how long does cbd oil take to work for nausea

Why Use CBD Mints Over Other CBD Products?

Why should you eat CBD mints over other CBD products? Read this guide to learn about the benefits of CBD mints.

According to a 2017 survey, nearly one-half of people who use CBD products have stopped taking traditional medication.

Moreover, if you’re interested in experimenting with CBD, there are a variety of ways to do it. However, in this article, we’ll be discussing why CBD mints are a great way to get in the CBD oil without any side effects.

If you’re new to CBD, you might want to consider purchasing CBD mints first. You might want to expand to other types of CBD once you’ve used it for a while.

Our CBD Mints Don’t Contain THC

Much of the worry and misconception surrounding using cannabis comes from the fact that marijuana plants contain THC. THC stands for tetrahydrocannabinol, which is what causes the “high” feeling that people get when they smoke pot.

However, THC isn’t typically in CBD oil or CBD products unless expressly stated. If you’re not looking to get high and want the benefits of CBD, CBD mints are the perfect place to begin.

CBD Edibles Last Longer in Your System

CBD edibles can act quickly or take up to an hour to start working. That depends on how you eat them. For example, a cake or cookie may take a while for you to start feeling the effects. That is because you have to digest it before it goes into your bloodstream and you begin to get relief from pain.

Candies and other edibles that you have to suck to get pure CBD will take effect almost immediately.

However, either way, edibles, like mints, are longer lasting than most other CBD products. That means that you don’t need to keep munching on them throughout the day to get the benefit.

CBD Mints are Safer Than Smoking CBD

One way to take CBD is to smoke or vape it. Smoking and vaping marijuana or hemp CBD are much better for you than smoking tobacco for a variety of reasons. However, no matter which way you slice it, you’re still smoking. Because of this, you’re again exposing your lungs to smoke, which can have negative and harmful consequences on your body.

While we don’t precisely know the long-term consequences of vaping yet, it is probably not as healthy as merely eating the CBD oil.

Vaping and smoking CBD isn’t very long lasting, which is why CBD mints are preferable for those who need the effects to last a while.

They Make Your Breath Smell Great

Mint is in almost every oral hygiene product. From toothpaste to breath mints to floss, mint helps breath that doesn’t offend people.

CBD mints are no exception to the rule. The mint can help you keep your mouth smelling fresh in between brushing. You can have some after a meal to ensure that your mouth doesn’t offend anyone, which comes in handy after work lunch meetings.

Plus, you’ll get the added benefit of CBD and helping you ease your pain or other ailments. That makes CBD mints necessary to carry around in your bag!

Mint Can Help with Nausea

If you’re feeling nauseated, many people suggest that you take mint essential oils or chew on mint leaves. CBD oil can also help combat nausea, primarily if caused by a medication or a side effect of other medical therapy. Combining both is literally the best of both worlds.

Individuals who struggle with digestive disorders that may make them feel nauseated and unable to eat may find that a CBD mint can help increase their appetite. For some people, increasing their appetite is vital to keep them healthy.

Mint Helps with Colds and Sinus Issues

Many people recommend eating or drinking mint flavored items to help with sinus issues or cold symptoms. CBD oil in itself can also help with these issues, and taking them in mint can double the effect. That makes CBD mints a must-have for anyone who wants to be prepared for the winter cold and flu season.

Mint Can Help with Irritable Bowel Syndrome

Many people suffer from Irritable Bowel Syndrome, and many of these individuals use either mint or CBD oil to help both keep them regular and help any pain that comes with it to subside.

Mint has been studied in contrast with placebos to see how much it helps individuals who have IBS. In a study, it found that mint helped with digestion and some of the other unpleasant symptoms that come with IBS. It performed better than a placebo, meaning that there is evidence that it can help.

As such, to combine the two can only help you and your IBS symptoms. While using them may not cure you of your problems, having them together will help ease some of the more unpleasant symptoms of IBS and can make your day easier.

Are CBD Mints Right For Me?

CBD mints may not be able to take the place of regular medication for everyone, but many people have seen an improvement using CBD oil. CBD oil comes in a variety of ways to consume it, and many people find that eating it is their preferred method. CBD as an ingredient in mint candy form may be the best way for you to consume them.

CBD oil with THC is legal in most states, but it is a good idea to check out your state’s policies before joining the party. However, with more and more individuals singing the praises of it, it is only a matter of time before it’s legal the world over.

Marinol

MARINOL is a controlled substance (CIII) because it contains dronabinol, which can be a target for people who abuse prescription medicines or street drugs. Keep your MARINOL in a safe place to protect it from theft. Never give your MARINOL to anyone else because it may cause death or harm them. Selling or giving away this medicine is against the law.

It is not known if MARINOL is safe and effective in children.

What are the possible side effects of MARINOL?

MARINOL may cause serious side effects, including:

  • See “What is the most important information I should know about MARINOL?”
  • Seizures. MARINOL may increase your risk of seizures. Stop taking MARINOL and call your doctor and get medical care right away if you have a seizure during treatment with MARINOL.
  • Drug and alcohol abuse. You may have an increased risk of abusing MARINOL if you have a history of drug or alcohol abuse or dependence, including marijuana. Tell your doctor if you develop abuse behaviors such as increased irritability, nervousness, restlessness or want more or higher doses of MARINOL during your treatment.
  • Nausea, vomiting, or stomach-area (abdominal) pain. Tell your doctor if you have nausea, vomiting, or abdominal pain or if your nausea, vomiting, or abdominal pain gets worse during treatment with MARINOL.

The most common side effects of MARINOL include:

  • dizziness
  • feeling extremely happy (euphoria)
  • overly suspicious or feeling people want to harm you (paranoid reaction)
  • sleepiness
  • abnormal thoughts
  • stomach-area (abdominal) pain
  • nausea
  • vomiting

These are not all the possible side effects of MARINOL. Tell your doctor if you have any side effect that bothers you or does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800FDA-1088.

DESCRIPTION

Dronabinol is a cannabinoid designated chemically as (6aR,10aR)-6a,7,8,10a-Tetrahydro-6,6,9trimethyl-3-pentyl-6H-dibenzo[b,d]-pyran-1-ol. Dronabinol has the following empirical and structural formulas:

Dronabinol, the active ingredient in MARINOL (dronabinol capsules, USP), is synthetic delta-9tetrahydrocannabinol (delta-9-THC).

Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7.

Each MARINOL capsule strength is formulated with the following inactive ingredients: 2.5 mg capsule contains gelatin, glycerin, sesame oil, and titanium dioxide; 5 mg capsule contains iron oxide red and iron oxide black, gelatin, glycerin, sesame oil, and titanium dioxide; 10 mg capsule contains iron oxide red and iron oxide yellow, gelatin, glycerin, sesame oil, and titanium dioxide.

INDICATIONS

MARINOL is indicated in adults for the treatment of:

  • anorexia associated with weight loss in patients with Acquired Immune Deficiency Syndrome (AIDS).
  • nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

DOSAGE AND ADMINISTRATION

Anorexia Associated With Weight Loss In Adult Patients With AIDS
Starting Dosage

The recommended adult starting dosage of MARINOL is 2.5 mg orally twice daily, one hour before lunch and dinner.

In elderly patients or patients unable to tolerate 2.5 mg twice daily, consider initiating MARINOL at 2.5 mg once daily one hour before dinner or at bedtime to reduce the risk of central nervous system (CNS) symptoms [see Use In Specific Populations].

Dosing later in the day may reduce the frequency of CNS adverse reactions. CNS adverse reactions are dose-related [see WARNINGS AND PRECAUTIONS]; therefore monitor patients and reduce the dosage as needed. If CNS adverse reactions of feeling high, dizziness, confusion, and somnolence occur, they usually resolve in 1 to 3 days and usually do not require dosage reduction. If CNS adverse reactions are severe or persistent, reduce the dosage to 2.5 mg in the evening or at bedtime.

Dosage Titration

If tolerated and further therapeutic effect is desired, the dosage may be increased gradually to 2.5 mg one hour before lunch and 5 mg one hour before dinner. Increase the dose of MARINOL gradually in order to reduce the frequency of dose-related adverse reactions [see WARNINGS AND PRECAUTIONS].

Most patients respond to 2.5 mg twice daily, but the dose may be further increased to 5 mg one hour before lunch and 5 mg one hour before dinner, as tolerated to achieve a therapeutic effect.

Maximum Dosage

10 mg twice daily.

Nausea And Vomiting Associated With Cancer Chemotherapy In Adult Patients Who Failed Conventional Antiemetics
Starting Dosage

The recommended starting dosage of MARINOL is 5 mg/m 2 , orally administered 1 to 3 hours prior to the administration of chemotherapy and then every 2 to 4 hours after chemotherapy, for a total of 4 to 6 doses per day.

In elderly patients, consider initiating MARINOL at 2.5 mg/m 2 once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS symptoms [see Use In Specific Populations].

Administer the first dose on an empty stomach at least 30 minutes before eating. Subsequent doses can be taken without regard to meals [see CLINICAL PHARMACOLOGY].

The timing of dosing in relation to meal times should be kept consistent for each chemotherapy cycle, once the dosage has been determined from the titration process.

Dosage Titration

The dosage can be titrated to clinical response during a chemotherapy cycle or subsequent cycles, based upon initial response, as tolerated to achieve a clinical effect, in increments of 2.5 mg/m 2 .

The maximum dosage is 15 mg/m 2 per dose for 4 to 6 doses per day.

Adverse reactions are dose-related and psychiatric symptoms increase significantly at the maximum dosage [see WARNINGS AND PRECAUTIONS].

Monitor patients for adverse reactions and consider decreasing the dose to 2.5 mg once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS adverse reactions.

HOW SUPPLIED

Dosage Forms And Strengths

MARINOL is supplied as round, soft gelatin capsules for oral use as follows:

  • 2.5 mg white capsules (Identified UM)
  • 5 mg dark brown capsules (Identified UM)
  • 10 mg orange capsules (Identified UM)
Storage And Handling
MARINOL ® (dronabinol capsules, USP)

2.5 mg white capsules (Identified UM).
NDC 0051-0021-21 (Bottle of 60 capsules).

5 mg dark brown capsules (Identified UM).
NDC 0051-0022-21 (Bottle of 60 capsules).

10 mg orange capsules (Identified UM).
NDC 0051-0023-21 (Bottle of 60 capsules).

Storage Conditions

MARINOL capsules should be packaged in a well-closed container and stored in a cool environment between 8° and 15°C (46° and 59°F) and alternatively could be stored in a refrigerator. Protect from freezing.

Manufactured by: Patheon Softgels Inc., High Point, NC 27265. Revised: Aug 2017

SLIDESHOW

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following serious adverse reactions are described below and elsewhere in the labeling.

  • Neuropsychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
  • Hemodynamic Instability [see WARNINGS AND PRECAUTIONS]
  • Seizures [see WARNINGS AND PRECAUTIONS]
  • Paradoxical Nausea, Vomiting, and Abdominal Pain [see WARNINGS AND PRECAUTIONS]

Studies of AIDS-related weight loss included 157 patients receiving MARINOL at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of nausea and vomiting related to cancer chemotherapy included 317 patients receiving MARINOL and 68 receiving placebo. In the tables below is a summary of the adverse reactions in 474 patients exposed to MARINOL in studies.

Studies of different durations were combined by considering the first occurrence of events during the first 28 days.

A cannabinoid dose-related “high” (easy laughing, elation and heightened awareness) has been reported by patients receiving MARINOL in both the antiemetic (24%) and the lower dose appetite stimulant clinical trials (8%). The most frequently reported adverse experiences in patients with AIDS during placebo-controlled clinical trials involved the CNS and were reported by 33% of patients receiving MARINOL. About 25% of patients reported a CNS adverse reaction during the first 2 weeks and about 4% reported such a reaction each week for the next 6 weeks thereafter.

Common Adverse Reactions

The following adverse reactions were reported in clinical trials at an incidence greater than 1%.

System Organ Class Adverse Reactions
General Asthenia
Cardiovascular Palpitations, tachycardia, vasodilation/facial flush
Gastrointestinal Abdominal pain*, nausea*, vomiting*
Central Nervous System Dizziness*, euphoria*, paranoid reaction*, somnolence*, thinking abnormal*, amnesia, anxiety/nervousness, ataxia, confusion, depersonalization, hallucination
* Actual incidence 3% to 10%
Less Common Adverse Reactions

The following adverse reactions were reported in clinical trials at an incidence less than or equal to 1%.

System Organ Class Adverse Reactions
General Chills, headache, malaise
Cardiovascular Hypotension, conjunctival injection [see CLINICAL PHARMACOLOGY]
Gastrointestinal Diarrhea, fecal incontinence, anorexia, hepatic enzyme elevation
Musculoskeletal Myalgias
Central Nervous System Depression, nightmares, speech difficulties, tinnitus
Respiratory Cough, rhinitis, sinusitis
Skin Flushing, sweating
Sensory Vision difficulties
Postmarketing Experience

The following adverse reactions have been identified during post-approval use of dronabinol capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General disorders and administration site conditions: Fatigue

Hypersensitivity reactions: Lip swelling, hives, disseminated rash, oral lesions, skin burning, flushing, throat tightness [see CONTRAINDICATIONS]

Injury, poisoning and procedural complications: Fall [see Use In Specific Populations]

Nervous system disorders: Seizures [see WARNINGS AND PRECAUTIONS], disorientation, movement disorder, loss of consciousness

Psychiatric disorders: Delirium, insomnia, panic attack

Vascular disorders: Syncope [see WARNINGS AND PRECAUTIONS]

DRUG INTERACTIONS

Additive CNS Effects

Additive CNS effects (e.g., dizziness, confusion, sedation, somnolence) may occur when MARINOL is taken concomitantly with drugs that have similar effects on the central nervous system such as CNS depressants [see WARNINGS AND PRECAUTIONS].

Additive Cardiac Effects

Additive cardiac effects (e.g., hypotension, hypertension, syncope, tachycardia) may occur when MARINOL is taken concomitantly with drugs that have similar effects on the cardiovascular system [see WARNINGS AND PRECAUTIONS].

Effect Of Other Drugs On Dronabinol

Dronabinol is primarily metabolized by CYP2C9 and CYP3A4 enzymes based on published in vitro studies. Inhibitors of these enzymes may increase, while inducers may decrease, the systemic exposure of dronabinol and/or its active metabolite resulting in an increase in dronabinolrelated adverse reactions or loss of efficacy of MARINOL.

Monitor for potentially increased dronabinol-related adverse reactions when MARINOL is co-administered with inhibitors of CYP2C9 (e.g., amiodarone, fluconazole) and inhibitors of CYP3A4 enzymes (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, erythromycin, grapefruit juice).

Highly Protein-Bound Drugs

Dronabinol is highly bound to plasma proteins, and therefore, might displace and increase the free fraction of other concomitantly administered protein-bound drugs.

Although this displacement has not been confirmed in vivo, monitor patients for increased adverse reactions to narrow therapeutic index drugs that are highly protein–bound (e.g., warfarin, cyclosporine, amphotericin B) when initiating treatment or increasing the dosage of MARINOL.

Drug Abuse And Dependence
Controlled Substance

MARINOL contains dronabinol capsules, a Schedule III controlled substance.

Abuse

MARINOL contains dronabinol, the main psychoactive component in marijuana. Ingestion of high doses of dronabinol increases the risk of psychiatric adverse reactions if abused or misused, while continued administration can lead to addiction. Psychiatric adverse reactions may include psychosis, hallucinations, depersonalization, mood alteration, and paranoia.

In an open-label study in patients with AIDS who received MARINOL for up to five months, no abuse, diversion or systematic change in personality or social functioning were observed despite the inclusion of a substantial number of patients with a past history of drug abuse.

Patients should be instructed to keep MARINOL in a secure place out of reach of others for whom the medication has not been prescribed.

Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. The appearance of a withdrawal syndrome when administration of the drug is terminated is the only actual evidence of physical dependence. Physical dependence can develop during chronic therapy with MARINOL, and develops after chronic abuse of marijuana.

A withdrawal syndrome was reported after the abrupt discontinuation of dronabinol in subjects receiving dosages of 210 mg per day for 12 to 16 consecutive days. Within 12 hours after discontinuation, subjects manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to include “hot flashes,” sweating, rhinorrhea, loose stools, hiccoughs, and anorexia. These withdrawal symptoms gradually dissipated over the next 48 hours.

Electroencephalographic changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of dronabinol.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Neuropsychiatric Adverse Reactions
Psychiatric Adverse Reactions

Dronabinol has been reported to exacerbate mania, depression, or schizophrenia. Significant CNS symptoms followed oral doses of 0.4 mg/kg (28 mg per 70 kg patient) of MARINOL in antiemetic studies.

Prior to initiating treatment with MARINOL, screen patients for a history of these illnesses. Avoid use in patients with a psychiatric history or, if the drug cannot be avoided, monitor patients for new or worsening psychiatric symptoms during treatment. Also, avoid concomitant use with other drugs that are associated with similar psychiatric effects.

Cognitive Adverse Reactions

Use of MARINOL has been associated with cognitive impairment and altered mental state. Reduce the dose of MARINOL or discontinue use of MARINOL if signs or symptoms of cognitive impairment develop. Elderly patients may be more sensitive to the neurological and psychoactive effects of MARINOL [see Use In Specific Populations].

Hazardous Activities

MARINOL can cause and may impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a motor vehicle or operating machinery. Concomitant use of other drugs that cause dizziness, confusion, sedation, or somnolence such as CNS depressants may increase this effect (e.g., barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, scopolamine, antihistamines, tricyclic antidepressants, other anticholinergic agents, muscle relaxants). Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that MARINOL does not affect them adversely.

Hemodynamic Instability

Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking MARINOL [see CLINICAL PHARMACOLOGY]. Patients with cardiac disorders may be at higher risk. Avoid concomitant use of other drugs that are also associated with similar cardiac effects (e.g., amphetamines, other sympathomimetic agents, atropine, amoxapine, scopolamine, antihistamines, other anticholinergic agents, amitriptyline, desipramine, other tricyclic antidepressants). Monitor patients for changes in blood pressure, heart rate, and syncope after initiating or increasing the dosage of MARINOL.

Seizures

Seizure and seizure-like activity have been reported in patients receiving dronabinol.

Weigh this potential risk against the benefits before prescribing MARINOL to patients with a history of seizures, including those receiving antiepileptic medication or with other factors that can lower the seizure threshold. Monitor patients with a history of seizure disorders for worsened seizure control during MARINOL therapy.

If a seizure occurs, advise patients to discontinue MARINOL and contact a healthcare provider immediately.

Multiple Substance Abuse

Patients with a history of substance abuse or dependence, including marijuana or alcohol, may be more likely to abuse MARINOL as well.

Assess each patient’s risk for abuse or misuse prior to prescribing MARINOL and monitor patients with a history of substance abuse during treatment with MARINOL for the development of these behaviors or conditions.

Paradoxical Nausea, Vomiting, Or Abdominal Pain

Nausea, vomiting, or abdominal pain can occur during treatment with synthetic delta-9-tetrahydrocannabinol (delta-9-THC), the active ingredient in MARINOL. In some cases, these adverse reactions were severe (e.g., dehydration, electrolyte abnormalities) and required dose reduction or drug discontinuation. Symptoms are similar to cannabinoid hyperemesis syndrome (CHS), which is described as cyclical events of abdominal pain, nausea, and vomiting in chronic, long-term users of delta-9-THC products.

Because patients may not recognize these symptoms as abnormal, it is important to specifically ask patients or their caregivers about the development of worsening of nausea, vomiting, or abdominal pain while being treated with MARINOL. Consider dose reduction or discontinuing MARINOL if a patient develops worsening nausea, vomiting, or abdominal pain while on treatment.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Neuropsychiatric Adverse Reactions[See WARNINGS AND PRECAUTIONS]
  • Advise patients that psychiatric adverse reactions may occur, especially in patients with a past psychiatric history or in those receiving other drugs also associated with psychiatric effects, and to report to their healthcare provider any new or worsening psychiatric symptoms.
  • Advise patients, especially elderly patients, that cognitive impairment or an altered mental state may also occur during treatment with MARINOL and to report to their healthcare provider if they develop signs or symptoms of cognitive impairment.
  • Advise patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that MARINOL does not affect them adversely. Alert patients to the potential for additive central nervous system depression if MARINOL is used concomitantly with alcohol or other CNS depressants such as benzodiazepines and barbiturates.
Hemodynamic Instability

Advise patients, especially those with cardiac disorders, to report to their healthcare provider if they experience any signs or symptoms of hemodynamic instability, including hypotension, hypertension, syncope or tachycardia, especially after initiating or increasing the dosage of MARINOL [see WARNINGS AND PRECAUTIONS].

Seizures

Advise patients to discontinue MARINOL and contact a healthcare provider immediately if they experience a seizure [see WARNINGS AND PRECAUTIONS].

Multiple Substance Abuse

Inform patients with a history of substance abuse or dependence, including marijuana or alcohol, that they may be more likely to abuse MARINOL. Advise patients to report to their healthcare provider if they develop abuse behaviors or conditions [see WARNINGS AND PRECAUTIONS].

Paradoxical Nausea, Vomiting, Or Abdominal Pain

Advise patients to report worsening nausea, vomiting or abdominal pain to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Pregnancy

Advise pregnant women of the potential risk to a fetus and to avoid use of MARINOL during pregnancy [see Use In Specific Populations].

Lactation
  • Advise HIV infected women with anorexia associated with weight loss, not to breastfeed.
  • Advise women with nausea and vomiting associated with cancer chemotherapy not to breastfeed during treatment with MARINOL and for 9 days after the last dose [see Use In Specific Populations].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility

In 2-year carcinogenicity studies, there was no evidence of carcinogenicity in rats at doses up to 50 mg/kg/day dronabinol (approximately 20 times the MRHD in AIDS patients on a body surface area basis) or in mice at doses up to 500 mg/kg/day (approximately 100 times the MRHD in AIDS patients on a body surface area basis).

Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. However, dronabinol produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells.

In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m 2 , equivalent to 2 to 10 times the MRHD of 15 mg/m 2 /day in AIDS patients or 0.3 to 1.5 times the MRHD of 90 mg/m 2 /day in cancer patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success, and testosterone levels were not affected. The significance of these animal findings in humans is not known.

Use In Specific Populations
Pregnancy
Risk Summary

MARINOL, a synthetic cannabinoid, may cause fetal harm. Avoid use of MARINOL in pregnant women. Although there is little published data on the use of synthetic cannabinoids during pregnancy, use of cannabis (e.g., marijuana) during pregnancy has been associated with adverse fetal/neonatal outcomes [see Clinical Considerations]. Cannabinoids have been found in the umbilical cord blood from pregnant women who smoke cannabis. In animal reproduction studies, no teratogenicity was reported in mice administered dronabinol at up to 30 times the MRHD (maximum recommended human dose) and up to 5 times the MRHD for patients with AIDS and cancer, respectively. Similar findings were reported in pregnant rats administered dronabinol at up to 5 to 20 times the MRHD and 3 times the MRHD for patients with AIDS and cancer, respectively. Decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions were observed in both species at doses which induced maternal toxicity. In published studies, offspring of pregnant rats administered delta-9-THC during and after organogenesis have been reported to exhibit neurotoxicity with adverse effects on brain development, including abnormal neuronal connectivity and impairments in cognitive and motor function [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Published studies suggest that during pregnancy, the use of cannabis, which includes THC, whether for recreational or medicinal purposes, may increase the risk of adverse fetal/neonatal outcomes including fetal growth restriction, low birth weight, preterm birth, small-for-gestational age, admission to the NICU, and stillbirth. Therefore, use of cannabis during pregnancy should be avoided.

Delta-9-THC has been measured in the cord blood of some infants whose mothers reported prenatal use of cannabis, suggesting that dronabinol may cross the placenta to the fetus during pregnancy. The effects of delta-9-THC on the fetus are not known.

Animal Data

Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m 2 , equivalent to 1 to 30 times the MRHD of 15 mg/m 2 /day in AIDS patients or 0.2 to 5 times the MRHD of 90 mg/m 2 /day in cancer patients, and in rats at 74 to 295 mg/m 2 (equivalent to 5 to 20 times the MRHD of 15 mg/m 2 /day in AIDS patients or 0.8 to 3 times the MRHD of 90 mg/m 2 /day in cancer patients). These studies have revealed no evidence of teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses that produced less maternal toxicity.

Review of published literature indicates that the endocannabinoid system plays a role in neurodevelopmental processes such as neurogenesis, migration, and synaptogenesis. Exposure of pregnant rats to delta-9-THC (during and after organogenesis) may modulate these processes to result in abnormal patterns of neuronal connectivity and subsequent cognitive impairments in the offspring. Nonclinical toxicity studies in pregnant rats and newborn pups have shown prenatal exposure to THC that resulted in impairment of motor function, alteration in synaptic activity, and interference in cortical projection of neuron development in the offspring. Prenatal exposure has shown effects on cognitive function such as learning, short-and long-term memory, attention, decreased ability to remember task, and ability to discriminate between novel and same objects. Overall, prenatal exposure to THC has resulted in significant and long-term changes in brain development, cognition, and behavior in rat offspring.

Lactation
Risk Summary

For mothers infected with the Human Immunodeficiency Virus (HIV), the Centers for Disease Control and Prevention recommends that HIVinfected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of the potential for HIV transmission (in HIVnegative infants) and serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving MARINOL.

For mothers with nausea and vomiting associated with cancer chemotherapy, there are limited data on the presence of dronabinol in human milk, the effects on the breastfed infant, or the effects on milk production. The reported effects of inhaled cannabis transferred to the breastfeeding infant have been inconsistent and insufficient to establish causality. Because of the possible adverse effects from MARINOL on the breastfeeding infant, advise women with nausea and vomiting associated with cancer chemotherapy not to breastfeed during treatment with MARINOL and for 9 days after the last dose.

Pediatric Use

The safety and effectiveness of MARINOL have not been established in pediatric patients.

Pediatric patients may be more sensitive to neurological and psychoactive effects of MARINOL [see WARNINGS AND PRECAUTIONS].

Geriatric Use

Clinical studies of MARINOL in AIDS and cancer patients did not include the sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Elderly patients may be more sensitive to the neuropsychiatric and postural hypotensive effects of MARINOL [see WARNINGS AND PRECAUTIONS].

Elderly patients with dementia are at increased risk for falls as a result of their underlying disease state, which may be exacerbated by the CNS effects of somnolence and dizziness associated with MARINOL [see WARNINGS AND PRECAUTIONS]. These patients should be monitored closely and placed on fall precautions prior to initiating MARINOL therapy. In antiemetic studies, no difference in efficacy was apparent in patients greater than 55 years of age compared to younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of falls, decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects, and of concomitant disease or other drug therapy [see DOSAGE AND ADMINISTRATION].

Effect Of CYP2C9 Polymorphism

Published data suggest that systemic clearance of dronabinol may be reduced and concentrations may be increased in the presence of CYP2C9 genetic polymorphism. Monitoring for potentially increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function [see CLINICAL PHARMACOLOGY].

OVERDOSE

Signs and symptoms of dronabinol overdosage include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth, tachycardia, memory impairment, depersonalization, mood alteration, urinary retention, reduced bowel motility, decreased motor coordination, lethargy, slurred speech, and postural hypotension. Patients may also experience panic reactions if they have a prior history of nervousness or anxiety, and seizures may occur in patients with existing seizure disorders.

It is not known if dronabinol can be removed by dialysis in cases of overdose.

If over-exposure of MARINOL occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

CONTRAINDICATIONS

MARINOL is contraindicated in patients with a history of a hypersensitivity reaction to dronabinol or sesame oil. Reported hypersensitivity reactions to dronabinol capsules include lip swelling, hives, disseminated rash, oral lesions, skin burning, flushing and throat tightness [see ADVERSE REACTIONS].

CLINICAL PHARMACOLOGY

Mechanism Of Action

Dronabinol is an orally active cannabinoid which has complex effects on the CNS, including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. These receptors may play a role in mediating the effects of dronabinol.

Pharmacodynamics
Effects On The Cardiovascular System

Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing [see WARNINGS AND PRECAUTIONS].

Effects On The Central Nervous System

Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great inter–patient variability. After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.

Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male subjects (N = 12) received 210 mg per day of MARINOL, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These subjects developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation.

Tachyphylaxis and tolerance do not appear to develop to the appetite stimulant effect of MARINOL. In clinical studies involving AIDS patients, the appetite stimulant effect of MARINOL was sustained for up to five months at dosages ranging from 2.5 mg to 20 mg per day.

Pharmacokinetics
Absorption

Dronabinol (delta-9-THC) is almost completely absorbed (90 to 95%) after single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Concentrations of both parent drug and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing and decline over several days.

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) have been studied in healthy subjects.

Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol in Healthy Subjects (n=34; 20-45 years) under Fasted Conditions

Mean (SD) PK Parameter Values
Twice Daily Dose Cmax ng/mL Median Tmax (range), hr AUC(0-12) ng•hr/mL
2.5 mg 1.32 (0.62) 1.00 (0.50-4.00) 2.88 (1.57)
5 mg 2.96 (1.81) 2.50 (0.50-4.00) 6.16 (1.85)
10 mg 7.88 (4.54) 1.50 (0.50-3.50) 15.2 (5.52)
Cmax: maximum observed plasma concentration; Tmax : time to maximum observed plasma concentration; AUC(0-12): area under the plasma concentration-time curve from 0 to 12 hours.

A slight increase in dose proportionality on mean Cmax and AUC(0-12) of dronabinol was observed with increasing dose over the dose range studied.

Effect of Food

In a published study, the effect of food on the pharmacokinetics of dronabinol was studied by concomitant dosing of MARINOL with a high-fat (59 grams of fat, approximately 50% of total caloric content of the meal), high calorie meal (approximately 950 calories). An appreciable food effect was observed, resulting in a 4-hour delay in mean Tmax and 2.9-fold increase in total exposure (AUCinf), but Cmax was not significantly changed [see DOSAGE AND ADMINISTRATION].

Distribution

Dronabinol has an apparent volume of distribution of approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97% [see DRUG INTERACTIONS].

Elimination

The pharmacokinetics of dronabinol can be described using 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. Values for clearance average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution.

Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-hydroxy-delta-9-THC, are present in approximately equal concentrations in plasma. Published in vitro data indicates that CYP2C9 and CYP3A4 are the primary enzymes in the metabolism of dronabinol. CYP2C9 appears to be the enzyme responsible for the formation of the primary active metabolite [see Pharmacogenomics].

Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces.

Due to its re–distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time. Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces.

In a study of MARINOL involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.

Drug Interaction Studies

Formal drug-drug interaction studies have not been conducted with dronabinol.

The enzyme inhibition and induction potential of dronabinol and its active metabolite are not completely understood.

Published data showed an increase in the elimination half-life of pentobarbital by 4 hours when concomitantly dosed with dronabinol [see WARNINGS AND PRECAUTIONS].

Pharmacogenomics

Published data indicate a potentially 2-to 3-fold higher dronabinol exposure in individuals carrying genetic variants associated with diminished CYP2C9 function.

Clinical Studies

The effectiveness of MARINOL has been established based on studies for the treatment of anorexia associated with weight loss in patients with AIDS and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

Appetite Stimulation

The appetite stimulant effect of MARINOL in the treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled study involving 139 patients. The initial dosage of MARINOL in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before dinner. In pilot studies, early morning administration of MARINOL appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of MARINOL on appetite, weight, mood, and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to 2.5 mg/day, administered as a single dose at supper or bedtime.

Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-controlled study, 99 patients had appetite data at 4- weeks (50 received MARINOL and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received MARINOL and 45 received placebo). A statistically significant difference between MARINOL and placebo was seen in appetite as measured by the visual analog scale at weeks 4 and 6 (see figure). Trends toward improved body weight and mood, and decreases in nausea were also seen.

After completing the 6-week study, patients were allowed to continue treatment with MARINOL in an open-label study, in which there was a sustained improvement in appetite.

Mean Appetite Change from Baseline

PATIENT INFORMATION

MARINOL ®
(mare in all)
(dronabinol) capsules, for oral use

What is the most important information I should know about MARINOL?

MARINOL can cause serious side effects, including:

  • Worsening mental (psychiatric) symptoms. Psychiatric symptoms can worsen in people who have mania, depression, or schizophrenia and who take MARINOL. MARINOL taken with medicines that cause psychiatric symptoms can worsen psychiatric symptoms. Elderly people who take MARINOL may have a greater risk of having psychiatric symptoms. Tell your doctor if you have new or worsening mood symptoms, including symptoms of mania, depression, or schizophrenia.
  • Problems thinking clearly. Tell your doctor if you have trouble remembering things, concentrating, have increased sleepiness, or confusion. Elderly people may have a greater risk of having problems thinking clearly.
  • Changes in your blood pressure. MARINOL may increase or decrease your blood pressure, especially when you start taking MARINOL or when your dose is changed. Tell your doctor if you have signs or symptoms of changes in your blood pressure including: headaches, vision problems, dizziness, feeling lightheaded, fainting, or a fast heartbeat. Elderly people, especially those with dementia, and people with heart problems may have an increased risk of changes in blood pressure and an increased risk of falls.

What is MARINOL?

  • MARINOL is a prescription medicine used in adults to treat:
    • loss of appetite (anorexia) in people with AIDS (Acquired Immune Deficiency Syndrome) who have lost weight.
    • nausea and vomiting caused by anti-cancer medicine (chemotherapy) in people whose nausea and vomiting have not improved with usual anti-nausea medicines.

    MARINOL is a controlled substance (CIII) because it contains dronabinol, which can be a target for people who abuse prescription medicines or street drugs. Keep your MARINOL in a safe place to protect it from theft. Never give your MARINOL to anyone else because it may cause death or harm them. Selling or giving away this medicine is against the law.

    It is not known if MARINOL is safe and effective in children.

    Do not take MARINOL if you:

    • had an allergic reaction to dronabinol. Signs and symptoms of an allergic reaction to dronabinol include: swelling of the lips, hives, a rash over your whole body, mouth sores, skin burning, flushing, and throat tightness.
    • had an allergic reaction to sesame oil.

    Before taking MARINOL, tell your doctor about all of your medical conditions, including if you:

    • have or had heart problems.
    • have or had problems with drug abuse or dependence.
    • have or had problems with alcohol abuse or dependence.
    • have or had mental health problems including mania, depression, or schizophrenia.
    • have had a seizure or have a medical condition that may increase your risk of having a seizure.
    • are pregnant or plan to become pregnant. MARINOL may harm your unborn baby. Avoid the use of MARINOL if you are pregnant.
    • are breastfeeding or plan to breastfeed. The Centers for Disease Control and Prevention recommends that mothers with HIV not breastfeed because they can pass the HIV through their breast milk to the baby. It is not known if MARINOL passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take MARINOL. Do not breastfeed while taking MARINOL and for 9 days after your last dose of MARINOL if you are being treated for nausea and vomiting caused by anti-cancer medicine.

    Tell your doctor about all the medicines you take or have taken in the last 14 days, including prescription and over-the-counter medicines, vitamins, and herbal supplements. MARINOL and certain other medicines can affect each other, causing serious side effects.

    How should I take MARINOL?

    • Take MARINOL exactly as your doctor tells you to. Your doctor may change your dose after seeing how it affects you. Do not change your dose unless your doctor tells you to change it.
    • If you are an adult with AIDS with loss of appetite and weight loss:
      • MARINOL is usually taken 2 times each day, 1 hour before lunch and 1 hour before dinner. If you are elderly or unable to tolerate this dose of MARINOL, your doctor may prescribe MARINOL to be taken 1 time each day, 1 hour before dinner or bedtime to reduce your chance of having nervous system problems.
      • MARINOL is usually taken 1 to 3 hours before your chemotherapy treatment and then every 2 to 4 hours after chemotherapy for up to 4 to 6 doses each day. If you are elderly, your doctor may prescribe MARINOL to be taken 1 to 3 hours before your chemotherapy, 1 time each day to reduce your chance of having nervous system problems.
      • Take your first dose of MARINOL on an empty stomach at least 30 minutes before eating. After your first dose of MARINOL, you can take MARINOL with or without food. Always take your dose at the same time with regard to meals.

      What should I avoid while taking MARINOL?

      • Do not drive, operate machinery, or do other dangerous activities until you know how MARINOL affects you. MARINOL taken with other medicines that cause dizziness, confusion, and sleepiness may make these symptoms worse.

      What are the possible side effects of MARINOL?

      MARINOL may cause serious side effects, including:

      • See “What is the most important information I should know about MARINOL?”
      • Seizures. MARINOL may increase your risk of seizures. Stop taking MARINOL and call your doctor and get medical care right away if you have a seizure during treatment with MARINOL.
      • Drug and alcohol abuse. You may have an increased risk of abusing MARINOL if you have a history of drug or alcohol abuse or dependence, including marijuana. Tell your doctor if you develop abuse behaviors such as increased irritability, nervousness, restlessness or want more or higher doses of MARINOL during your treatment.
      • Nausea, vomiting, or stomach-area (abdominal) pain. Tell your doctor if you have nausea, vomiting, or abdominal pain or if your nausea, vomiting, or abdominal pain gets worse during treatment with MARINOL.

      The most common side effects of MARINOL include:

      • dizziness
      • feeling extremely happy (euphoria)
      • overly suspicious or feeling people want to harm you (paranoid reaction)
      • sleepiness
      • abnormal thoughts
      • stomach-area (abdominal) pain
      • nausea
      • vomiting

      These are not all the possible side effects of MARINOL. Tell your doctor if you have any side effect that bothers you or does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

      How should I store MARINOL?

      • Store MARINOL in a cool place such as in a refrigerator, at a temperature between 46°F to 59°F (8°C to 15°C).
      • Do not freeze MARINOL capsules.
      • Keep the MARINOL container closed tightly.

      Keep MARINOL and all medicines out of the reach of children.

      General information about the safe and effective use of MARINOL

      Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use MARINOL for a condition for which it was not prescribed. Do not give MARINOL to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about MARINOL that is written for health professionals.

      What are the ingredients in MARINOL?

      Active ingredient: dronabinol

      Inactive ingredients: 2.5 mg capsules contain gelatin, glycerin, sesame oil, and titanium dioxide; 5 mg capsules contain iron oxide red and iron oxide black, gelatin, glycerin, sesame oil, and titanium dioxide; 10 mg capsules contain iron oxide red and iron oxide yellow, gelatin, glycerin, sesame oil, and titanium dioxide.

      The Pros and Cons of Medical Cannabis: Current Evidence

      Cannabis is one of the most commonly used drugs in the United States. More than 48.2 million people in the US aged 12 years and older (17.5%) have used cannabis in the last year. 1 Although evidence suggest that some medical conditions may benefit from cannabis use, there is a lack of high-quality randomized controlled trials examining the potential therapeutic uses of cannabis and a lack of prospective studies looking at associated adverse effects.

      The risks and benefits of any cannabinoid-­containing compound need to be carefully weighed for each patient. This includes consideration of potential effects on comorbidities and drug-drug interactions. The increasingly widespread use of cannabis makes screening and counseling patients about the potential risks vs benefits a priority.

      Pharmacology

      Cannabis sativa and Cannabis indica are the 2 most commonly used strains of cannabis, a plant containing approximately 540 chemical compounds, of which more than 100 are classified as cannabinoids. 2 The compound generally responsible for producing intoxication (high) is delta-9-tetrahydrocannabinol (THC); cannabidiol (CBD) does not produce this effect but may have therapeutic effects. 3

      Cannabis can be found in natural and synthetic formulations that contain psychoactive and inactive compounds. Cannabis concentrates can be inhaled or vaporized. Products for oral ingestion include pills, teas, edibles, tinctures, and gummies. Lozenges, lollipops, and dissolvable strips can be taken sublingually. Topical products include oils, lotions, and bath salts. 4

      The potency of THC content in samples of recreational cannabis has increased dramatically, from less than 4% in the early 1990s to more than 15% in 2018; some current variants and cannabis concentrates can have much higher THC levels. 4 In the last 2 decades, the percentage of nonpsychoactive components has steadily decreased, resulting in an increase in the psychoactive to nonpsychoactive component ratio from 14 times in 2001 to 80 times in 2017. 5 The result is that some currently available products may have a greater ability to produce a high.

      Psychoactive Drug Components

      The absorption and distribution of THC is highly variable depending on the route of administration and individual patient characteristics. When consumed via inhalation (smoking or vaping), the onset of action is typically within 10 minutes; systemic bioavailability is 11% to 45%. 6 When THC is consumed orally there is a greater variability in onset and effects due to first-pass metabolism through the liver and significant degradation by gastric acid. Peak THC levels have been reported at 1 to 6 hours after oral ingestion; systemic bioavailability is 4% to 20%. 6

      The metabolism of cannabis occurs via 2 hepatic cytochrome oxidases, CYP2C9 and CYP3A4. Its plasma half-life ranges from 1 to 3 days in occasional users to up to 13 days in chronic users, and it is eliminated through feces (65%) and urine (20%). 6 The elimination half-life can be substantially longer in regular cannabis users because cannabis is highly lipophilic. With regular use, cannabis accumulates in adipose tissues over time, resulting in a slow release when blood levels are low and accounting for a positive urine drug screening for up to 6 weeks after last consumption vs 4 weeks in occasional users. 7

      Receptors and Reward Pathways

      Endogenous cannabinoid receptors are found in the brain, spine, and peripheral nervous system, with components of cannabis acting as a partial agonist at both cannabinoid receptor type 1 (CB1) and type 2 (CB2) sites. 8 Within the central nervous system, THC strongly binds to CB1 receptors accounting for its psychoactive properties; CBD does not. 8 Cannabis impacts the release of several neurotransmitters such as acetylcholine, norepinephrine, γ-aminobutyric acid, and serotonin within multiple regions of the brain. Areas impacted include the frontal cortex, basal ganglia, cerebellum, hippocampus, and cerebral cortex, accounting for some of the drug’s clinical effects. 6,8,9

      Binding within the peripheral tissues occurs at CB2 receptors, primarily located within cells in the immune system (B lymphocytes and splenic macrophages), peripheral nerve terminals, and the vas deferens. 8 The mechanism of action in the periphery is less clear, but cannabinoids may play a role in the regulation of immune and/or inflammatory reactions. 8 Both CB1 and CB2 cells are found in the cardiovascular system. 6

      Like alcohol and other psychoactive substances, cannabis is processed through the mesolimbic dopamine pathway, the same circuitry involved in the regulation of reinforcement and reward. 9 This pathway is associated with reinforcement of adaptive behaviors and the natural high associated with joy or accomplishment. Cannabis binding bypasses the brain’s neurotransmitters and directly stimulates the release of dopamine within the reward pathway, triggering an artificial high. Long-term cannabis use eventually causes changes in this reward circuit. Over time, this results in an increase in impulsiveness to use the substance, which provides a reward, and a decrease in the pleasure or gratification associated with it, accounting for clinical symptoms related to tolerance. 9

      Physiologic Effects of Cannabis Use
      Acute Intoxication

      Physiologic effects of acute intoxication may include euphoria, tachycardia, hypertension, conjunctival injection, dry mouth, increased appetite, impaired judgment, and paranoid delusions. 10 Acute neuropsychiatric effects can be highly variable in presentation and appear to be dose dependent. At low doses, mood is described as euphoric, with decreased depression, anxiety, and tension; conversely, at higher doses there is increased anxiety, dysphoria, and panic. 10 Other neurologic or psychiatric effects may include 10-12 :

      • Slowed reaction times and impaired motor coordination
      • Impaired attention, concentration, short-term memory, and risk assessment
      • Distortions in time and spatial perception
      • Increased intensity of visual/auditory perception
      • Depersonalization, hallucination, grandiosity, paranoia, and/or other signs of psychosis

      These effects are additive when combined with other central nervous system (CNS) depressants. Mood-altering effects typically resolve within hours, but residual effects of a dose of cannabis might last for 24 hours. In laboratory studies of cognitive and behavioral effects, evidence suggests that the effects of cannabis increase as the dose consumed or level of THC in blood increases. Evidence also suggests that effects of cannabis on driving simulator performance and collision risk increase as dose consumed and levels in the body increase. 13

      Cardiovascular Effects

      The heart and vascular smooth muscle contain CB1 and CB2 receptors; thus, dose-dependent increases in heart rate and blood pressure can occur with acute intoxication. 11,12 Orthostatic hypotension is a common side effect in older adults. 14 Other potential physiologic changes can include increased platelet aggregation, arterial vasospasm, and increased cerebral vascular tone, which can result in decreased cerebrovascular blood flow. 12 In the hours after ingestion, cannabis increases the risk for major cardiovascular events, such as hypertensive emergency, myocardial infarction, transient ischemic attack, and cerebrovascular accident. 11 Chronic use in individuals with a history of angina may lower the angina threshold and, thus, precipitate chest pain. 12 There also is evidence to suggest a link to new cardiac arrhythmia secondary to ischemia. 12 Atrial fibrillation, ventricular fibrillation, and Brugada pattern (ventricular arrhythmia) are the most commonly associated arrhythmias; when such arrhythmias occur, the mortality rate is estimated at 11%. 12,15

      Pulmonary Effects

      Inhalation of cannabis and associated respiratory irritants can cause acute or chronic cough, increased mucous production, and shortness of breath. 16 Pneumomediastinum can be an acute complication associated with holding ones breath in during inhalation. 17 Evidence suggests that long-term cannabis use may lead to large airway inflammation, increased airway resistance, and lung hyperinflation. 11 In individuals with underlying pulmonary disease, such as asthma or chronic obstructive pulmonary disease (COPD), this may increase the risk for respiratory infection and acute exacerbations of chronic disease.

      Although cannabis is known to contain potential carcinogens, the connection between lung carcinoma and cannabis use remains less clear. 14 By comparison, cannabis contains 50% more benzopyrene and 75% more benzanthracene than tobacco. 11 Evidence also suggests cannabis is associated with 4 times more deposition of tar than tobacco products, suggesting that an underlying link to carcinoma is possible, although there is no definitive evidence linking cannabis to increased head, neck, or lung cancer. 4,11,14

      Prolonged Neuropsychiatric Effects

      Cannabis use in children has the potential to alter brain development and can be linked to poor educational outcomes, such as increased drop-out rates. 11 Use in adolescents is correlated with cognitive impairment and lower IQ scores. 11 In adults, use causes memory impairment and difficulty learning new information. 18 In some individuals, cannabis increases the risk of developing or worsening of depression, anxiety, and post-traumatic stress disorder. 11 Cannabis use is linked with the development of psychosis, particularly among youth who have preexisting genetic vulnerability, and may advance onset of first psychotic episode by 2 to 6 years in such individuals. 11,18 Long-term use has been linked with the development of amotivational syndrome and reports of decreased life satisfaction. 18

      Cannabis Hyperemesis Syndrome

      There are no clinically established diagnostic or treatment guidelines for cannabis hyperemesis syndrome (see Case Presentation), but there are definitive patterns in clinical presentation. Patients typically present with intense and unremitting abdominal pain with persistent nausea and vomiting, often with reports of multiple episodes over months to years. 19 Clinical history reveals a heavy use of cannabis daily over a prolonged period of time. Often patients report the only effective alleviating factor for associated abdominal pain is the use of hot baths or showers. Generally, symptom presentation occurs in 3 phases: prodromal, acute nausea and diffuse abdominal pain, the intensity of which often causes fear of vomiting; hyperemetic, multiple episodes of vomiting, driving the patient to seek medical care; and recovery, during which normal eating patterns resume. 19

      Case Presentation
      A 32-year-old mother of 3 presents to the emergency department with a 10-day history of persistent nausea with intermittent nonbiliary, nonbloody emesis, and diffuse abdominal pain. She denies alcohol or “illicit” drug use but does admit to smoking cannabis 2 to 3 times a day for the last several years. Her vital signs are within normal limits, her electrocardiogram is normal, and her laboratory tests (complete blood cell count, comprehensive metabolic panel, lipase, and serial troponins) are normal. Computed tomography of the abdomen shows no acute pathology. She has received 2 liters of normal saline, as well as multiple doses of intravenous ondansetron and metoclopramide, without improvement in nausea and continued active emesis.

      Cannabis has dose-dependent biphasic effects. At a low dose, it acts as an antiemetic; at higher doses, it becomes proemetic. 19 Clinical priorities lay in achieving cessation of hyperemesis, addressing any secondary issues, such as dehydration, electrolyte disturbance, acute kidney injury, or rhabdomyolysis, and advising the patient about long-term cessation of cannabis use. 19

      It is unclear why traditional antiemetics are ineffective in addressing nausea and emesis associated with cannabis use. However, it is known that cannabis is active within the dopaminergic pathways of the brain; clinically, dopamine-blocking agents such as intravenous haloperidol (5 mg) often are more effective in treating nausea in these patients. 19 Other treatments, including topical capsaicin (applied to the stomach), corticosteroids, benzodiazepines, and tricyclic antidepressants have been studied but none have demonstrated consistently effective symptom relief. 19

      Potential Drug Interactions, Toxicity, and Overdose

      The large volume of chemical compounds within cannabis makes examining potential drug-drug interactions challenging, and knowledge in this area is largely theoretical. Cannabinoids bind at a wide variety of sites to impact gene expression. 20 It is presumed that specific chemical components and formulations affect actions and that the duration of exposure may dictate potential drug interactions. The primary metabolism of cannabinoid compounds is via cytochrome P450 (CYP450): THC (CYP2C9/CYP3A4), CBD (CYP2C19/CYP3A4), and cannabinol (CYP2C9/CYP3A4). 20

      Any prescription drug processed through one or more of these CYP450 pathways, including commonly used medications (eg, NSAIDs, opioids, statins, anticonvulsants, selective serotonin reuptake inhibitors, and antibiotics) has the potential to cause a drug-drug interaction. Generally, data demonstrate that even low doses of alcohol increase plasma levels of THC. 20 When cannabis is used in combination with opioid pain medications, there may be increased opioid analgesic effects without correspondingly increased plasma levels. 20 Cannabinoids also may work synergistically with gabapentin to improve therapeutic window and effects. 20

      Adverse effects are more common when cannabis is orally ingested, and symptoms can last up to 12 hours. Naturally occurring cannabinoids act as partial agonists at CB1/CB2 receptors, limiting fatal overdoses. 21 However, children have an increased risk for overdose, most commonly through unintentional oral ingestion, and they are significantly more likely than adults to experience severe or life-threatening symptoms including hyperkinesis, respiratory depression, lethargy, coma, and death. 22 Duration of symptoms in children can vary from 4 to 48 hours postingestion, with treatment involving supportive care. 22

      Synthetic cannabinoids act as pure agonists with very high affinity at the CB1 receptor and, thus, their effects are more intense and longer lasting. 23 Synthetic formulations are not detectable on routine laboratory screening tests. If potential ingestion is suspected, cannabis toxicity should be included within a differential diagnosis, regardless of a negative toxicology screening. Synthetic compounds have a greater potential for serious neuropsychiatric toxicity, producing hallucinations, delirium, and/or psychosis in up to 66% of individuals. 23 Life-threatening toxicity, most characteristically manifesting as severe agitation or seizures, is possible at any age. 23

      Considerations in Recommending Medical Cannabis

      The US Food and Drug Administration (FDA) has approved medical cannabis for 3 clinical syndromes. 24 Naturally derived cannabis, labeled as cannabidiol (Epidiolex), is approved for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older. The agent is approved in the United Kingdom for treatment of seizures associated with tuberous sclerosis complex. 25 The synthetic cannabinoid dronabinol (Marinol and Syndros) is approved for the management of anorexia with associated weight loss in patients with AIDS and nausea associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. 24 Nabilone (Cesamet) is also a synthetic cannabinoid approved for the treatment of nausea associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. 24

      Potential Off-Label Therapeutic Uses

      The use of cannabinoids in the treatment of chronic pain (fibromyalgia, rheumatoid arthritis, central pain in multiple sclerosis, and neuropathic pain) is supported by study evidence, with no serious adverse events related to its use. 2,26 There has been clear efficacy established in the improvement of chemotherapy-induced nausea and vomiting with medical cannabis products that are not FDA-approved, particularly with ingestible products vs inhaled products. 11,26

      The treatment of seizures beyond those associated with Lennox-Gastaut syndrome and Dravet syndrome is perhaps the most discussed applications for cannabis, but data are highly variable, ranging from no improvement to an estimated 50% reduction in symptoms. 26 In the treatment of mental health disorders, studies have shown improvement in generalized and social anxiety disorders but no clear benefits in major depression and variability in the efficacy for psychotic disorders. 26 No clear benefit has been found in the treatment of acute postoperative or dental pain, and use improves intraocular pressure in those with glaucoma only transiently. 264 The application in Alzheimer disease is purely theoretical, minimal data is available in Parkinson’s disease, and no efficacy has been established in the treatment of Huntington disease (Table). 26 No cannabis formulation has yet proven to have greater efficacy than other FDA-approved medications options for these conditions. 26

      Use in Pregnancy and Breastfeeding

      Minimal data exist on the safety and effects of cannabis use in pregnancy. Both the American College of Obstetrics and Gynecology and the American Academy of Pediatrics advise against cannabis use during pregnancy and breastfeeding, citing concern for adverse neurodevelopmental effects. 27,28

      Some psychoactive components of cannabis likely cross the placental barrier, with fetal plasma concentrations estimated to be 10% to 30% of maternal serum concentrations. 29 With the highly lipophilic nature of THC, it is important to counsel patients that fetal exposure may occur for 4 to 6 weeks after maternal cessation. 29

      Based on the available evidence, complications of use during pregnancy may include higher rates of maternal anemia, up to twice the rate of preterm births, reduced birth weight, increased likelihood of neonatal intensive care unit stays, and learning/attention deficits into childhood. 30

      Studies suggest that THC accumulates in breast milk. Peak levels occur approximately 4 hours after maternal inhalation and detectable levels persist for at least 6 days after last maternal use. 31 Lack of federal regulation in cannabis supply and distribution also raises concern for the potential secondary exposure to pesticides, heavy metals, bacteria, and fungi through cannabis use. 32

      Conclusion

      Research on use of cannabis in the treatment of medical conditions is emerging at a rapid pace. The expanding number of states that have legalized recreational marijuana use is likely to increase the number of patients who present in the primary care setting seeking information on cannabis use for medical conditions. Clinicians will need to remain updated on evolving evidence to provide tailored patient education on the benefits and risks associated with cannabis use.

      Click here for an accompanying article by Dr Kalensky on cannabis use disorder, intoxication,
      withdrawal, and other cannabis-related disorders.

      Melissa Kalensky, DNP, APRN, FNP-BC, PMHNP-BC, CNE, is an assistant professor at Rush University College of Nursing in Chicago.

      References

      1. Substance Abuse and Mental Health Service Administration. Key substance use and mental health indicators in the United States: results from the 2019 National Survey on Drug Use and Health. September 2020. Accessed August 26, 2021. https://www.samhsa.gov/data/sites/default/files/reports/rpt29393/2019NSDUHFFRPDFWHTML/2019NSDUHFFR1PDFW090120.pdf

      2. National Center for Complimentary and Integrative Health. Cannabis (marijuana) and cannabidnoids: what you need to know. Accessed August 26, 2021. https://www.nccih.nih.gov/health/cannabis-marijuana-and-cannabinoids-what-you-need-to-know

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