History of cannabis :
Marijuana has too many other names such as weed, herb, grass... etc. It is a greenish-gray
mixture of the dried flowers of Cannabis Sativa. People use marijuana for its psychoactive
chemical (delta-g- tetrahydrocannabinol)THC, which is responsible For the mind-altering and
recreational effect, this chemical is found in the resin produced by the leaves and buds
primarily of the female cannabis plant.
This plant contains more than 500 Chemicals other than THC 100 of which are related to the
THC called cannabinoids. (1)
Besides the use of cannabis for its “high” effect, it has also been used as a medicine. The
first use of the plant was in China dating back to around 2700 B.C as their father of Chinese
medicine the emperor Shen Nang has documented its usefulness in treating too many
medical conditions such as rheumatism, gout, malaria, and absent-mindedness.
The use of marijuana, then spread outside China to other countries including Korea, India,
and Eastern Africa. An Egyptian papyrus advised that inflammation could be treated by
using cannabis.Marijuana has other uses far away From the medical field, Spanish brought
cannabis to grow this crop For hemp strong fibers that might be used to make clothes, bags
and For rigging ships.
Cannabis was an important crop because it has a property despite a wet, salty environment,
hemp rope remains durable.
Cannabis transported to Brazil by African slaves and then they worked on Brazilian Farms
so they were allowed to grow marijuana for the purpose of smoking.
Cannabis appeared as an ingredient in many patent medicines the use of drugs began to
ban.
In European and American legislators.
For the first time, the Harrison act of 1914 criminalized the use of cannabis and other drugs,
cannabis use was restricted in 13 countries by 1925 including the U.S. this law didn’t go into
effect until 1938.
The use of marijuana for its recreational effect was largely restricted to jazz musicians.
Marijuana didn't consider as a social threat because it showed no
Evidence of marking harm of themselves or disturbing the community, for this reason, it was
not illegal and was tolerated by authorities.
As mentioned previously marijuana was prescribed to treat various conditions including labor
pain, nausea, and was listed in U.S pharmacopeia from 1850 until 1941.
The U.S federal bureau of narcotics conducted a campaign in the 1930s that tried to portray
marijuana a powerfully addictive substance that may lead users to become violent.
In 1970 The controlled substances classified marijuana as a schedule 1 drug along with
other substances such as heroin and LSD, drugs listed in this category means that the
substance abuse potential is high and can't be used For medical purposes. Then the main
supplier of marijuana became Colombia.
There was a war on drugs resulted in domestic cultivation rather than reliance on imported
supplies, especially in Hawaii and California, but Colombia still supply the U.S with their
boatloads of high potency marijuana
Marijuana, domestic potency has been increased at the beginning of 1982 leading to
increased attention to Marijuana farms in the U.S as well by the Drug enforcement
administration. The use of marijuana increased until 1997. (2)
(1) NIDA. 2020, April 13. What is marijuana? . Retrieved from
https://www.drugabuse.gov/publications/research-reports/marijuana/whatmarijuana on 2021, January 28
(2) https://www.narconon.org/drug-information/marijuana-history.html
Conditions for cultivation
Marijuana needs direct sunlight, preferably in the middle of the day and from 5 to 6 hours a
day, as the sun's rays are in their best condition and quality.
It is very important to use proper soil identification. Marijuana prefers soil that retains
moisture, drains well, and warms easily. Which allows oxygen and contains a lot of
nutrients. The best soil for marijuana needs is set, as it is very good at retaining moisture
and keeps the marijuana out of harm's way to allow adequate drainage. The best time to
prepare the soil for growing marijuana is about one month by digging holes and applying
compost, worm castings, and other decaying organic matter. Marijuana does not need
watering on a daily basis due to the moist soil, but it does require a large amount of water
per day if the weather is particularly warm. (3)
(3) https://fremont.edu/growing-marijuana-outdoors/
The cannabis plant contains two main subspecies, Cannabis indica and Cannabis sativa,
and they can be distinguished by the difference in physical properties. The dominant indica
strains are short plants with broad, dark green leaves and have a higher CBD content
compared to the dominant sativa plants which are taller, have thin leaves of pale green color
and have higher THC content. sativa is the preferred choice by users because it contains a
high amount of THC. It is considered a complex plant with about 426 chemical entities, of
which more than 60 are marijuana compounds.The four main compounds are d-9-THC,
CBD, d-8-THC and cannabinol. (4)
(4) Pertwee R. (2008) The diverse CB1 and CB2 receptor pharmacology of three plant
cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and
delta9-tetrahydrocannabivarin. Br J Pharmacol 153: 199–215 [PMC free article]
[PubMed] [Google Scholar]
Cannabinoid receptor system:
The first pure form thought to be the active compound isolated from the plant was
cannabinol where's the second is cannabidiol (CBD), In 1964 Gaoni and Mechoulam isolated
the actual main active compound, delta -9- tetrahydrocannabinol
The identification of the specific binding site of D -9THC in the brain was a cornerstone in
cannabinoid research, followed by cloning of the cannabinoid 1 receptor (CB1R).The binding
affinity of D-9-THC for these receptors as partial agonist was the reason this system was
named (cannabinoid receptor system).then a second receptor (CB2R) was discovered.
Around the same time
Devane and colleagues confirmed the existence of an endocannabinoid system after the
extraction of a molecule( ethanolamine of arachidonic acid ) that bound to these receptors .
Three years later the second endocannabinoid neurotransmitter 2- arachidonoylglycerol
(2-AG) had been isolated by Mechoulam and colleagues.
Recent research has shown similarities between d-9-THC and anandamide, the d-9-THC
found to beResembles anandamide in it's CB1 affinity as a partial agonist but with less
efficacy at CB2Rs than at CB1Rs in vitro.
CB1Rs are mainly found in many areas in the brain, also found in the peripheral nervous
system liver,Thyroid, uterus, bones and testicular tissue.CB2Rs are expressed in immune
cells, spleen, and GI system. To some extent it might be found in the brain and peripheral
nervous system.
Both types of receptors are found in the human placenta and play a role in regulating
serotonin transporter activity, some research shows that the endocannabinoid system plays
a significant roleIn various aspects of human reproduction.
Due to the presence of CB1Rs at the terminals of central and peripheral neurons, they
mostly mediate inhibitory action on the ongoing release of too many excitatory and inhibitory
dopaminergic, GABA, glutamatergic, serotonergic, noradrenaline and acetylcholine
neurotransmitter systems.
These systems affect functions including cognition, memory, motor movement, and lastly
pain perception
D-9-THC binds to CB1R and acts as a partial agonist in a less selective manner by inhibiting
the release of neurotransmitters normally modulated endocannabinoids such as AEA and
2-AG .
It has been suggested that it may also increase the release of dopamine, glutamate and Ach
in specific
Brain areas, possibly by inhibiting the release of an inhibitory neurotransmitter such as
GABA on dopamine, glutamate or Ach- releasing neurons.
The functionalities of CB1Rs are not always straightforward because of the complex
interactions with
Other neurotransmitter systems. CB1Rs and CB2Rs are members of G- protein-coupled
receptors. (5)
5- Atakan Z. (2012). Cannabis, a complex plant: different compounds and different effects on
individuals. Therapeutic advances in psychopharmacology, 2(6), 241–254.
https://doi.org/10.1177/2045125312457586
Routes of Cannabis Use :
Inhaled CannabisSmoking herbal cannabis is the most common way to use cannabis and is
the dried mature cannabis flower and adjacent leaves. Intoxication occurs as soon as 2
minutes after the first inhalation .The drug's peak effect occurs about 30 minutes after use.
Users remain intoxicated usually for 2 to 4 hours after use. But some minor effects can last
more than 24 hours, such as impaired memory.(6)
The amount of cannabinoids in medicinal cannabis consumed does not match the amount
consumed. When smoking, about a quarter of the cannabinoids found in herbal cannabis are
absorbed. (6)
(6) Abramovici H. Information for Health Care Professionals: Cannabis (Marihuana,
Marijuana) and the Cannabinoids. Ottawa, Ontario: Health Canada, Controlled Substances
and Tobacco Directorate at Health Canada; 2013.
Using an herbal vaporizer is also a common method of using herbal cannabis (7), but users
will put fresh cannabis in their vaporizer rather than dried. More efficient compared to
smoking, the user absorbs up to 33% of the total cannabinoids present in herbal cannabis
when inhaled through the vaporizer. (8)
(7) Pertwee RG. Pharmacological actions of cannabinoids. Handb Exp Pharmacol.
2005;(168):1-51.
(8) Hill KP. Marijunana: The Unbiased Truth About the World's Most Popular Weed. Center
City, MN: Hazelden Publishing; 2015.
Edible Cannabis
Edible products are commonly called the way they are eaten, and it is also used as a
beverage. For example, in the state of Oregon recreational cannabis is permitted and legal,
as many food products are produced in cannabis-infused forms, including, sweets, sweets,
biscuits, honey sticks, butter, and cooking oils. The total milligrams of THC and CBD are
listed on the package labels. THC levels in products vary from 2.5 mg to 1 gram. (9)
The THC is absorbed inconsistently. When cannabis products are ingested orally. And
metabolized via first-pass effect. Persons who ingest cannabis products experience a more
intense and long time effect. The effects of THC begin about 2 to 4 hours after ingestion, and
its effects last for 6 to 8 hours. THC is hydroxylated When cannabis ingested, to a higher
amount of 11-OH-THC, which is a highly active metabolite, This intensification occurs by the
cytochrome p450 enzyme compared to smoking. (9)
(9) Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers.
2007;4(8):1770-1804. [CrossRef] [PubMed]
Studies have shown that for every 1 mg of THC consumed via smoking or vaporizing, about
2.5 mg of THC needs to be ingested to experience the same effect. (6,10)
(10) Zuurman L, Ippel AE, Moin E, van Gerven JM. Biomarkers for the effects of cannabis
and THC in healthy volunteers. Br J Clin Pharmacol. 2009;67(1):5-21. doi:
10.1111/j.1365-2125.2008.03329.x [CrossRef] [PubMed]
Homemade Cannabis Oils and TopicalsIt’s Another form of cannabis concentrates is
cannabis oils, often called Rick Simpson Oil. They are often made at home and are raw
concentrates. Simple extraction methods are used, such as extracting grain alcohol or
cooking, herbal hemp in fatty substances (such as naphtha, butane, coconut oil, and olive
oil). (11)
(11) Romano LL, Hazekamp A. Cannabis oil: chemical evaluation of an upcoming
cannabis-based medicine. Cannabinoids. 2013;1(1):1-11.
Cannabis oil has seen a rise in popularity after its purported anti-cancer properties.
However, Cannabis oil has not been shown as an effective anti-cancer agent.(12)
(12) Galve-Roperh I, Sánchez C, Cortés ML, Gómez del Pulgar T, Izquierdo M, Guzmán M.
Anti-tumoral action of cannabinoids: Involvement of sustained ceramide accumulation and
extracellular signal-regulated kinase activation. Nat Med. 2000;6(3):313-319. [CrossRef]
[PubMed]
Dosage estimates are difficult because these oils are often homemade. Cannabis oils can be
taken orally as a liquid, and sometimes they are incorporated into food and are rarely
smoked. Cannabis oils also can be used topically. Very few studies have regarded the use
of topical Cannabis products. The data indicate that topical cannabinoids can be absorbed
with a systemic effect when in specific carriers. Topical cannabis available in the form of
lotions, creams, and oils. These topical preparations may help with local inflammation and
pain, but the systemic absorption is minimal, and users will not feel intoxicated. (13)
(13) Touitou E, Fabin B, Dany S, Almog S. Transdermal delivery of tetrahydrocannabinol. Int
J Pharm. 1998;43(1-2):9-15. [CrossRef]
Marijuana toxicity:Marijuana intoxication is dose-related and the amount that can be absorbed by the body
differs from the route of administration and the concentration used. Usually, it's smoked or
vaporized due to rapid Once of symptoms
The acute intoxication represents the symptoms that users enjoy like: euphoria, time and
spatial distortion, and motor impairment. Besides these recreational effects, there is
unpleasant psychological
Reactions that some users may experience such as panic, fear, or depression. Acute
intoxication will also affect the heart and vascular system, resulting in cannabis-induced
tachycardia and postural hypotension. For CNS and respiratory depression, it hasn't been
noted in human models.
There are certain doses that will exhibit these acute intoxication effects some studies show
that Doses of 2 to 3 mg taken by inhalation and oral doses of 5 to 20 mg THC can cause
impairment of Attention, memory, executive functioning, and short-term memory.
More severe symptoms such as hypertension, panic, anxiety, myoclonic
jerking/hyperkinesis, delirium
Respiratory depression, and finally ataxia can occur at doses > 7.5 mg/m2 inhaled in adults
and
5 to 300 mg orally in pediatrics. Regardless of the route of administration conjunctivitis is a
consistent
Manifestation.
Children may exhibit signs of Life-threatening Toxicity as neurologic abnormalities including
lethargyAnd hyperkinesis.The duration of these impairments after taking cannabis is still
controversial, but may range fromHours to days.
Cannabis intoxication can cause acute psychosis and exacerbate pre-existing psychotic
disorders such as schizophrenia.
Management of cannabis intoxication: if an individual experiences chest pain, it's rational to
obtain a 12-lead electrocardiogram and cardiac markers to assess for myocardial ischemia
or infarction, there's an elevated risk for MI up to 4.8 times within one hour of marijuana use.
Treatment of marijuana intoxication is only symptomatic management
Since marijuana is a schedule 1 and for obvious ethical reasons, there’s no experimental
evidence to determine the lethal dose of marijuana in humans, but for animals the dose that
can kill them ranges from 40 mg/kg to 130 mg/kg through the IV route.
Marijuana is contraindicated during breastfeeding due to its high affinity for lipids and
accumulates in human milk. (14)
(14) Turner AR, Spurling BC, Agrawal S. Marijuana Toxicity. [Updated 2020 Jul 19]. In:
StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK430823/
The medicinal use of marijuana and the approved drugs:
The United state of food and drug administration realized that there is an enlarged interest in
the potential benefit of cannabis use in treating numerous disease states along with their
possible adverse events.
The agency has approved one cannabis - derived drug product which is cannabidiol
(Epidiolex) Besides three synthetic cannabis-related drug products: two dronabinol (Marinol
and Syndros) and nabilone (Cesamet). They are available only with prescriptions from
licensed health care professionals, as they are the only FDA approved drugs currently on the
market.
Epidiolex: is the only FDA approved drug which contains a highly purified form of (CBD, it
doesn’t cause intoxication or the high unlike THC) as oral solutions (100 mg/ml) for the
treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet
syndrome (DS) which are rare and critical forms of Epilepsy in affected individuals aged 2
years and older.
• Dravet syndrome is a genetic disease with frequent febrile seizures. Then myoclonic
seizures generally arise in addition to status epilepticus which is a life-threatening condition
that necessitates emergency medical care.
• Lennox-Gastaut syndrome is described as multiple types of seizures, patients almost have
tonic seizures.
This approval, particularly for Dravet patients will provide considerable improvement in the
therapeutic approach along with the other important treatment options.The effectiveness of
epidemics that has been studied in three randomized, double- blind, placebo controlled
clinical trials consisting of 516 individuals affected either by Lennox-Gastaut or Dravet
syndromes. When compared to placebo, epidiolex were effective in decreasing the
frequency of seizures while taken with other medications.
The most common adverse effects patients experienced during the study with the use of
epidiolex were: sleep disorders such as Somnolence/insomnia, sedation and lethargy,
decreased appetite, infection, diarrhea, rash, fatigue, increase liver enzymes, Also cause
liver injury, typically mild. Most severe liver injuries cause symptoms like N/V abdominal pain,
anorexia, and jaundice.
As is the case with other antiepileptic drugs, the most serious risks are suicidal thoughts,
agitation, new onset or worsening pre existing depression, lastly aggression and panic
attack.
Epidiolex approved by the FDA for a new indication for the treatment of seizures associated
with tuberous sclerosis complex (TSC) in patients 1 year of age and older, it's the second
FDA approved drug for treating this type of seizures.
The FDA believed that the drug approval procedure performs the best way to make
medicines, like drugs driven from cannabis.
• TSC is a genetic condition that causes benign tumors which grow in the brain and many
other parts of the body-like the heart, lungs, eyes, typically affects the CNS causing
symptoms including seizures, developmental and behavioral problems.
The effectiveness of Epidiolex for the treatment of seizure associated with tuberous sclerosis
complex has done in a randomized, double-blind placebo-controlled trial, involves 148
affected individuals out of a total of 224 in the study received the drug.The trial measured the
seizure frequency changes from the baseline, patients received Epidiolex had a magnificent
reduction in the seizure frequency than patients received placebo throughout the treatment
duration. It takes eight weeks to see the effect and remains consistent during the 16 week
treatment period.
Epidiolex should be distributed with a patient medication guide that provides important
information about the uses and risks of the drug. Patients, their care providers, and families
must be aware to monitor and report any extraordinary changes in mood or behaviors of
concerns such as worsening
Depression, suicidal thoughts immediately to the healthcare giver. (15,16)
(15)https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-compris
ed-active-ingredient-derived-marijuana-treat-rare-severe-forms
(16)https://www.fda.gov/news-events/press-announcements/fda-approves-new-indication-dr
ug-containing-active-ingredient-derived-cannabis-treat-seizures-rare
MOA of epidiolex: the exact mechanism of cannabidiol in humans still unknown.
It seems that cannabidiol doesn’t exert its effect by interacting with cannabinoid receptors.
Dosage of Cannabidiol : the initial dose is 2.5 mg/kg two times a day, one week later the
dose can be gradually titrated upward to a maintenance dose of 5 mg/kg twice daily, patients
requiring further reduction of seizure may increase the dose to the maximum maintenance
dose of 10 mg / kg twice daily. A dose of 10 mg/ kg (20 mg/ kg/day) resulted in greater
reduction in seizure but may also increase the adverse events.
For all patients to be treated with Epidiolex should obtain serum transaminases and total
bilirubin levels before starting the therapy due to the risk of liver injury, therefore (ALT, AST)
and bilirubin levels should be obtained at 1 month, 3 months, 6 months after the start of the
treatment.
• Patients with moderate to severe hepatic insufficiency require dose adjustment:For mild
hepatic impairment no need to adjust the dose.For moderate hepatic impairment the starting
dose is (2.5 mg / kg/ day), maintenance dose of (5mg/kg/day) and maximum dose of (10
mg/kg/day).
For severe hepatic impairment The starting dose is (1mg/kg/day), maintenance dose of
(2mg/kg/day), and the maximum dose of (4 mg/kg/day).
Epidiolex shouldn't be used in patients with previous history of hypersensitivity reaction to
the drug,
Epidiolex should be gradually withdrawn due to the risk of increased seizure frequency.
Epidiolex use in geriatric populations: clinical trials didn't involve any patients of 55 years of
age and above to determine if they respond in a different way compared to younger patients.
Generally, elderly patients should be started at the low end of the dosing range.
Pharmacokinetics: ADME
Absorption: the time for Max plasma concentration (Tmax) of 2.5 to 5 hr at steady state
(CSS),Administrating Epidiolex with food rich in fat will increase Cmax by 5- fold, and the
area under the curve by 4- fold, and decreased total variability.
Distribution: the volume of distribution was 20963L to 42849L. Cannabidiol protein binding
was >94% in vitro.
Metabolism: it's metabolized primarily in the liver by CYP3A4 and CYP2C19. The active
metabolite of Epidiolex is 7-OH-CBD and has 38 % lower AUC, which is then converted to
the inactive form 7-COOH-. CBD
Elimination: after twice daily dosing for a week of Cannabidiol the half-life in plasma was 56
to 61 hours. Epidiolex mainly excreted in feces, with small renal clearance.
Drug interactions:
As Epidiolex is metabolized mainly by CYP3A4 and CYP2C19 , so coadministration with
intermediate or strong CYP3A4 or CYP2C19 inhibitors will elevate Epidiolex concentrations,
therefore decreasing the dose should be considered. While coadministration with strong
inducers will reduce Cannabidiol serum concentrations , so increasing the dose may be
considerable.
Cannabidiol is the active ingredient along with other inactive ingredients including:
strawberry flavor, sucralose, sesame seed oil, and dehydrated alcohol. (17)
(17)https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf
Marijuana plant description:
Cannabis sativa L it's an important plant due to its wide range of applications and it's a
source of oil and fibers.Cannabinoids are the most studied components, generally because
of their pharmaceutical effects, terpenes and phenolic compounds have also therapeutic and
commercial interests.
Hemp stem has antibacterial properties and a source of fibers, The rapid growth of
herbaceous species as textile hemp that contains THC 0.3 %, can supply high biomass
quantities in a brief time.The stem of the fiber crop provides cellulosic and woody fibers, the
core is lignified, but the cortex port long cellulose - rich fibers, called bast fibers.
Hemp fibers are of interest due to their natural antibacterial property, hemp includes different
compounds such as cannabinoids, terpenes and phenolic compounds.
Typically compound concentration depends on various factors as tissue type, age, growth
conditions Harvest time and storage circumstances. Hemp-seed contains low levels of
phytocannabinoids as the nucleus contains only trace levels of THC and CBD, the outer
surface of the seed coat found to have higher THC concentrations .(18)
Cannabinoid concentrations found in different parts of marijuana plant :
Cannabis sativa seed contains almost 27.1% protein, 25.6% of fat, 7.4% carbohydrate, and
lastly 6.1% ash. The leaves contain 0.215% carotene (19)
Cannabis sativa composition in seed/100g of food
• water 0%, 487 calories/ 100g.
• Macronutrients: protein 31.4g , fat 29.6g , carbohydrates 31.9g , fiber 23.5g , ash 7.1g .
• Minerals: phosphorus 1123mg , calcium 139mg , iron 13.9mg , but it doesn’t contain
magnesium, sodium, potassium, or zinc.
• Vitamins: A 518 mg,B1 0.37 mg (thiamine),B2 0.2mg ( riboflavin), 2.43 mg niacin.(20)
Female plant that produces oil is left to stand after the male plant is harvested which
produces fiber in the temperate zone. When the plant is shaken, the female plant falls off
then seed can be harvested . Early in The morning is the best time to collect the seed when
fruits are swollen and conditions wet. Fruits began to dry in the middle of the day, seed loss
increased due to smashing.
As mentioned previously, male plants that produce best fibers can be harvested when the
flowers start to open and the plant became brown.(21,22,23)
Cannabis sativa is a yearly growing to 8 ft( 2.5 m) by 2ft 7 inch( 0.8 m), it's flowering in July.
Single flower may either be a male or female, however, only one female or male is to be
found in the plant therefore, if the seed is desired, both sexes must be grown. Plant is not
able to fertilize itself but it's pollinated by wind. It was totable that wildlife is attracted to the
plant.(24)
(18) Andre, C. M., Hausman, J. F., & Guerriero, G. (2016). Cannabis sativa: The Plant of the
Thousand and One Molecules. Frontiers in plant science, 7, 19.
https://doi.org/10.3389/fpls.2016.00019
(19) Reid. B. E. Famine Foods of the Chiu-Huang Pen-ts'ao. Taipei. Southern Materials
Centre 1977
A translation of an ancient Chinese book on edible wild foods. Fascinating.
(20) Duke. J. A. and Ayensu. E. S. Medicinal Plants of China Reference Publications, Inc.
1985 ISBN 0-917256-20-4
Details of over 1,200 medicinal plants of China and brief details of their uses. Often includes
an analysis, or at least a list of constituents. Heavy going if you are not into the subject.
(21) Duke. J. Handbook of Energy Crops - 1983
Published only on the Internet, excellent information on a wide range of plants.
(22) Hill. A. F. Economic Botany. The Maple Press 1952
Not very comprehensive, but it is quite readable and goes into some bit of detail about the
plants it does cover.
(23) Encyclopaedia Britannica. 15th edition.
It contains a few things of interest to the plant project.
(24) Cannabis sativa Hemp, Marijuana PFAF Plant Database. (2021). Retrieved 1 April
2021, from https://pfaf.org/User/plant.aspx?LatinName=Cannabis+sativa
Side effects:
Driving While Intoxicated
- THC affects vision and psychomotor performance, potentially increasing the likelihood of
causing a traffic accident.
- According to a systematic review and meta-analysis of nine observational studies, acute
cannabis consumption is linked to an increased risk of motor vehicle accidents.
- THC was linked to a 29% rise in dangerous driving in a case-control report, compared to
101% for alcohol.
Reproductive Effects
1- Exposure During Pregnancy
Cannabis use during pregnancy is not recommended.
- Heavy cannabis use during pregnancy may have negative consequences for early
neurodevelopment, including subtle cognitive impairment and later declines in executive
function.
- There is no evidence that cannabis use raises the risk of congenital abnormalities.
- Some research, but not all, have found a reduction in fetal development.
- There is a possibility that the baby will be born early.
2-Fertility and Lactation
It is not advisable to use cannabis when breastfeeding.
- THC is excreted in breast milk, as are its metabolites.
- When compared to non-exposed children, those who were exposed to marijuana during
lactation had lower Psychomotor Developmental Index ratings (effects could not be
separated from prenatal exposure).
Effects of Fertility on Men
-According to some research, chronic marijuana use reduces plasma testosterone, as well
as sperm count, concentration, and motility.
Psychiatric Effects
Dependence
- Cannabis addiction is possible: the global prevalence of 0.23% in males and 0.14% in
females is estimated.
- The prevalence of the disease peaks in the 20-24 year old age group and slowly declines
with age.
- A study of 6,917 drug users found that 15% of those polled meet the requirements for a
marijuana use disorder. Weekly drug usage, early marijuana use, other substance use
disorders, substance abuse treatment, and severe psychological distress were all linked to
people who met the requirements for marijuana use disorder.
Neuropsychiatric Effects
Cognitive Function
-Cannabis patients who have been using for a long time have issues with prospective
memory and executive function.
Drug Interactions
Cytochrome P450 Enzymes
•
CYP3A4 and CYP2C9 are the enzymes that break down THC and CBD.
- CYP3A4 inhibitors increase THC levels by a small amount.
- CYP3A4 inducers reduce THC and CBD levels by a small amount.
•
CBD is metabolized by CYP2C19, but not THC.
•
THC is a CYP1A2 inducer
-THC will potentially lower clozapine, duloxetine, naproxen, cyclobenzaprine, olanzapine,
haloperidol, and chlorpromazine serum concentrations.
•
CBD inhibits the enzymes CYP3A4 and CYP2D6.
-CBD can increase serum concentrations of macrolides, calcium channel blockers,
benzodiazepines, cyclosporine, sildenafil (and other PDE5 inhibitors), antihistamines,
haloperidol, antiretrovirals, and some statins because CYP3A4 metabolizes about a quarter
of all drugs (atorvastatin and simvastatin, but not pravastatin or rosuvastatin).
- CBD can increase serum concentrations of SSRIs, tricyclic antidepressants, antipsychotics,
beta blockers, and opioids since CYP2D6 metabolizes many antidepressants (including
codeine and oxycodone).(25)
CESAMET(nabilone) Capsules
DESCRIPTION
Cesamet (Nabilone) is a synthetic cannabinoid which is taken orally. It is a raw material
looking like white to off-white polymorphic crystalline powder. In liquids, the solubility is less
than 0.5 mg/L, pH range 1.2 to 7.0.
Chemically active ingredient similar to Cannabis sativa L. [Marijuana;
delta-9-tetrahydrocannabinol (delta-9-THC)]. Nabilone (±)-trans-3-(l,l-dimethylheptyl)6,6a,7,8,10,10a-hexahydro-l-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one and a
C24H36O3 empirical formula. Its molecular weight is 372.55. The chemical structure is :
Cesamet capsules contain 1 mg (2.7 mol) of nabilone, as well as povidone and cornstarch
as inactive ingredients. Shells of capsule contain also inactive ingredients: F D & C Blue No.
1, Red D&C Nos. 28 and 33, gelatin, and titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacodynamic
Cesamet has a CNS complex effect. The interaction between nabilon and cannabinoid
receptors produce an antiemetic effect. I.e. The CB (1) receptor, which is discovered in
neural tissues.
Non Therapeutic Effects: Cesamet, have a possibility to be abused and mental reliance. Has
a complex effect on the CNS that effects on the mental state similar to cannabis.The
individual is taken Cesamet they have changes in mood experience (e.g., euphoria,
detachment, depression, anxiety, panic, paranoia). Decreases in cognitive capacity and
memory, a diminished ability to regulate drives and desires, and changes in one's
understanding of reality (e.g.hallucinations, distortions of object perception and sense of
time). These symptoms tend to be more frequent when higher doses of Cesamet are given;
however, patients receiving doses in the lower half of the therapeutic range may develop a
full-blown case of psychosis (psychotic organic brain syndrome). Tolerance to these side
effects grows faster and can be reversed.
There is no data on chronic Cesamet use; however, experience with cannabis indicates that
chronic cannabinoid use is linked to a number of negative effects on motivation, memory,
judgment, and other mental state changes. Whether these occurrences are a reflection of
the underlying personality
Cesamet and alcohol or barbiturates taken together can have additive depressive effects on
CNS activity. Patients taking Cesamet can experience mood swings and other negative
behavioral effects. When using Cesamet, patients should be monitored by a responsible
adult.
Cesamet stimulates the CNS. In the prescribed dose range, it causes relaxation,
drowsiness, and euphoria. Tolerance to these side effects grows quickly and can be
reversed.
Cesamet has many systemic effects in addition to mental effects, the most important of
which are dry mouth and hypotension. Cesamet has been shown to cause supine and
orthostatic hypotension as well as elevated supine and standing heart rates. In clinical trials,
oral administration of 2 mg of Cesamet reduced airway resistance in healthy volunteers but
had no impact in patients. The oral administration of 2 mg of Cesamet lowered airway
resistance in healthy volunteers but had no effect on asthmatics. Cesamet has not been
linked to any other nontherapeutic side effects that are clinically significant.
Pharmacokinetics
Absorption and Distribution: When Cesamet is taken orally, it tends to be fully absorbed by
the human gastrointestinal tract. Peak plasma concentrations of approximately 2 ng/mL
nabilone and 10 ng equivalents/mL total radioactivity are reached within 2.0 hours after oral
administration of a 2-mg dose of radiolabeled nabilone. Nabilone's plasma half-life (T1/2) is
about 2 and 35 hours of total radioactivity of identified and unidentified metabolites. The
rapid disappearance of radioactivity is due to nabilone uptake and distribution in tissue,
accompanied by a slower process of elimination by metabolism and excretion. Nabilone's
apparent volume of delivery is about 12.5 L/kg.
Within its therapeutic range , Nabilone has dose linearity. Food consumption does not
appear to influence the rate or extent of absorption, according to clinical evidence.
Metabolism: Nabilone undergoes extensive metabolism, and many metabolites have been
identified. There is no precise knowledge about the metabolites that could accumulate. It is
unknown what the relative activities of the metabolites and the parent drug are. The
biotransformation of nabilone involves at least two metabolic pathways. The stereospecific
enzymatic reduction of the 9-keto moiety of nabilone to generate the isomeric carbinol
metabolite initiates a minor pathway. Although the peak concentrations of nabilone and its
carbinol metabolites are close, their combined plasma exposures do not account for more
than 20% of overall radioactivity. The second point is that A diol formed by reduction of the
9- keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain has
been known as a metabolite of nabilone in feces. Cesamet is also believed to be extensively
metabolized by several P450 enzyme isoforms. Nabilone did not significantly inhibit
CYP1A2, 2A6, 2C19, 2D6, or 3A4 in vitro P450 inhibition studies using human liver
microsomes (using midazolam and nifedipine as substrates). Nabilone had a weak inhibitory
effect on CYP 2E1 and 3A4 (using testosterone; IC50 > 50 μM) and had a moderate
inhibitory effect on CYP2C8 and 2C9 (IC50 > 10 μM). The very low plasma concentration of
nabilone, on the other hand, is unlikely to interfere with the P450-mediated degradation of
co-administered drugs in clinical use. Three subjects received chronic oral administration of
1 mg t.i.d. for 14 days and showed no signs of nabilone accumulation. According to the data,
one or more of the metabolites have a terminal removal half-life that is longer than that of
nabilone. As a result, after repeated use, the metabolites can accumulate at levels higher
than the parent drug.
Elimination: The removal route and rate of nabilone and its metabolites are close to those of
other cannabinoids, such as delta-9-THC (dronabinol). After being given intravenously,
nabilone and its metabolites are often removed in the feces (approximately 67%) and to a
lesser degree in the urine (approximately 22%). The parent compound made up 5% of the
67 percent recovered from the feces, while the carbinol metabolite made up 16%.
Approximately 60% of nabilone and its metabolites were recovered in the feces, and about
24% in the urine, after oral administration. As a consequence, it seems that the biliary
system is the main excretory system.
Age, gender, hepatic dysfunction, and renal insufficiency have not been studied in relation
to nabilone metabolism and elimination.
Special Populations: Cesamet's pharmacokinetic profile has not been studied in pediatrics
(see PRECAUTIONS for Pediatric, geriatric ,patients use).
CLINICAL TRIALS
Cesamet was investigated for its effectiveness and safety in the treatment of nausea and
vomiting induced by cancer chemotherapy in patients undergoing a variety of chemotherapy
regimens, including low-dose cisplatin (20 mg/m2).
Patients undergoing Cesamet treatment showed a higher rate of side effects. Drowsiness,
vertigo, dry mouth, and euphoria were the most common. However, the majority of
Cesamet's side effects were mild to moderate in severity.
INDICATIONS AND USAGE
Cesamet capsules are used to treat nausea and vomiting caused by cancer chemotherapy
in patients who haven't had success with other antiemetic medicines. Since a significant
proportion of patients treated with Cesamet are likely to experience distressing
psychotomimetic responses not seen with other antiemetic agents, this restriction is
necessary.
Cesamet is intended for use under conditions that allow for close monitoring of the patient by
a competent person, especially during the initial use of Cesamet and during dose changes,
due to its potential to alter mental state.
Cesamet contains the controlled substance nabilone, which is specified in Schedule II of the
Controlled Substances Act. Substances known as Schedule II have a high potential for
violence. Cesamet prescriptions should be limited to the amount required for a single
chemotherapy cycle (i.e., a few days).
Cesamet capsules should not be used on an as-needed basis or as a patient's first
antiemetic drug.
CONTRAINDICATIONS
Cesamet is not recommended for someone who has a history of cannabinoid
hypersensitivity.
Warning
·
Cesamet's effects will last a long time after it's been taken orally. Adverse psychiatric
reactions will last for up to 72 hours after treatment is stopped.
·
Cesamet can cause dizziness, drowsiness, euphoria "high," ataxia, anxiety,
disorientation, depression, hallucinations, and psychosis by affecting the CNS.
·
Tachycardia and orthostatic hypotension are potential side effects of Cesamet.
·
Patients should be supervised by a competent adult during the initial use of Cesamet
and during dosage changes due to individual differences in reaction and responsiveness
to the effects of Cesamet.
·
Patients taking Cesamet should be expressly advised not to drive, operate equipment, or
engage in any other potentially dangerous operation while on the drug.
·
Cesamet should not be taken with alcohol, sedatives, hypnotics, or other psychoactive
drugs because they can intensify the effects of nabilone on the CNS.
GENERAL PRECAUTIONS
Because of individual variance in reaction and tolerance to Cesamet's effects, the
benefit/risk ratio of Cesamet use should be carefully assessed in patients with the following
medical conditions.
· Cesamet should be used with caution in the elderly and in patients with hypertension or
heart failure because it can raise supine and standing heart rates and cause postural
hypotension.
·
Cesamet should be used with caution in patients who have current or previous
psychiatric disorders (such as bipolar depressive syndrome, depression, or
schizophrenia), as cannabinoids can unmask the symptoms of these diseases.
·
Because of the potential for additive or synergistic CNS effects, Cesamet should be used
with caution in people who are taking sedatives, hypnotics, or other psychoactive
substances.
·
Since Cesamet contains a similar active compound to marijuana, it should be used with
caution in patients who have a history of drug abuse, including alcohol abuse or
dependency and marijuana usage.
·
The effects of hepatic and renal dysfunction on their protection have not been studied.
·
Nabilone is said to be strongly bound to plasma proteins and goes through a lot of
first-pass hepatic metabolism. These characteristics have the potential to trigger
drug-drug interactions, influencing the pharmacokinetics of co-administered drugs with
similar pharmacokinetic profiles or Cesamet itself.
·
The implications of Cesamet's QT prolongation potential have yet to be determined.
·
Cesamet should be used with caution in pregnant women, nursing mothers, and children
since these patient groups have not been examined.
Information for Patients
People taking Cesamet should be aware that taking it with alcohol or other central nervous
system depressants like benzodiazepines or barbiturates can cause additive central nervous
system depression. This pairing should be avoided at all costs. Patients taking Cesamet
should be explicitly advised not to drive, operate equipment, or perform any other activities
that require focus, or take part in any risky activity Patients taking Cesamet should be
informed about the drug's potential for mood swings and other negative behavioral
consequences so that they don't panic if they experience them. When using Cesamet,
patients should be supervised by a responsible adult.
Drug Interactions
15 subjects were screened for potential interactions between Cesamet 2 mg and diazepam 5
mg, sodium secobarbital 100 mg, alcohol 45 mL (absolute laboratory alcohol), or codeine 65
mg. At any one time, only one combination was used. Physiologic (heart rate and blood
pressure) as well as psychometric, psychomotor, and subjective parameters were used to
assess the participants. The depressant effects of the combinations were additive in this
analysis, as predicted. When diazepam was used together, psychomotor control was
significantly harmed. When using nabilone in conjunction with any CNS depressant, extreme
caution is recommended. The depressant effects of the combinations were additive in this
analysis, as predicted. When diazepam was used together, psychomotor control was
significantly harmed. When using nabilone in conjunction with any CNS depressant, extreme
caution is recommended.
Since nabilone is said to be strongly bound to plasma proteins, it can displace other
protein-bound drugs. When prescribing nabilone to patients who are also taking other highly
protein-bound medications, practitioners should keep an eye on them for any changes in
dosage requirements. The following table summarizes reported drugs of cannabinoid-related
drug interactions.
CONCOMITANT DRUG
CLINICAL EFFECT(S)
Amphetamines, cocaine, other
sympathomimetic agents
Additive hypertension, tachycardia, possibly
cardiotoxicity
Atropine, scopolamine, antihistamines,
other anticholinergic agents Atropine,
scopolamine, antihistamines, other
anticholinergic agents
Additive or super-additive tachycardia,
drowsiness
Amitriptyline, amoxapine, desipramine,
other tricyclic antidepressants
Additive tachycardia, hypertension,
drowsiness
Barbiturates, benzodiazepines, ethanol,
lithium, opioids, buspirone, antihistamines,
muscle relaxants, other CNS depressants
Additive drowsiness and CNS depression
Disulfiram
A reversible hypomanic reaction was
reported in a 28 y/o man who smoked
marijuana; confirmed by dechallenge and
rechallenge
Fluoxetine
A 21 y/o female with depression and bulimia
receiving 20 mg/day fluoxetine X 4 wks
became hypomanic after smoking
marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates
Decreased clearance of these agents,
presumably via competitive inhibition of
metabolism
Theophylline
Increased theophylline metabolism reported
with smoking of marijuana; effect similar to
that following smoking tobacco
Opioids
Cross-tolerance and mutual potentiation
Naltrexone
Oral THC effects were enhanced by opioid
receptor blockade.
Alcohol
Increase in the positive subjective mood
effects of smoked marijuana
Toxicology and/or pharmacology of animals
Cesamet was given to monkeys at doses as high as 2 mg/kg/day for a year with no apparent
side effects. This finding contrasts with the results of a proposed 1-year dog study that was
cut short due to deaths linked to convulsions in dogs receiving as little as 0.5 mg/kg/day. The
earliest deaths of dogs receiving 2 mg/kg/day occurred at 56 days. The dog's peculiar
susceptibility to Cesamet is unknown; however, it is speculated that the cause lies in the fact
that the dog's Cesamet metabolism varies significantly from that of other organisms.
Carcinogenesis, Mutagenesis, and Fertility Impairment
There have been no long-term animal studies to assess nabilone's carcinogenic potential.
The Ames test, the rat hepatocyte unscheduled DNA synthesis (UDS) test, the Chinese
hamster bone marrow cell sister chromatid exchange (SCE) test, the male rat dominant
lethal tests, and the rat micronucleus test all showed that nabilone was not genotoxic.
In male and female rats, dietary administration of nabilone up to 4 mg/kg/day (roughly 6
times the recommended maximum human dose based on body surface area) had no effect
on fertility or reproductive efficiency.
Teratogenic Effects of Pregnancy. Class C Pregnancy
Teratology experiments in pregnant rats at doses up to 12 mg/kg/day (approximately 16
times the human dose on a body surface area basis) and pregnant rabbits at doses up to 3.3
mg/kg/day (approximately 9 times the human dose on a body surface area basis) revealed
no evidence of nabilone's teratogenic potential. Embryo lethality, fetal resorptions, reduced
fetal weights, and pregnancy disruptions were all evidence of dose-related developmental
toxicity in both organisms. Postnatal developmental toxicity has also been observed in rats.
In pregnant women, there is no appropriate and well-controlled research. Cesamet can only
be used during pregnancy if the potential advantage outweighs the potential risk to the fetus,
as animal tests cannot rule out the possibility of injury.
Nursing Mothers
This medication is not known if it is excreted in breast milk. Cesamet should not be given to
nursing mothers since certain medications, including certain cannabinoids, are excreted in
breast milk.
Pediatric
Patients under the age of 18 have not been studied for safety or efficacy. Cesamet should be
used with caution in children due to its psychoactive effects.
Geriatric
Cesamet clinical trials did not involve a large enough number of participants aged 65 and up
to assess if they react differently than younger people. In general, dose selection for an
elderly patient should be conservative, beginning at the low end of the dosing spectrum to
account for the higher likelihood of reduced liver, kidney , or heart function, as well as
concomitant disease or other drug therapy. Cesamet should be used with caution in elderly
patients aged 65 and up because they are more susceptible to the psychoactive effects of
medications, and Cesamet can induce postural hypotension by elevating supine and
standing heart rates.
Adverse Reactions
Common Adverse Reactions: During Cesamet's controlled clinical trials, almost every patient
had at least one adverse reaction. Drowsiness, vertigo, dry mouth, euphoria (feeling “high”),
ataxia, headache, and attention problems were the most common side effects.
Comparative Reaction Incidence: It's difficult to get accurate estimates of the frequency of
adverse effects associated with the use of any medication. Factors such as drug dosage,
detection method, environment, and physician decisions, among others, affect estimates. As
a result, the tables below are only intended to show the relative frequency of adverse effects
recorded in representative controlled clinical trials performed to assess Cesamet's safety
and efficacy under relatively similar conditions of use. The statistics cited cannot be used to
accurately forecast the occurrence of untoward incidents in routine medical practice, where
patient characteristics and other variables could vary from those seen in clinical trials. Since
each group of drug trials is performed under a particular set of conditions, these incidence
statistics cannot be compared to those collected from other clinical research involving similar
drug products.
Finally, it is important to note that these figures do not represent the magnitude or clinical
significance of the adverse events. The WARNINGS and PRECAUTIONS sections give a
greater understanding of the significant adverse effects associated with the use of Cesamet.
The adverse reactions experienced by a significant proportion of patients treated with
Cesamet who participated in representative controlled clinical trials are described in the
tables below, in decreasing order of frequency.
DRUG ADDICTION AND DEPENDENCY
Cesamet, a synthetic cannabinoid with pharmacological similarities to Cannabis sativa L.
(Marijuana; (delta-9-THC), is a widely abused drug. Cesamet is classified as a Schedule II
(CII) controlled substance under the Controlled Substances Act. Cesamet prescriptions
should be limited to the amount required for a single chemotherapy cycle (i.e., a few days).
At therapeutic doses, Cesamet can cause subjective side effects that mimic euphoria or a
marijuana-like "high."
It's unclear how many people who are exposed to Cesamet or other cannabinoids on a
long-term basis will develop psychological or physical dependency. Long-term use of these
compounds, on the other hand, has been linked to problems with motivation, reasoning, and
cognition. However, it is uncertain if this is a result of chronic users' underlying personalities
or whether cannabinoids are specifically responsible for these effects. After discontinuing
delta-9-THC at high doses of 200 mg per day for 12 to 16 days, an abstinence syndrome
has been reported. Psychic anxiety, insomnia, and symptoms of autonomic hyperactivity
characterized the acute period (sweating, rhinorrhea, loose stools, hiccups). Subjects who
recorded sleep disturbances for several weeks after discontinuing delta-9-THC may have
experienced a prolonged abstinence period.
Addiction - At therapeutic doses, Cesamet can induce subjective side effects such as
euphoria or a marijuana-like "high." Cesamet was found to be qualitatively and quantitatively
close to permitted oral delta-9-THC in producing cannabis-like effects, suggesting its abuse
potential.
Dependence - At this time, Cesamet's physical dependence potential is uncertain. Patients
who took part in up to 5-day clinical trials had no withdrawal effects after stopping the
medication.
OVERDOSAGE
Signs and Symptoms - Overdose signs and symptoms are a result of Cesamet's
psychotomimetic and physiologic impact.
Treatment -Your accredited Regional Poison Control Center is a good resource for
up-to-date information on overdose care. The Physicians' Desk Reference includes phone
numbers for certified poison control centers (PDR). Consider the risk of multiple medication
overdoses, drug interactions, and irregular drug kinetics in your patient when treating
overdose.
If troubling medical symptoms are present, overdosage can be suspected, even at
prescribed dosages. The patient should be observed in a calm atmosphere and calming
strategies, such as reassurance, should be used in these situations. Subsequent doses
should be deferred until patients have regained their baseline mental status; if clinically
indicated, regular dosing will then resume. In such cases, a lower initial dose is
recommended. In controlled clinical trials, changes in mental state caused by Cesamet were
reversed within 72 hours without the need for specific medical treatment.
Vital signs should be controlled in overdose cases since both hypertension and hypotension
have been recorded; tachycardia and orthostatic hypotension were the most frequently
reported.
During clinical trials, no cases of nabilone overdosage with doses greater than 10 mg/day
were recorded. Psychotic episodes, such as hallucinations, anxiety reactions, respiratory
collapse, and coma, are common signs and symptoms of large overdose circumstances.
If psychotic episodes do occur, the patient should be treated conservatively. Verbal help and
comforting can be appropriate for mild psychotic symptoms and anxiety reactions.
Antipsychotic medications can be effective in more serious situations. Antipsychotic drugs'
efficacy in cannabinoid psychosis, on the other hand, has not been thoroughly studied.
Antipsychotics have been used to treat cannabis overdoses in the past, but there isn't much
evidence to back up their use. Such patients should be closely monitored due to the risk of
drug-drug interactions (e.g., additive CNS depressant effects from nabilone and
chlorpromazine).
Support ventilation and perfusion thus protecting the patient's airway. Track and keep the
patient's vital signs, blood gases, serum electrolytes, and other laboratory values and
physical tests within reasonable limits. Giving activated charcoal, which is often more
effective than emesis or lavage in minimizing drug absorption from the gastrointestinal tract,
can be used instead of or in addition to gastric emptying. Over time, repeated doses of
charcoal can help to eliminate some drugs that have been absorbed. When using gastric
emptying or charcoal, keep the patient's airway clear.
There has been no mention of forced diuresis, peritoneal dialysis, hemodialysis, charcoal
hemoperfusion, or cholestyramine. The biliary system eliminates the majority of a nabilone
dose in the presence of proper renal activity.
Symptomatic and supportive treatment are used to treat respiratory distress and comatose
states. The incidence of hypothermia should be given special consideration. Consider fluids,
inotropes, and/or vasopressors if the patient becomes hypotensive.
DOSAGE AND ADMINISTRATION
Adults should take 1 or 2 mg b.i.d. The initial dose should be given 1 to 3 hours before the
chemotherapeutic agent is given on the day of chemotherapy. It is recommended that the
lower starting dose be used and that the dose be increased as required to reduce side
effects. It could be helpful to take 1 or 2 mg the night before. The effective daily dose is 6
mg, administered in divided doses t.i.d.
Cesamet can be taken 2 or 3 times a day for the duration of each chemotherapy cycle and, if
necessary, for up to 48 hours after the last dose of each cycle.
HOW SUPPLIED
Cesamet capsules (purple and white) 1 mg (bottles of 20 capsules) NDC 0187-0247-01.
Valeant will be imprinted on the white body of the capsule and a four-digit code (0247) will be
imprinted on the purple hat. Store at 25oC (77oF) in a controlled room temperature
environment; excursions to 15-30oC (59-86oF) are allowed [see USP Controlled Room
Temperature].
Rx only
Dronabinol (MARINOL®, SYNDROS®)
DESCRIPTION: Dronabinol is a cannabinoid (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. The empirical formula and chemical structure
is :
Dronabinol is a synthetic delta-9-tetrahydrocannabinol (delta-9-THC) is the active ingredient
in MARINOL® Capsules and SYNDROS® Oral Solution. Cannabis sativa L. Also, naturally
produce delta-9-tetrahydrocannabinol (Marijuana).
At room temperature, dronabinol is a light yellow resinous oil with a sticky consistency that
hardens when refrigerated. Dronabinol is a non-water soluble cannabinoid that is formulated
in sesame oil. At pH 7, it has a pKa 10.6 and 6,000:1 octanol-water partition coefficient.
Oral administration capsules: MARINOL® Capsules are round, soft gelatin capsules
containing 2.5 mg, 5 mg, or 10 mg dronabinol. FD&C Blue No. 1 (5 mg), FD&C Red No. 40
(5 mg), FD&C Yellow No. 6 (5 mg and 10 mg), gelatin, glycerin, methylparaben,
propylparaben, sesame seed, and titanium dioxide are all inactive ingredients in each
MARINOL® Capsule.
Oral administration solution: SYNDROS® Solution 5 mg/mL, is a smooth, pale yellow to
brown liquid. The active ingredient in each mL of SYNDROS® is 5 mg of dronabinol, with the
following inactive ingredients: 50% (w/w) Dehydrated alcohol, polyethylene glycol 400,
propylene glycol, sucralose, methyl paraben, propylparaben, butylated hydroxyanisole, and
water.
CLINICAL PHARMACOLOGY
Dronabinol is an orally active cannabinoid with diverse effects on the CNS, like central
sympathomimetic function, similar to other cannabinoids. In neural tissues, cannabinoid
receptors have been discovered. These receptors can play a role in dronabinol and other
cannabinoids' effects being mediated.
Pharmacodynamics: Tachycardia and/or conjunctival injection can occur as a result of
dronabinol-induced sympathomimetic behavior. Its effects on blood pressure are
inconsistent, but it has been known to cause orthostatic hypotension and/or syncope in
some people when they suddenly stand up.
Dronabinol has reversible effects on appetite, mood, intellect, memory, and vision, among
other things. These occurrences tend to be dose-related, increasing in frequency with higher
dosages and being highly variable between patients.
Dronabinol has a half-hour to one-hour onset of action and a two- to four-hour peak effect
after oral administration. Since the psychoactive effects of dronabinol last 4 to 6 hours, the
appetite stimulant effect will last up to 24 hours after administration.
Chronic use of dronabinol and other cannabinoids contributes to tachyphylaxis and
tolerance to some of the pharmacologic effects, meaning indirect impact on a sympathetic
neuron. Healthy male volunteers (N = 12) were given 210 mg/day dronabinol, administered
orally in divided doses, for 16 days in a study of the pharmacodynamics of chronic
dronabinol exposure. Dronabinol-induced tachycardia was gradually replaced by natural
sinus rhythm and then bradycardia. Initially, a drop in supine blood pressure was detected,
which was exacerbated by standing. Within 12 days of starting treatment, these volunteers
had gained immunity to the cardiovascular and subjective adverse CNS effects of
dronabinol.
Tachyphylaxis and tolerance to the appetite stimulant effect of MARINOL® Capsules, on the
other hand, do not seem to improve. The appetite stimulant effect of MARINOL® Capsules
has been maintained for up to five months in clinical trials involving patients with Acquired
Immune Deficiency Syndrome (AIDS), at dosages ranging from 2.5 mg/day to 20 mg/day.
Pharmacokinetics: Absorption: After a single oral dose, it is almost fully absorbed (90 to 95
%). Just 10 to 20% of the administered dose enters the systemic circulation due to the
combined effects of first-pass hepatic metabolism and high lipid solubility.
Distribution: Because of its lipid solubility, dronabinol has a wide apparent volume of
distribution (approximately 10 L/kg). Dronabinol and its metabolites bind to plasma proteins
at a rate of about 97%.
A two compartment model with an initial (alpha) half-life of about 4 hours and a terminal
(beta) half-life of 25 to 36 hours can be used to describe the elimination process of
dronabinol. Dronabinol and its metabolites can be excreted at low levels for long periods of
time due to their wide amount of distribution. The pharmacokinetics of dronabinol after single
doses (2.5, 5, and 10 mg) and multiple doses (2.5, 5, and 10 mg given twice a day; BID)
were examined in healthy women and men.
Summary of Multiple-Dose Dronabinol Pharmacokinetic Parameters in Safe Volunteers in
Fasted Conditions (n=34; 20-45 years)
Over the dose range studied, there was a small increase in dose proportionality on mean
Cmax and AUC (0-12) of dronabinol with increasing dose.
Metabolism: Dronabinol undergoes extensive first-pass hepatic metabolism, with active and
inactive metabolites produced primarily by microsomal hydroxylation. In plasma, dronabinol
and its most active metabolite, 11-OH-delta-9-THC, are contained in nearly equal quantities.
Both parent drug and metabolite concentrations peak between 0.5 and 4 hours after oral
dosing and then gradually decline over several days. Because of the difficulty of cannabinoid
delivery, clearance values range about 0.2 L/kg-hr, although they are highly variable.
Elimination: Both feces and urine contain dronabinol and its biotransformation products. The
main route of removal is biliary excretion, with about half of a radio-labeled oral dose
retrieved from the feces within 72 hours, compared to 10 to 15% recovered from urine. In the
urine, less than 5% of an oral dose is retrieved intact.
Low levels of dronabinol metabolites have been observed in the urine and feces for more
than 5 weeks following a single dose administration.
Urinary cannabinoid/creatinine concentration ratios were measured bi-weekly over a
six-week span in a study of dronabinol capsules in AIDS patients. The ratio of urinary
cannabinoid to creatinine was found to be highly associated with dosage. For the first two
weeks of therapy, there was no rise in the cannabinoid/creatinine ratio, suggesting that
steady-state cannabinoid levels had been achieved. This inference is in line with projections
based on dronabinol's observed terminal half-life.
Special Populations: The pharmacokinetic profile of MARINOL and SYNDROS in pediatric
patients has not been studied.
There were insufficient numbers of subjects aged 65 and up in clinical trials of MARINOL in
AIDS and cancer patients to decide if they react differently than younger subjects.
The neuropsychiatric and postural hypotensive effects of SYNDROS can be more
pronounced in elderly patients. As a consequence of their underlying disease state, elderly
patients with dementia are more likely to fall, which could be compounded by the CNS
symptoms of somnolence and dizziness associated with SYNDROS. Prior to starting
SYNDROS therapy, these patients should be closely monitored and put on fall precautions.
In antiemetic trials, there was no difference in effectiveness between patients over 55 years
old and younger patients. In general, dosage selection for an elderly patient should be
conservative, typically beginning at the low end of the dosing spectrum, to account for the
increased risk of falls, reduced hepatic, renal, or cardiac function, increased susceptibility to
psychoactive effects, and the presence of concurrent disease or drug therapy.
Clinical Trials
Appetite Stimulation:
Ø A randomized, double-blind, placebo-controlled study involving 139 patients looked at the
appetite stimulant effect of MARINOL® (Dronabinol) Capsules in the treatment of
AIDS-related anorexia with weight loss. All patients were started on 5 mg of MARINOL®
Capsules a day, given in 2.5 mg doses one hour before lunch and one hour before
dinner. When opposed to dosing later in the day, early morning administration of
MARINOL® Capsules tended to be associated with an increased incidence of adverse
experiences in pilot studies. During the six-week treatment cycle, the effect of
MARINOL® Capsules on appetite, weight, mood, and nausea was assessed at regular
intervals. At this dosage level, side effects (high, dizziness, nausea, somnolence)
occurred in 13 of 72 patients (18%), so the dosage was reduced to 2.5 mg/day, given as
a single dose at supper or bedtime.
MARINOL® Capsules treatment resulted in a statistically significant increase in appetite, as
calculated by the visual analog scale, as opposed to placebo (see figure). There were also
improvements in body weight and mood, as well as a decline in nausea.
Patients were able to continue treatment with MARINOL® Capsules in an open-label trial
after completing the 6-week study, and there was a sustained increase in appetite.
Ø Based on studies of dronabinol capsules, the protection of SYNDROS has been identified.
157 patients were given dronabinol capsules and 67 were given a placebo in studies of
AIDS-related weight loss. 317 patients were given dronabinol capsules and 68 were
given a placebo in studies of nausea and vomiting caused by cancer chemotherapy. The
adverse reactions in 474 patients who were given dronabinol capsules in studies are
summarized in the tables below.
The first instance of adverse reactions within the first 28 days was used to integrate studies
of various lengths.
Patients taking dronabinol capsules reported a cannabinoid dose-related “high” (easy
laughing, elation, and heightened awareness) in both antiemetic (24%) and lower dose
appetite stimulant clinical trials (8%).The CNS was the most widely recorded adverse
experience in patients with AIDS during placebo-controlled clinical trials, with 33% of
patients receiving dronabinol capsules reporting it. Approximately 25% of patients had a
CNS adverse reaction during the first two weeks, and approximately 4% experienced one
per week for the next six weeks.
Common Adverse Reactions: In clinical trials of dronabinol capsules, the following adverse
reactions were reported at a rate of more than 1%.
Less Common Adverse Reactions: In clinical trials of dronabinol capsules, the following
adverse reactions were identified at a rate of less than or equal to 1%.
Antiemetic: The treatment of chemotherapy-induced emesis with MARINOL® (Dronabinol)
Capsules was examined in 454 cancer patients who obtained a total of 750 courses of
treatment for different malignancies. Patients undergoing cytotoxic treatment with MOPP for
Hodgkin's and non-lymphomas Hodgkin's had the highest antiemetic efficacy of MARINOL®
Capsules. Doses of MARINOL® Capsules ranged from 2.5 mg to 40 mg per day, given in
evenly divided doses every four to six hours (four times daily). As shown in the table below,
raising the dosage of MARINOL® Capsules above 7 mg/m2 increased the frequency of
adverse events while providing no additional antiemetic gain.
Combination antiemetic therapy with MARINOL® Capsules and a phenothiazine
(prochlorperazine) can have synergistic or additive antiemetic effects and reduce the toxicity
of each agent.
In AIDS and cancer patients, the recommended dose ranges for SYNDROS are intended to
achieve the same systemic dosage ranges as the recommended dose ranges for dronabinol
capsules. As a result, the animal to human dose multiples are based on the Maximum
Recommended Human Doses (MRHDs) for dronabinol capsules rather than the 15% lower
MRHDs for SYNDROS. Dronabinol's pharmacologic effects are dose-dependent and subject
to significant interpatient variability. As a result, dose individualization is important for getting
the most out of care.
Appetite Stimulation: The majority of patients in the clinical trials were given 5 mg/day
MARINOL® Capsules, though dosages varied from 2.5 to 20 mg/day. For adult:
1.
Start with 2.5 mg at lunch and 2.5 mg at dinner. If CNS symptoms (e.g., euphoria,
dizziness, fatigue, or somnolence) occur, they normally go away after 1 to 3 days if the dose
is maintained.
2.
Reduce the dose to 2.5 mg before supper if CNS symptoms are serious or persistent.
If symptoms persist, taking a single dose in the evening or before bedtime can help to lessen
their severity.
3.
Increase the dose to 2.5 mg before lunch and 5 mg before supper or 5 and 5 mg
when adverse effects are absent or limited and more therapeutic effect is needed. While
most patients respond to 2.5 mg twice daily, appetite stimulation studies have shown that 10
mg twice daily is tolerated by about half of the patients.
Dronabinol pharmacologic effects are reversible when treatment is stopped.
Antiemetic: The majority of patients respond well to 5 mg three or four times a day. Based
on initial outcomes, dosage can be increased during a chemotherapy cycle or at subsequent
cycles. The lowest recommended dose should be started and titrated according to clinical
response. When combined with phenothiazines like prochlorperazine, MARINOL® Capsules
have shown to be more effective than any drug alone, with no additional side effects.
INDICATIONS AND USAGE
Dronabinol is used to treat the following conditions:
1. In AIDS patients, anorexia is associated with weight loss.
2. Patients who have failed to respond to traditional antiemetic medications
experience nausea and vomiting as a result of cancer chemotherapy.
CONTRAINDICATIONS
Any patient with a history of hypersensitivity to any cannabinoid or sesame oil should avoid
taking dronabinol.
WARNING: Patients taking Dronabinol should be clearly warned not to drive, operate
equipment, or engage in any dangerous activity until the drug's tolerability and ability to
perform those activities safely has been identified.
PRECAUTIONS: General: Because of individual variance in reaction and tolerance to
Dronabinol's effects, the risk/benefit ratio of Dronabinol use should be carefully assessed in
patients with the following medical conditions.
In patients who have a history of drug abuse, including alcohol abuse or dependency,
dronabinol should be used with caution.
In patients with mania, depression, or schizophrenia, dronabinol should be used with
caution and under close medical supervision because it can worsen these illnesses.
Drug Interactions
Dronabinol Capsules have been co-administered with a number of drugs (e.g., cytotoxic
agents, anti-infective agents, sedatives, or opioid analgesics) in research involving patients
with AIDS and/or cancer without triggering any clinically relevant drug/drug interactions.
Despite the fact that no drug-drug interactions were discovered during the Dronabinol
Capsules clinical trials, cannabinoids may interact with other medications through metabolic
and pharmacodynamic mechanisms. Dronabinol has a high protein binding affinity for
plasma proteins, which means it could displace other protein-bound drugs.
Pregnancy (Category C) : In mice, dronabinol has been used to study reproduction. There
was no proof of teratogenicity in these trials. Dronabinol decreased maternal weight gain and
the number of viable pups in mice and rats at these doses, thus increasing fetal mortality
and early resorptions. These effects were dose based, resulting in less maternal toxicity. In
pregnant women, Dronabinol can only be used if the possible advantage outweighs the risk
to the unborn child.
Nursing Mothers Dronabinol is concentrated in and secreted in human breast milk, and is
consumed by the breastfeeding infant, so it is not recommended in nursing mothers.
ADVERSE REACTIONS
Adverse effects The data in the tables below comes from 474 patients who were exposed to
Dronabinol Capsules in well-controlled clinical trials performed in the United States and US
territories. 157 patients were given dronabinol at a dosage of 2.5 mg twice daily and 67 were
given a placebo in trials of AIDS-related weight loss. The first occurrence of occurrences
within the first 28 days was used to integrate studies of various lengths. 317 patients were
given dronabinol and 68 were given a placebo in studies of nausea and vomiting caused by
cancer chemotherapy. The CNS was the most widely reported adverse experience in
patients with AIDS during placebo-controlled clinical trials, with 33% of patients receiving
Dronabinol Capsules reporting it. Approximately 25% of patients experienced a mild CNS
adverse condition during the first two weeks, and approximately 4% experienced one per
week for the next six weeks.
DRUG ABUSE AND DEPENDENCE
Dronabinol is a psychoactive compound found in cannabis that is abused and regulated
under the Controlled Substances Act [Schedule III (CIII)]. In healthy individuals receiving
dronabinol, both psychological and physiological dependence have been observed, but
addiction is rare and has only been observed after
sustained high dose administration Chronic cannabis misuse has been linked to problems
with motivation, memory, judgment, and perception. The cause of these impairments is
unclear, but they may be linked to the complicated process of addiction rather than a single
drug effect.
OVERDOSAGE
Signs and symptoms- Drowsiness, euphoria, heightened sensory sensitivity, altered time
perception, reddened conjunctiva, dry mouth, and tachycardia are all signs of moderate
Dronabinol intoxication. Memory disturbance, depersonalization, mood changes, urinary
retention, and decreased bowel motility are all symptoms of MODERATE intoxication.
Reduced muscle control, lethargy, slurred voice, and postural hypotension are all symptoms
of SEVERE intoxication.
Intravenous dronabinol has a lethal dosage of 30 mg/kg (2100 mg/70 kg) in humans. In
antiemetic trials, oral doses of 0.4 mg/kg (28 mg/70 kg) induced severe CNS symptoms.
Management- If the oral ingestion recently , it should be treated with gut decontamination.
Instill activated charcoal (30 to 100 g in adults, 1 to 2 g/kg in infants) through a nasogastric
tube in unconscious patients with a secure airway. To the first dose of activated charcoal, a
saline cathartic or sorbitol may be added. Extreme anxiety may be treated with
benzodiazepines (5 to 10 mg diazepam po). Trendelenburg location and IV fluids are
normally effective in treating hypotension.
STORAGE CONDITIONS
(Dronabinol) should be held in a tightly sealed bottle. MARINOL® should be kept between 8°
and 15°C (46° and 59°F) in a cool setting, or in the refrigerator. SYNDROS® should be held
between 36°F and 46°F (2°C and 8°C) in the refrigerator.
Cannabis toxicity in geriatric population:
A study has been done to describe the clinical outcomes with acute cannabis exposure in
individuals 60 years or older in comparison to adults 19-59 years old.
Data were collected when physicians reported cases to the poison center or the patients
themselves called the center , these data includes, personal information : age, weight, sex,
cannabis product type and name, how the product was obtained, dose and route of
exposure, urine cannabis screen results, vital signs and final disposition.
Heart rate > 100 bpm in adults defined as tachycardia, while heart rate < 60 bpm defined as
bradycardia..
Data collected after the 17- month study period is ended for all cases, cases where those
patients ≥ 60 years, controls were individuals between the age of 19 - 59 years.
Chi square were used to compare categorical variables, t-test were used to compare
continuous variables, fisher exact test has also been used. p- values < 0.05 considered as
statistically significant.
Finically, social science statistics were used for statistical calculations.
The institutional review board of the Oregon health and science university has approved this
study.
Results: total number of exposed individuals identified are 127 adults, 102 were between 19
- 59 years and 25 aged 60 years or above.
All the 25 patients experienced neurotoxicity and CNS adverse effects include sedation,
lightheadedness, weakness, paranoia or anxiety, decreased consciousness.
The majority of these individuals had normal heart rate, but 48% reported HR ranged from
50 - 120 bpm, 17% had bradycardia and 8% developed tachycardia.
Most of the patients were able to either stay at home or discharged after brief observation in
the ED.
Only one patient died in the ED.
When compared to adults aged 19- 59, patients ≥60 years had normal HR rather than
tachycardia, moreover ,they developed sedation rather than excitation.
Exposure to low doses of cannabis leads to euphoria, tachycardia while higher doses
causes somnolence, bradycardia, and slurred speech.
Lastly this study had several limitations, information is provided voluntarily to the poison
center by healthcare providers and the public. And the data obtained were fully legal
Cannabis and may not represent cases that use illegal cannabis.
Robert G. Hendrickson , Nathanael J. McKeown , Shana G. Kusin & Annette M. Lopez
(2020) Acute cannabis toxicity in older adults, Toxicology Communications, 4:1, 67-70, DOI:
10.1080/24734306.2020.1852821