An Introduction to

Medical Cannabis
D AVID WOLF E , M.D., FA CR
A RT HRIT IS A N D RHE U MAT IS M
A S S OCIATES, P C
ME D ICA L CA N N A BIS IN S T ITUT E
WWW. AR APC . C O M/MC I
 Objectives
Cannabis and the cannabinoids
The human endocannabinoid system
Cannabis research
Cannabis and pain
Cannabis and sleep
How to use cannabis
Cannabis safety
Cannabis legality
**References provided at the end
 Cannabinoids and
terpenes

Indica: Shorter and

bushier. Smaller
wider leaves. Said to Hemp: Cannabis plant
be more sedating containing < 0.3% THC.
and relaxing. Male and female cultivated.

Sativa: Taller and Marijuana: Cannabis plant

slimmer. Leaves are Containing > 0.3% THC
longer and thinner. Female cultivated.
Said to be more
uplifting and to
promote alertness.

Image from https://www.leafly.com/learn/growing/marijuana-plant-anatomy

Female cannabis plant with flower (bud) Cannabis trichomes containing resin
(cannabinoids and terpenes)
 Cannabinoids
Phyto-cannabinoids (plant produced)

Endo-cannabinoids (animal produced)

Synthetic cannabinoids

Purified cannabinoids
 Phyto-cannabinoids
Produced by the cannabis plant – Over 100 different phyto cannabinoids discovered to date

◦ Major Cannabinoids –More abundant in cannabis. Better researched

◦ Delta-9-Tetrahydrocannabinol (THC)
◦ Cannabidiol (CBD)

◦ Minor Cannabinoids– Less abundant in cannabis. Not as well researched

◦ Cannabigerol (CBG)
◦ Cannabinol (CBN)
◦ Cannabichromene (CBC)
◦ Tetrahydrocannabivarin (THCV)

Every plant (chemovar) has a distinct ratio of cannabinoids

Terpenes also appear to have therapeutic potential
 Endocannabinoids
Produced by almost every vertebrate animal including humans
◦ Anandamide (Bliss in Sanskrit)
◦ 2 AG
◦ Palmitoylethanolamide (PEA)
Produced by the body and have short duration of action
◦ Quickly broken down by enzymes (FAAH and MAL)
Interact with receptors in the body (Endocannabinoid system)
Appear to have a role in moderating pain, inflammation, anxiety, sleep
 Synthetic Cannabinoids
◦ FDA approved medications ◦ Experimental compounds (clinical
trials only)
◦ Synthetic THC
◦ Dronabinol (Marinol) ◦ Animal (preclinical) studies
◦ For treatment of anorexia in patients ◦ Probing the function and therapeutic
with AIDS implications of endocannabinoid system
◦ JHW-133 etc.
◦ For nausea and vomiting due to
cancer chemotherapy
◦ Human trials
◦ Nabilone (Cesamet) ◦ Lenabasum
◦ For nausea and vomiting due to
cancer chemotherapy
 Purified pharmaceutical cannabinoids
Epidiolex
◦CBD compound
◦Approved in US for rare pediatric seizure disorders
Nabiximols (Sativex)
◦CBD:THC compound
◦Approved in Europe for multiple sclerosis-related symptoms
of pain and spasticity
 Cannabinoid Receptors
CB1: Brain, central, peripheral nervous system
◦ Pain processing and perception
◦ Sleep
◦ Anxiety
CB2: Immune system. Bone. Gut
◦ Inflammation
◦ Bone health
◦ Gut health
 Endocannabinoid System

THC, minor cannabinoids, Anandamide, and 2AG

binding to CB1 and CB2 receptors constitute the
human Endocannabinoid System
 Delta-9-Tetrahydrocannabinol (THC)

Most abundant cannabinoid in marijuana

The psychoactive/intoxicating chemical in cannabis
Assumed to be involved in cannabis plant’s self defense against
insects, predation, and environmental stress
Binds directly to CB1 and CB2 receptors
◦Reduces pain, inflammation, and anxiety and promotes sleep
 Cannabidiol (CBD)
Abundant in marijuana and hemp
Not psychoactive
Does not bind directly to CB1 or CB2 receptors
Raises Anandamide levels
◦ Inhibits the enzyme (FAAH) that breaks down Anandamide
Anandamide binds to CB1 and CB2 receptors
◦ Reduces pain, inflammation, and anxiety and promotes sleep
CBD makes it harder for THC to bind to CB1 in brain
◦ Can blunt intoxicating effects of THC
CBD also binds to other receptors in brain + spinal cord to modulate pain
 Cannabinol (CBN)
The breakdown product of THC
Most often found in aged cannabis products
Best known for sedative properties – often used to treat
insomnia
May enhance THC’s sedating qualities1
Preclinical data suggests anti-inflammatory properties2
There is no known risk associated with using CBN
 3
Cannabigerol (CBG)
Thought to have pain relieving, anti-inflammatory,
and anti-anxiety properties
Present in small amounts in cannabis
Due to its effects on alpha receptors in the body, it
may carry some risks of slow heart rate, low blood
pressure, or dry mouth when used in large amounts
 4
Cannabichromene (CBC)
Found in preclinical studies to enhance the anti-
inflammatory effects of CBD and THC
Likely has pain-relieving properties
May prolong the effects of other cannabinoids
There is no known risk associated with using CBC
 Minor cannabinoids-Summary
While minor cannabinoids CBN, CBG, and CBC appear
promising in treating pain, inflammation, anxiety, and
insomnia, more well-designed human studies are required
prior to drawing any firm conclusions
Available studies indicate that they are safe and non-
intoxicating when used in small quantities and may be
synergistic when used in conjunction with one another as well
as with CBD and/or THC
 5-8
Palmitoylethanolamide (PEA)
Endocannabinoid/phyto-cannabinoid that works in a similar way as CBD
Inhibits breakdown of Anandamide by FAAH, interacts with an enzyme called P-
PAR alpha, inhibits mast calls
Not from the cannabis plant: From peanuts, soy, eggs
Taken in a capsule form. Available as a dietary supplement
Good option for those who cannot legally use cannabis
Data from human trials showing effectiveness for chronic pain due to
osteoarthritis, fibromyalgia, neuropathy, and sciatica
Also has anti-anxiety properties and some data for sleep
 Terpenes
Class of chemicals found in many plants including cannabis
Protect plants by repelling pests and attracting pollinators
Essential oils = terpenes
Give many plants their characteristic smell or taste
Evidence suggests that terpenes may have beneficial effects in the body
and interact synergistically or antagonistically with other cannabinoids
Research on terpenes is in its early phases. While they appear to be
quite safe, most available information comes from preclinical studies
and anecdotal reports from patients
 Myrcene 9-10

The most abundant terpene in cannabis

Also found in thyme, basil, lemongrass, mango, and hops
A strong sedative with potentially potent pain reducing and
anti-inflammatory properties
May enhance the effects of THC
Present in larger amounts in Indica strains of cannabis and
likely makes those strains relaxing and sedating
 Other terpenes
Limonene11-12
◦ The second most common terpene in cannabis
◦ Gives citrus fruits their characteristic aroma
◦ Reported to be uplifting, euphoric, and anxiety relieving
◦ Some studies have also shown anti-depressant properties
Pinene13-14
◦ Gives pine trees their characteristic smell
◦ May counteract the intoxicating affects of THC and increase alertness
 Other terpenes
Caryophyllene15-16
◦ Present in cloves and black pepper
◦ Reported to have anti-inflammatory and pain-relieving qualities
◦ Has been shown to reduce the anxiety and paranoia that can result
from excessive consumption of THC
Linalool17-18
◦ Found in lavender and gives it its characteristic aroma
◦ Is reported to have calming, relaxing, anti-anxiety, and anti-depressant
effects
 Cannabis Research
Most data comes from preclinical (animal studies)
Federal restrictions on human trials
◦Marijuana DEA Schedule I
◦Only 1 strain (chemovar) grown in Mississippi allowed for
study
Each cannabis plant is a unique mix of cannabis chemicals
◦Hard to isolate and replicate effects of compounds alone or
in combination
 Cannabis Research
Most human studies done with inhaled high-THC cannabis
◦High rates of side effects (intoxication)
Little funding for cannabis clinical trials
◦Trials expensive to organize and administer
◦Studies usually funded by Pharma
◦ Cannot patent and profit from cannabis plant
◦ Are investigating synthetic cannabis compounds
 DEA Drug Schedules
1970 Controlled Substances Act

Schedule I: Heroin, LSD, Ecstasy, Peyote, and Marijuana (and its constituents including cd-CBD)
**High risk of harm and abuse and no scientific evidence of benefit
Clinical research highly restricted
Schedule II: Hydrocodone, Cocaine, Methamphetamine, Methadone, hydromorphone (Dilaudid),
meperidine (Demerol), oxycodone (OxyContin), Fentanyl, Dexedrine, Adderall, and Ritalin
Schedule III: Tylenol with codeine, Ketamine, Anabolic steroids, Testosterone
**HHS recently recommended rescheduling marijuana to this category. DEA deciding.
Schedule IV: Xanax, Soma, Darvon, Darvocet, Valium, Ativan, Talwin, Ambien, Tramadol
 What has preclinical research shown?

Osteoporotic mouse given Mice given A CB2 receptor agonist JHW133 were protected
synthetic CB2 receptor agonist JWH133- against developing rheumatoid arthritis 20
Reversed osteoporosis 19

Although these and other preclinical studies have produced impressive results in animal models of disease,
it is important to acknowledge that they were performed using high doses of synthetic cannabinoid
compounds and not with plant cannabinoids per se. Therefore, these results cannot be extrapolated
to medical cannabis. However, they do point towards future research possibilities and the
prospect of pharmaceutical products that interact with the human endocannabinoid system
 Cannabis pre-clinical data: Other conditions
Neuropsychiatric illness Depression*
◦ Autism, ADHD, PTSD, alcoholism, addiction
Glaucoma*
Neuroprotection
◦ Concussion and Alzheimer’s Skin Disorders
Autoimmune disease
◦ Inflammatory bowel disease, multiple sclerosis
Coronary artery disease
Cancer
Diabetes
Irritable bowel syndrome
 The Endocannabinoids and Pain
Cannabinoid CB1 receptors are
found throughout the nerves,
spinal cord, and brain along the
TRPV1 pain pathway. By interacting with
CB1, and other receptors such as
TRPV1, phyto-cannabinoids such
as THC and CBD, and human
endocannabinoids such as
On/off cells Anandamide and PEA moderate
Retrograde the transmission, processing, and
signaling
perception of pain21-27

From Hillsphysiotherapy.com.au
 Cannabis and Pain
Cannabinoids share mechanisms of action with many common
medications including Capsaicin, NSAIDs, Pregabalin (Lyrica),
Gabapentin (Neurontin), and Duloxetine (Cymbalta) 21-25
Cannabinoids can also enhance the effectiveness of opiates without
increasing the risk of opiate overdose28-30
Most research shows that pain is best treated with a combination
of CBD and THC as these compounds work synergistically and are
more effective together than either compound is alone
 Cannabis and Pain
Inflammation also plays a primary role in causing pain
Inflammatory chemical mediators can generate pain signals and
increase perception of pain in the brain
Inflammation is driven by the immune system
Cannabinoid CB2 receptors are present throughout the immune
system and, by binding these, cannabinoids reduce
inflammation and, by extension, inflammation-mediated pain
There is no evidence that plant cannabinoids treat
autoimmune diseases in humans
 Cannabis and Pain
After examining all the available data, the National Academy of
Sciences released a report in 2017 which found “substantial
and conclusive evidence” for the effectiveness of cannabis in
treating chronic pain31
Cannabinoids can help some patients reduce or eliminate the
use of potentially harmful opioids
◦ A study in 2016 showed a 64% reduction in opioid use in chronic pain
patients who were using medical cannabis32
 33-34
Cannabis and Sleep
Most human research into cannabis for sleep has used THC
due to its known sedating qualities
It is thought that cannabinoids help with sleep by binding to
CB1 receptors in the brain which increase levels of a sleep-
promoting chemical called adenosine and by suppressing the
brain’s arousal system
Several human studies have shown that THC can be effective in
inducing and/or maintaining sleep
 35-37
Cannabis and Sleep
One human study using synthetic THC (Dronabinol), showed
improved sleep parameters in individuals with moderate or
severe sleep apnea
Another review of human studies showed that CBD can be
effective for insomnia and REM sleep disorder
Anecdotal evidence suggests the minor cannabinoid CBN
and the terpene Myrcene can help promote sleep
 How to Use Cannabis
Cannabis compounds present in the native plant
occur as acid structures which have no biologic effect
in the human body: THC-A, CBD-A, CBN-A, CBC-A,
CBG-A, etc. For the acid component to be broken off
and for the chemicals to become activated, heating is
required.
Heating is used in processing of cannabis products
and when smoking or vaporizing cannabis
 How to use cannabis
Common methods of administration of cannabis include
inhalation (smoking/vaping), under the tongue (sublingual
tinctures), administered into the sides of mouth (oromucosal
spray) swallowed (edibles), transdermal through the skin
(creams and patches), or transrectal (suppositories)
In all cases, except for transdermal use, the goal is to get
cannabis compounds into the bloodstream where they can be
circulated throughout the brain and body
 How to use cannabis

Because cannabinoids have lipophilic properties, they don’t

dissolve in water. Therefore, oral preparations must be dissolved
in alcohol or oil to be absorbed
Alcohol can be caustic, so vegetable oil is recommended
Micronized cannabis preparations are cannabis molecules that
are suspended in microscopic lipid balls which maximizes the
amount of oral cannabis that is absorbed into the body
 How to use cannabis
Because most of those who use medical cannabis prefer to
avoid intoxication, dizziness, loss of coordination, and
general impairment, they are advised to start with cannabis
preparations that are higher in CBD than THC (higher CBD to
THC ratio)
As a person slowly adjusts the ratio of CBD to THC, tolerance
to the intoxicating effects of THC can develop
Most individuals do not exceed 1:1 CBD/THC ratio
 Cannabis Inhalation

Cannabis can be inhaled by smoking cannabis flower or by

vaping cannabis flower or cannabis oil
Inhaling cannabis has the most rapid onset, within minutes,
but a relatively short duration (2-4 hours)
Controlling the dose of inhaled cannabis is difficult although
newer metered inhalers can deliver specified amounts of
cannabis vapor
 Smoking cannabis flower
When cannabis flower is heated by flame in a bowl, water pipe (bong), or
cigarette (joint), very high temperatures are produced (> 450 F) which combusts
not only cannabinoids but also potentially harmful plant material including
cancer-causing chemicals such as benzene and tar which are also breathed into
the lungs with the smoke
While using a water pipe offers theoretical advantages by using water to filter
our harmful plant compounds from the smoke, they may also trap harmful
toxins in water droplets which are inhaled into the lungs
The risks of regular smoking of cannabis flower are reflected by recent research
showing that regular cannabis smokers have higher rates of emphysema than
regular cigarette tobacco smokers as smoking cannabis is equivalent to regularly
smoking unfiltered tobacco cigarettes 38
 Vaping Cannabis Flower or Oil
When cannabis is vaped by heating in a vaporizer device or
by vaporizing cartridges of cannabis oil, the cannabis is
boiled, and cannabinoids are released at lower
temperatures (280-360 F) that are too low to release the
potentially harmful plant materials
Therefore, vaping cannabis flower or oils is safer than
smoking cannabis flower
 Vaporizing cannabis flower
Tabletop Vaporizers:
◦ Boil and vaporize dried cannabis flower (bud)
◦ More expensive
◦ Offer the most advanced technology by allowing a user to set the specific temperatures they
want to heat cannabis flower
◦ Because every cannabinoid and terpene is known to boil and be released at different
temperatures, these devices allow a user to specifically target those cannabinoids or terpenes
they wish to inhale and receive
Portable Vaporizers:
◦ Use dried cannabis flower (bud)
◦ Also boil and vaporize dried cannabis flower
◦ Battery powered and come in various sizes, levels of complexity (ability to set temperatures), and
expense
Portable vaporizer device T-VAPE TABLETOP VAPORIZER
 Vaping cannabis oil
Boil cannabis oil in in cartridges releasing
cannabinoids in vapor without harmful
plant products
Come in various ratios of CBD and THC
Can irritate the airways but otherwise
quite safe
Prior reports of deaths from cannabis
vaping were due to illegal black-market
cannabis cartridges which were “cut”
with vegetable oil
 Oral cannabis ingestion
Orally ingested cannabis (gummies, brownies, oil
mixed with tea or other drink) pass into the
stomach then to the small intestine where they are
absorbed into the blood
The cannabinoids then pass through the liver
where a large proportion of them are metabolized
into less active forms
The remaining active cannabinoids then enter the
blood and travel to the rest of the body
Because of the long distance it travels from the
mouth to the blood stream, oral cannabis has the
longest time to onset (30-60 minutes) and its
effects peak in 1-2 hours
 Oral Cannabis Ingestion
The time to onset and absorbed dose of oral cannabis varies
depending on when a person has eaten and what they have eaten
relative to when they ingest cannabis
◦ When cannabis is ingested with food, and especially with fatty
foods, the time to onset is delayed and the effects are prolonged
relative to taking it on an empty stomach
◦ Because of the delayed and somewhat unpredictable onset of
action, it is important to always start with low doses of oral
cannabis and wait at least 60 minutes to assess the effects before
taking more
 Sublingual Cannabis
Sublingual cannabis (tincture) is absorbed directly
into the blood vessels under the tongue and
therefore starts working more quickly than oral
cannabis
Effects can be noticed in as little as 5-10 minutes
By passing directly into the blood stream, there is no
initial metabolism by the liver
Of all dose forms, sublingual tincture is the easiest to
control (based on number of drops)
Because of its absorption under the tongue, it is
unaffected by food and has a more predictable time
to onset, duration, and effect
 Transdermal Cannabis:
Creams, salves, roll on, bath salts, patches
Transdermal cannabis compounds do not penetrate very well
through the skin
This can limit the effectiveness of topical cannabis when used
to treat pain in muscles or joints
Voltaren gelc is an over-the-counter topical anti-inflammatory
medication that is mixed with a proprietary compound called
Emugelc, an absorption enhancer, which allows the medication
to penetrate more deeply into body tissues
Mixing topical cannabis with Voltaren gel, can allow the
cannabis compound to penetrate more deeply into the body
and, anecdotally, may be more effective
Because little is absorbed into the blood, topicals tend not to
be intoxicating
How to choose a method of cannabis use
Because of its shorter duration of action, vaporized cannabis is optimal for
treatment of breakthrough pain and to initiate sleep
Due to their longer duration of action, oral and sublingual cannabis are optimal
for treatment of chronic pain and to maintain sleep
It is easier to control the dose of sublingual or oral cannabis and more difficult to
control the dose of smoked or vaporized cannabis
Topical cannabis is optimal for treatment of localized areas of pain or if one
wants to minimize risk of intoxication
When ever starting out with cannabis, begin with a low dose and increase
slowly (start low and go slow)
 Cannabis Safety
Because there are no CB1 receptors in the brainstem,
there is no risk of overdose death with cannabis
Also, no increased risk of overdose when used with
morphine or benzodiazepines
 Cannabis Safety
In medical cannabis programs, cannabis is tracked
and tested “from seed to sale”
It is tested and certified by independent outside labs
Laws require that medical cannabis must be grown
organically
 Cannabis Safety
Most of the reported adverse effects of cannabis use are related to high
doses of THC

Acute high doses of THC can produce intoxication, lack of coordination,

dizziness, nausea, vomiting, anxiety, or paranoia as well as an increase in
heart rate or a rise or fall in blood pressure
--Individual sensitivity to THC can vary

Long term regular smoking of cannabis flower has been shown to be

harmful to the lungs and can even lead to chronic health conditions such
as emphysema.
 Cannabis Safety
Approximately 5% of those who use high dose THC can
develop a severe, though not life-threatening reaction, called
Cannabis Hyperemesis Syndrome (abdominal pain, vomiting,
diarrhea)39
Approximately 10% of those who regularly use high doses of
THC may become physically addicted to THC, a condition
called Cannabis Use Disorder40
Not exceeding 1:1 ratio of CBD:THC minimizes the risk of
side effects or addiction
 Cannabis Safety
There are potentially serious interactions between CBD and
certain prescription medications including some blood thinners,
anti-psychotics, seizure medications, statin drugs, and opiates
including propoxyphene and buprenorphine
Because of a lack of data, it is recommended that those who
are pregnant, who are planning to become pregnant, or who
are breastfeeding NOT use cannabis compounds. In addition,
regular use of high dose THC may lower sperm counts and
decrease fertility in men41
 Cannabis Legality

Marijuana occupies a legal gray area in the United States in so far as

medical and/or recreational (adult use) cannabis are legal in some
states and illegal in others
Even in states where cannabis is legal, there are restrictions
◦ In Maryland, registered gun owners cannot register to use medical
cannabis
◦ In all states and jurisdictions in which cannabis is legal, it is against
the law to consume cannabis products in public, to drive while
intoxicated, or to provide it to minors
 Cannabis Legality
Cannabis in all forms remains illegal at the Federal level
◦ It is illegal to transport cannabis across state lines, even if cannabis
is legal in both states or jurisdictions (e.g., from MD to DC or VA)
◦ It is illegal to carry cannabis on a plane, even if you are flying
within the same state
◦ It is illegal to use or possess cannabis on Federal government
property such as the National Mall or National Parks
◦ Itis illegal for Federal Government employees to use cannabis in
any form, including recreationally or medically
 Cannabis Legality
Some states and jurisdictions offer (non-federal) employees protections for using
cannabis and others do not

--Maryland law allows employers to deny employment and/or discipline a prospective

or current employee after testing positive for marijuana based on their own companies’
policies
--Virginia law prohibits an employer from “discharging, discipling, or discriminating
against and employee for lawful use of cannabis oil (including those containing THC)
based on a valid written certification.”
--In the District of Columbia, employers may not refuse to hire, fire, suspend, fail to
promote, or otherwise penalize a protected individual based on: “The individual’s
marijuana use, their status as a medical marijuana program patient, or the presence of
marijuana on a drug test, absent additional factors indicating that the individual is
impaired.”
 Cannabis Legality
In DC, MD, VA it is legal to possess certain amounts of marijuana in public

--In Maryland, adults 21 or older may posses up to 1.5 ounces of cannabis flower, 12 grams of
concentrated cannabis, or a total amount of cannabis products that does not exceed 750 mg THC
--In Virginia adults 21 or older can legally possess up to 1 ounce of marijuana
--In DC, adults 21 or older can legally possess up to 2 ounces of marijuana
--In Delaware, adults 21 or older can legally possess up to 1 ounce of marijuana leaf or
equivalent amounts of marijuana products in other forms.

While DC allows Maryland and Virginia medical cannabis patients go to dispensaries in the
District of Columbia, Maryland and Virginia only allow patients certified in their own states go to
their dispensaries
 Cannabis Legality
In Maryland, Virginia, and Delaware, Recreational (Adult Use) cannabis has
been signed into law
In Maryland, cannabis can be purchased by anyone age 21 and older at the
same dispensaries where medical cannabis is sold. Recreational products are
fewer in number, are lower in potency, and are taxed
In Virginia and Delaware, there are currently no recreational cannabis
dispensaries
Although the District of Columbia has sought to legalize recreational cannabis,
they have been over-ruled by Congress. In DC, there is what is called “gifting” of
cannabis at brick-and-mortar stores
Unlike medical cannabis in DC, “gifted” cannabis is not regulated or tested
 Medical Cannabis - Summary
Using cannabis for pain, inflammation, anxiety, or
insomnia can be complicated, and it is recommended that
an individual consult with a cannabis-literate clinician to
help with dosing and to ensure that cannabis is used
safely and effectively
Cannabis will not work for everyone all the time
The providers at the ARA Medical Cannabis Institute
stand ready to offer guidance, oversight, and support
 How to learn more and schedule

https://arapc.com/mci

Call 240-621-7433
1. John McPartland and Ethan Russo, MD. Cannabis and Cannabis Extracts: Greater Than the Sum of Their
Parts? In Cannabis Therapeutics in HIV/AIDS. (Vol. 1, No. 3/4, 2001) p. 107.
2. Ibid p. 107
3. Ibid p. 108
4. Ibid pp. 107-108
5. Davis MP, Behm B, Mehta Z, Fernandez C. Am. The Potential Benefits of Palmitoylethanolamide in
Palliation: A Qualitative Systematic Review. J Hosp Palliat Care. 2019 Dec;36(12):1134-1154].
6. Cruccu G, Di Stafano G, Marchettini P, Truini A. Micronized Palmitoylethanolamide: A Post Hoc Analysis
of a Controlled Study in Patients with Low Back Pain. CNS and Neurological Disorders. 2019, 18. 491-
495.
7. Scaturro D, Asario C, et al. Combination of Rehabilitative Therapy with Ultramicronized
Palmitoylethanolamide for Chronic Low Back Pain: An Observational Study. Pain Ther (2020) 9: 319-
326
8. Paul Clayton, Mariko Hill, Nathasha Bogoda, Silma Subah, and Ruchitha Venkatesh.
Palmitoylethanolamide: A Natural Compound for Health Management. Int J Mol Sci. 2021 May; 22(10):
5305.
9. Mark H. Kimmins, MD. Medical Cannabis in Canada. Milner and Associates 2019. P. 53.
10. John McPartland and Ethan Russo, MD. Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts? In Cannabis
Therapeutics in HIV/AIDS. (Vol. 1, No. 3/4, 2001) p. 115
11. Kimmins, p 54.
12. McPartland and Russo, p 115.
13. Kimmins, p 54.
14. McPartland and Russo, p 118.
15. Kimmis p 54.
16. McPartland and Russo, p 115
17. Kimmins, p 54.
18. McPartland and Russo, p 116
19. Bab et al. Endocannabinoids and the regulation of bone metabolism. J. Neuroendocrinol. 2008 May;20 Suppl 1:69-74.
20. Kinsey SG et al. Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related
thermal hyperalgesia in mice. Pharmacol Biochem Behav. 2011 Oct; 99 (4): 718-725.
21. Costa B, et al. Vanilloid TRPV1 receptor mediates the anti-hyper analgesic effect of the non-psychoactive cannabinoid,
cannabidiol, in a rat model of acute inflammation. Br J Pharmacol. 2004 Sept; 143 (2): 247-50.
22. Vaughn CW et al. Retrograde signaling by endocannabinoids. Handb Exp Pharmacol. 2005; (168): 367-83.
23. Alger BE. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol. 2002.
Nov; 68 (4): 247-86.
24. Masanobu K. Control of synaptic function by endocannabinoid-mediated retrograde signaling. Proc Jpn Acad Ser B Phys Biol
Sci. 2014 Jul 31; 90(7): 235–250
25. Maione S et al. non-psychoactive cannabinoids modulate the descending pathway of antinociception in
anesthetized rates through several mechanisms of action. Br J Pharmacol (2011);162. 584-596.
26. Xiong W et al. Cannabinoids suppress inflammatory and neuropathic pain by targeting a3 glycine receptors. J
Exp Med. Vol. 209. No. 6. 1121-1134.
27. Corchero J, et al. Delta 9-tetrahydrocannabinol increases prodynorphin and proenkephalin gene expression in
the spinal cord of the rat. Life Sci. 1997;61:L39–L43.
28. Wilson AR et al. Repeated cannabinoid injections into the rat periaqueductal gray enhance subsequent
morphine antinociception. Neuropharmacology. 2008;55(7):1219–1225.
29. Cichewicz, D.L. & McCarthy, E.A. 2003. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and
opioids after oral administration. Journal of Pharmacology and Experimental Therapeutics 304 (3): 1010–15.
30. Cichewicz, D.L. & Welch, S.P. 2003. Modulation of oral morphine antinociceptive tolerance and naloxone-
precipitated withdrawal signs by oral Delta 9-tetrahydrocannabinol. Journal of Pharmacology and Experimental
Therapeutics 305 (3): 812–17.
31. The Health Effects of Cannabis and Cannabinoids. The Current State of Evidence and Recommendations for
Research. National Academies of Sciences, Engineering, and Medicine; Health and Medicine
Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of
Marijuana: An Evidence Review and Research Agenda. Washington (DC): National Academies Press
(US); 2017 Jan 12.
 32. Boehnke, KF, Litinas, E, Clauw, D. Medical cannabis use is associated with decreased opiate medication use in
a retrospective cross-sectional survey of patients with chronic pain. J Pain.17. 739-744 (2016).
33. Cousens, K and DiMascio A. Delta 9 THC as a hypnotic: an experimental study of three dose levels.
Psychopharmacologia 33, 355-364 (1973).

34. Kuhathasan, A, Dufort, A, MacKillop J et al. The use of cannabinoids for sleep: A critical review on clinical
trials. Exp Clin Psychopharmacol. 2019 Aug; 27 (4): 383-401.
35. Carlini, E.A and Cunha, J.M. Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol. 21, 417-427S
(1981).
36. Ware, M.A. Fitzcharles, M.A, Joseph, L et al. The effects of nabilone on sleep in fibromyalgia: results of a
randomized controlled trial. Anesth. Analg. 110, 604-610 (2010).
37. Carley, D. W et al. Pharmacotherapy of apnea by cannabimimetic enhancement, the PACE clinical trial: effecs
of dronabinol in obstructive sleep apnea. Sleep 41.
38. Luke Murtha, Paul Sathiadoss, Jean-Paul Salameh, et al. Chest CT Findings in Marijuana Smokers. Radiology.
Vol 307, No. 1
39. Mark H. Kimmins, MD. Medical Cannabis in Canada. Milner and Associates. 2019. p. 77
40. Ibid, p. 79
41. Mirra Srinivasan, Ranim Hamouda, Baba Ambedkar, et al. The Effect of Marijuana on the Incidence and
Evolution of Male Infertility: A Systemic Review. Cureus. 2021. Dec; 13 (12).