect occurred, he added two more drops. She quickly fell to sleep
and slept for what I calculate from O’Shaughnessy’s reporting to be over twelve hours.
Upon waking, she began screaming for food, was fed, and fell back to sleep again. The
dosage set, he continued the application of hemp for the next four days, upon which all
convulsions ceased, the child behaved normally (“the pulse, countenance and skin
perfectly natural”), and she began to gain weight.
But a day after the child had been released to her parents, convulsions returned.
O’Shaughnessy decided to up the dose once more (five drops every hour), but the
convulsions only continued to occur. He then decided to examine the hemp medicine the
child’s servants were using to dose her. It turned out that instead of stoppering the
medical vial with the rubber cap he had provided, the servants were using tissue paper.
This caused evaporation and drying of the hemp extract, leaving water or a very diluted
extract in the bottom of the vial. “The infant in fact had been taking drops of water
during the previous day,” O’Shaughnessy wrote. He mixed a new hemp preparation,
administered it, and the child recovered as the dosage was adjusted. O’Shaughnessy
pointed out that her treatment had become “manifestly a struggle between the disease
and the remedy,” as administering large amounts of hemp just put the baby to sleep.
Indeed, some of the doses administered were huge, and according to O’Shaughnessy
would induce effects as “profound as a trance in two men laboring under rheumatism.”
Once a proper dosage was found, the child recovered completely and “regained her
natural plump and happy appearance.”
This original “sample size of one” clinical trial had everything a clinical trial
should have, although not in the best order. It involved a distinctive medical problem
that could be quantified easily (convulsions), close observation of attempts to determine
the right dose of a treatment, a placebo treatment (although not intended), and more dose
adjustment to refine what was safe. The unintended placebo was serendipitously
administered as a result of leaving the medicine vial capped with tissue paper.
While the origin of clinical trials and a scientific approach to understanding
marijuana use in medicine goes back to O’Shaughnessy, several other historical events
affected how cannabis was treated as a medicinal and how its use was eventually
legalized. It is difficult to provide a cogent summary of the legal history of cannabis,
because it encompasses many laws but has been different for different countries, and for
different states within the United States. I will focus first on US drug approval and legal
history and then touch on international law.
Clinical Trials
There have been many different kinds of clinical trials over the intervening two
centuries since O’Shaughnessy’s initial study. What is a modern clinical trial, and why
do we put so much effort and money into them? A clinical trial has two main purposes
and several minor ones. The first main purpose is to gauge how safe the drug or
procedure is. This is usually carried out with an animal model system. Any compound
that is slated as a medicinal agent needs to show minimal to no adverse impact on the
people it will be administered to. Certain adverse side effects can be tolerated in a drug
treatment scenario, but it is important for physicians to know the side effects so that they
can evaluate the impact of such effects on an individual basis. For instance, if a side
effect of a drug treatment is slightly raised blood pressure, you probably wouldn’t
choose to administer it to a person with heart problems. On the other hand, this side
effect might be tolerable if a patient has no history of heart problems.
Randomization is an important factor in a clinical trial. If a previous treatment
exists, the efficacy and safety of a new drug can be tested against the existing one. In this
kind of trial, the participants in the trial are separated into controls (those taking the
older treatment) and the trials (those taking the new treatment). The assignments are
done either double-blindly or “open-label.” Double-blind simply means that neither the
clinicians doing the testing nor the subjects of the clinical test know the source of the
treatment (that is, whether it is the older or newer treatment). After the collection of
data relevant to the effect of the two treatments are collected, the identity of the
treatment is revealed for analysis. Open-label means that both the clinician and patient
know the kind of treatment being administered.
Randomization removes any bias a clinician might have introduced into the trial,
and so it is usually the best approach to a clinical trial, although many clinical trials
early in the development of a drug are designed as open-label. A second kind of trial
involves the use of a placebo, which is a treatment that should have no physiological,
neurological, or disease-related effects. The trial treatment is then tested for efficacy
and safety against the placebo, and again the treatments (placebo and trial) are
administered in a double-blind fashion. Quantitative data are best for these kinds of
trials, as they are the best suited to statistical testing. The statistical testing usually tells
the clinician how different the results are compared to randomness (called
significance). If the significance level is set at less than 5 percent (which means that the
results would only be obtained 5 percent of the time if the system was completely
random), then the treatment is deemed to be better than random 95 percent of the time.
This statistic has what is called a P-value of less than 5 percent.
Table 14.1. CLINICAL TRIAL DATA FOR DRAVET SYNDROME
Variable Cannabidiol Placebo Median Difference P-value
Convulsive seizures per month
Baseline 12.4 14.9
Treatment 5.9 14.1
Variable Cannabidiol Placebo Median Difference P-value
Percentage change seizures –38.9 –13.3 22.8 0.01
The statistical test is a good one, as one wants to know whether there is a real trend
toward an effect with the administration of a novel treatment, and using randomness as a
benchmark is fully appropriate in this context. As an example, consider the results of the
first double-blind placebo clinical trial conducted by neurologist Orrin Devinsky and
colleagues, who tested 120 children with Dravet syndrome, a debilitating disorder
involving epileptic seizures. Table 14.1 shows the results of the clinical trial. Placebo
treatment resulted in nearly the same number of convulsive seizures per month (about
14) as a baseline estimate of number of seizures. But cannabidiol treatment reduced the
number of seizures almost 40 percent (from the 12.4 baseline to 5.9 in treated children).
The P-value estimating the difference between this result and random is significant at
less than 1 percent, meaning that the result would only occur 1 percent of the time if the
treatment had a random impact. This is strong evidence that the treatment is much better
than random. In the same study, Devinsky and colleagues showed that the treatment had
little impact on side effects such as sleep disruption, quality of life, and
hospitalizations.
The Bottleneck
There are four formal phases to a clinical trial. Each of these phases is examined by the
Food and Drug Administration (FDA), which has the authority to pass the drug or
procedure to the next phase and ultimately to approve the treatment or drug. Phase I
trials involve either animal systems or healthy humans (twenty to one hundred people),
to judge how safe the treatment is and to settle on proper dosage for the proposed drug
or procedure. Once the FDA review passes the drug or procedure on Phase I, the trials
go to Phase II, which emphasizes tests on effectiveness—in other words, whether the
drug does what its developers say it does. Designing a Phase II trial is tricky, because
the data collected need to convince the FDA that the drug or treatment is effective.
Usually between 100 and 500 people are used in these trials, and they can take up to
several years to complete. Safety and long-term side effects are other issues that are
expanded upon in Phase II trials. Phase III trials involve an order of magnitude more
people (about 3,000), enabling the FDA to assess the impact of the drug on different
groups of people, different dosages, and using the drug with other medications. If the
FDA deems the treatment or compound as passing Phase III, it is okayed for use by the
general public. But the full trial process isn’t truly over, as a complete assessment of a
drug’s efficacy and safety can only be addressed with very large sample sizes and
longer-term analyses of side effects, which can only be assessed with manufactured and
approved compounds. This latter process, called Phase IV, remains an ongoing process
even after the compound or procedure has been approved by the FDA.
On average it takes 10 to 15 years for a compound or treatment to pass Phase III,
after which the item then is manufactured and used in commonplace medical decisions.
A typical trial to bring a new drug to market costs between $1 and 2 billion. Figure 14.1
outlines the pharmaceutical drug development cycle and shows the success rate at
different phases of clinical trials. Because drug development is so expensive, some
significant and sometimes alarming new trends have been observed. The number of
compounds passing at each phase is getting smaller and smaller. Only 40 percent of all
compounds tested even make it out of Phase I and are passed on to Phase II, and onethird of these advance to Phase III, with only one-third of these finally being approved
by the FDA. If you do the math (one-third of one-third of two-fifths), only about 5 to 10
percent of any compounds entering clinical trials will end up being approved. This
creates a huge financial problem for drug companies. Most of the expense for
development and research for a clinical trial occurs later in the process, after close to
60 percent of the funds for a drug approval have been spent (Phase II and Phase III are
particularly expensive).
Figure 14.1. Clinical trial sequence, as explained in the text. Data from Harrer et al. (2019).
If a compound doesn’t pass Phase III trials, there can be a huge financial loss for
the drug developer (some estimate that the loss will be around $1 billion). In fact, the
number of new drugs approved by the FDA has halved about every nine years. Those
readers familiar with data processing might remember Moore’s law (it involves the
numbers of transistors on microchips, but can be summarized as the expectation that
computing speed and capability will double about every two years). What is happening
with drug development is the opposite, resulting in what is called Eroom’s law,
essentially the opposite of Moore’s law: the number of new drugs that are made
available halves every nine years or so. This is an alarming problem that begs for a
revised clinical trial process to cut the costs of clinical trials. Cost cutting would also
presumably result in quicker trial times. Such changes would enhance the development
of cannabis-related drugs for approval by the FDA.
The Test Case to End All Test Cases
In fact, we already have a great test case, in which a drug was developed at so-called
warp speed: the COVID-19 vaccines. As Anthony Fauci has stated, “The development
of several highly efficacious vaccines against a previously unknown viral pathogen,
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in less than 1 year
from the identification of the virus is unprecedented in the history of vaccinology.”
Understanding how the vaccines for COVID-19 were expedited might give us some
insight into potential expedited cannabis approval.
Most people believe that the development of the COVID-19 vaccines was triggered
by the pandemic, and that actual work toward vaccines started with the sequencing of
the SARS-CoV-2 genome during the pandemic. It then took less than a year to win
approval for the first vaccines. This notion that the vaccines were developed at
lightning speed and with insufficient care has contributed to vaccine hesitancy and is
used by anti-vaxxers as a reason to distrust the vaccines. As Fauci has pointed out,
though, there was a lot of previous science extending back a decade that was involved
in the development of the vaccines.
There is a basic misunderstanding among the public that scientists start from ground
zero when they develop a vaccine. But the basic science that goes on daily in
laboratories across the globe contributes greatly to any and all advancements in
medicine and especially vaccinology. Fauci observes that “two activities predate the
successful COVID-19 vaccines: the utilization of highly adaptable vaccine platforms
such as RNA (among others) and the adaptation of structural biology tools to design
agents (immunogens) that powerfully stimulate the immune system.” Using these
important principles, it was straightforward to design a vaccine. Because of a previous
SARS outbreak and a previous MERS outbreak, the core technology had been honed
and tested in early phase trials. Indeed, design of vaccines in the future will continue to
benefit from these two building blocks. All that was needed was the DNA sequence of a
target molecule that our immune systems could focus on. When the genome of SARSCoV-2 was generated, researchers highlighted the gene sequence of the spike protein of
the virus, which attaches it to our cells during infection.
The rapid development of the vaccine was not the only part of drug development
that needed to be accelerated. The development of the vaccine coincided with a huge
spike in frequency of infection with the virus. This meant that clinical trials for COVID19 could easily recruit large sample sizes that most clinical trials cannot match. Indeed,
COVID-19 sample sizes provided 90 percent efficacy estimates for Phase III tests in
less than a year because of the large number of people enrolled in the studies. FDA
regulatory steps were easily passed because of the safety of mRNA and viral vector
vaccine platforms established well before the pandemic, and the efficacy of the specific
COVID-19 vaccines established in Phase III.
Is it possible to speed the adoption of cannabis-derived drugs like the SARS-CoV2 vaccines demonstrated? The most time-consuming and costly step in drug
development is Phase III testing. Can Phase III testing be compressed for cannabis? It
remains to be seen, but there are other ways to move cannabis-related pharmaceuticals
through the approval process.
Step by Step
Because the approval process for cannabis as a medicinal product and the
commercialization of such a product are both complicated, let’s review how cannabis
or a cannabis-derived product would move through an FDA approval process. First, we
need to make a distinction between cannabis products from the plant itself (cannabisderived) and cannabis synthetics or derivatives that in one way or another mimic natural
cannabinoids. The approval guidelines for compounds in these categories differ from
each other. Because the synthetics involve inherently different kinds of chemicals than
naturally occurring ones, the regulations for these two kinds of cannabinoids are
different. Sometimes a synthetic can cross lines, such as synthetically derived
dronabinol that also occurs naturally in the cannabis plant. Compare this to the synthetic
cannabinoid nabilone, which is not naturally occurring.
The difference between synthetic and naturally occurring cannabinoids should be
clear. How they are treated during the approval process differs as a result of the THCA
concentration in the drug being tested. Currently, as a result of the US Agriculture
Improvement Act of 2018, any cannabis product containing THCA at a concentration
higher than 0.3 percent is considered a Schedule 1 narcotic, while cannabis products
under 0.3 percent THCA are not Schedule 1, so there are two pathways a cannabisderived pharmaceutical can follow.
The approval of a novel pharmaceutical starts with a sponsor (usually a
pharmaceutical company) that has developed the drug. For the products with less than
0.3 percent THC, the steps are:
1. The sponsor obtains a pre-investigational new drug (IND) number through the FDA Center for Drug
Evaluation and Research (CDER). At this point the sponsor can request a meeting with the FDA to
explain the drug and ask for guidance. This part of step 1 is optional.
2. The sponsor explains to the FDA all the relevant chemistry, manufacturing, and controls (CMC) if the
product is a synthetic, or botanical raw material (BRM) information if the product is a botanical. This
step is reviewed by the CDER.
3. The third step involves a mechanism the FDA has developed called a Drug Master File (DMF). These
are files describing the nitty-gritty of drug manufacture that the sponsor can use in the application.
There are nearly 38,000 of these master file subjects that the FDA has considered. The DMFs make
the application less redundant if previous technology or chemistry is part of the novel drug. Safe use in
humans is the major focus of this step, and if a DMF is not used then the sponsor has to provide
information on safe use in humans.
4. The IND and clinical protocol are officially submitted to the FDA.