Idrasil™ Information for Doctors

What is Idrasil™?

Its Simply Medicine The Cannabis Pill Without the Euphoria:

What is Idrasil™ used for?

Primary Indications:

Patient Ailments:

How do I prescribe Idrasil™?

On your standard Doctors Prescription pad, Idrasil 25mg, PRD / Qd

Is it Legal for Doctors to prescribe Idrasil™?

Please become informed with the following applicable information Links and take it upon yourself to become further educated and informed in support of The Quality of Life for your Patients.

Medical Board of California link:

California Health & Safety Code:

California Senate Bill SB420:

California Compassionate Use Act / Prop 215:

Physicians Responsibility:

Is Idrasil™ reimbursable by Insurance?

YES, by private insurance, HMO or better:

Adverse Indications?

Very few, as Cannabis is generally used as a Harm Reduction Agent:

Benefits of Medical Cannabis

•  Wide margin of safety
•  Rapid onset of action- Able to easily self titrate without euphoria
•  Decrease pain without mental clouding
•  Improve sleep without after effects
•  Quell Nausea / Vomitting and improve appetite
•  Anti-Inflammatory
•  Decrease and/or eliminate other conventional medications
•  Harm reduction medication
•  Not Habit Forming- Not addictive by classic definitions

PDF
A Guide to the Benefits of Medical Cannabis (Idrasil™)

Safety of Cannabis

•  No recorded deaths
•  LD-50 = 20,000- 40,000 : 1 joint > Would Require 1500 pounds consumed in 15 minutes
•  Low risk with high benefits

“one of the safest therapeutic substances known to man. It would be unreasonable, arbitrary and capricious for the DEA to continue to stand between those sufferers and the benefits of this substance in the light of the evidence in this record.”

1988 ruling by Francis Young, Chief Administrative Law Judge for the DEA

Risk vs. Benefit 

“ …Except for the harms associated with smoking, the adverse effects of cannabis use are within the range of effects tolerated for other medications.”

Institute of Medicine – 1999

marijuana-risk-graph

Comparative Addiction Rates

•  Tobacco 32%
•  Heroin 23%
•  Cocaine 17%
•  Alcohol 15%
•  Cannabis 9%

Indications for Cannabis

IndicationsForCannabis
(Patients may have more than one diagnosis)


Precautions

  • Bronchitis- No COPD, Emphysema, or Lung/Airway Cancers
  • Metabolism by cytochrome p450 2C and 3A families


Cannabis-Induced Euphoria

  • Often described as a “side effect” of Rx
  • Is it really an “adverse experience”, particularly in the terminal patient?
  • Is a single treatment that increases appetite, decreases nausea and vomiting, relieves pain and improves mood and sleep for overall Quality of Life.
  • A potentially useful tool in palliative medicine.


What can (will) you do?

  • Call it CANNABIS
  • Learn more
  • Ask patients about their use
  • Assess and monitor
  • Don’t include in drug testing if not necessary
  • Talk to your legislators
  • Talk to your colleagues
  • Advocate for federally legal cannabis and regulations for medical use


Bad Medical Practice

  • Refuse to learn about the science
  • Refuse to treat patient
  • Refuse opioids for pain management
  • Encourage drug addiction treatment
  • Use more powerful medications with untoward side effects
  • Take off transplant lists (“substance abuser”)


Department of Veteran Affairs

“If a Veteran obtains and uses medical cannabis in a manner consistent with state law, testing positive for cannabis would not preclude the Veteran from receiving opioids for pain management in a Department of Veteran Affairs (VA) Facility.

Robert A. Petzel, MD
July 2010

“The provider will take the use of medical cannabis into account in all prescribing decisions just as the provider would for any other medication.”

Robert A Petzel, MD
July 2010

Human Receptor Information

How Cannabis Helps the Body

Scientists have begun speculating that the root cause of disease conditions such as migraines and irritable bowel syndrome may be endocannabinoid deficiency.

For several years it has been postulated that marijuana is not, in the strict sense of the word, an intoxicant.

As written in the book Marijuana Is Safer: So Why Are We Driving People to Drink? (Chelsea Green, 2009), the word ‘intoxicant’ is derived from the Latin nountoxicum (poison). It’s an appropriate term for alcohol, as ethanol (the psychoactive ingredient in booze) in moderate to high doses is toxic (read: poisonous) to healthy cells and organs.

Of course, booze is hardly the only commonly ingested intoxicant. Take the over-the-counter painkiller acetaminophen (Tylenol). According to the Merck online medical library, acetaminophen poisoning and overdose is “common,” and can result in gastroenteritis (inflammation of the gastrointestinal tract) “within hours” and hepatotoxicity (liver damage) “within one to three days after ingestion.” In fact, less than one year ago the U.S. Food and Drug Administration called for tougher standards and warnings governing the drug’s use because “recent studies indicate that unintentional and intentional overdoses leading to severe hepatotoxicity continue to occur.”

By contrast, the therapeutically active components in cannabis — the cannabinoids — appear to be remarkably non-toxic to healthy cells and organs.This notable lack of toxicity is arguably because cannabinoids mimic compounds our bodies naturally produce — so-called endocannabinoids — that are pivotal for maintaining proper health and homeostasis.

In fact, in recent years scientists have discovered that the production of endocannabinoids (and their interaction with the cannabinoid receptors located throughout the body) play a key role in the regulation of proper appetite, anxiety control, blood pressure, bone mass, reproduction, and motor coordination, among other biological functions.

Just how important is this system in maintaining our health? Here’s a clue: In studies of mice genetically bred to lack a proper endocannabinoid system the most common result is premature death.

Armed with these findings, a handful of scientists have speculated that the root cause of certain disease conditions — including migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis — may be an underlying endocannabinoid deficiency.

Now, much to my pleasant surprise, Fox News Health columnist Chris Kilham has weighed in on this important theory.

Are You Cannabis Deficient? via Fox News

If the idea of having a cannabis deficiency sounds laughable to you, a growing body of science points at exactly such a possibility.

… [Endocannabinoids] also play a role in proper appetite, feelings of pleasure and well-being, and memory. Interestingly, cannabis also affects these same functions. Cannabis has been used successfully to treat migraine, fibromyalgia, irritable bowel syndrome and glaucoma. So here is the seventy-four thousand dollar question. Does cannabis simply relieve these diseases to varying degrees, or is cannabis actually a medical replacement in cases of deficient [endocannabinoids]?

… The idea of clinical cannabinoid deficiency opens the door to cannabis consumption as an effective medical approach to relief of various types of pain, restoration of appetite in cases in which appetite is compromised, improved visual health in cases of glaucoma, and improved sense of well being among patients suffering from a broad variety of mood disorders. As state and local laws mutate and change in favor of greater tolerance, perhaps cannabis will find it’s proper place in the home medicine chest.

Perhaps. Or maybe at the very least society will cease classifying cannabis as a ‘toxic’ substance when its more appropriate role would appear to be more like that of a supplement.

Cannabinoid Receptor Type 1

  • CB1 receptors are found primarily in the brain, to be specific in the basal ganglia and in the limbic system, including the hippocampus.
  • They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.

Cannabinoid Receptor Type 2

  • CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen.
  • While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum.
  • CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.

Harnessing the Cannabinoid system

  • Exogenous compounds
  • Phytocannabinoids
  • THC, CBD, combinations
  • Synthetic cannabinoids
  • Nabilone
  • Endogenous manipulation
  1. – FAAH inhibitors
  2. -MAGL, DAGL inhibitors

  • Receptor targets
  1.  -CB1
  2. -CB2
  3. -TRPV1
  4. -PPAR
  5. -5-HT

Endocannabinoid system regulates activity in a wide variety of systems

GreenPieChart

  • The endocannabinoid system refers to a group of neuromodulatory lipids and their receptors that are involved in a variety of physiological processes including appetite, pain-sensation, mood, memory and it mediates the psychoactive effects of cannabis.
CB1 Receptors

Cannabin_CBI

  • The CB1 receptor is expressed mainly in the brain central nervous system but also in the lungs, liver and kidneys.
Distribution of CB1 Receptors

CB1-receptor-distribution-5

  • CB1 cannabinoid receptors appear to mediate most, if not all of the psychoactive effects of delta-9-tetrahydrocannabinol and related compounds. This G protein-coupled receptor has a characteristic distribution in the nervous system: It is particularly enriched in cortex, hippocampus, amygdala, basal ganglia outflow tracts and cerebelluma distribution that corresponds to the most prominent behavioral effects of cannabis.
Cannabinoid Synaptic Circuit Breakers

3 - Figure 2 - Modulating Cannabinoids

  • Cannabinoid receptors and endocannabinoid signaling are distributed throughout the rostrocaudal neuraxis. Retrograde signaling via endocannabinoid mediates synaptic plasticity in many regions in the central nervous system.
Enteric Nervous System

nrgastro.2012.32-f1

  • The nervous system exerts a profound influence on all digestive processes, namely motility, ion transport associated with secretion and absorption and gastrointestinal blood flow. Some of this control emanates from connections between the digestive system and central nervous system, but just as importantly, the digestive system is endowed with its own, local nervous system referred to as the enteric or intrinsic nervous system. The magnitude and complexity of the enteric nervous system is immense it contains as many neurons as the spinal cord.
Cannabinoids as Immune Modulators

immune-system-brain.fw

  • Cannabinoid receptors are G protein-coupled receptors and they have been linked to signaling pathways and gene activities in common with this receptor family. In addition, cannabinoids have been shown to modulate a variety of immune cell functions in humans and animals and more recently, have been shown to modulate T helper cell development, chemotaxis, and tumor development. Many of these drug effects occur through cannabinoid receptor signaling mechanisms and the modulation of cytokines and other gene products.

Idrasil Pharmacology

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinsons and Huntingtons disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

  1. Pál Pacher,
  2. Sándor Bátkai, and
  3. George Kunos

Comparing THC and CBD

cannabinoids6

Acid vs. Neutral
Cannabinoid
Decarboxylation

US20110098348A1-20110428-D00001

Non-psychoactive Phytocannabinoids

phytocannabinoid-terpenoid_2

Health Effects of Cannabinoids

cannabinoids-body-and-brain

Non-THC Components of Cannabis
  1. △9-tetrahydrocannabinol (THC) is the primary active ingredient in cannabis
  2. Secondary compounds may enhance the beneficial effects of THC
  3. Other cannabinoids and non-cannabinoid compounds may reduce THC-induced anxiety, anticholenergic effects and immunosuppression
  4. Terpenoids and flavonoids may increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens and provide anti-inflammatory activity
Cannabidiol (CBD)
  1. Modulates the pharmacokinetics of THC
  • -Very low affinity for CB1 And CB2 receptors
  • -Slight affinity for CB receptors as an antagonist
  • -May modulate downstream signal transduction
  • -Potent cytochrome P450 3A11 inhibitor thus blocking formation of 11-OH metabolite
  • -CBD possesses sedative properties, reduces anxiety and other unpleasant psychological side effects of pure THC
Idrasil is CBD-Rich
  1. Second to THC as the most prevalent cannabinoid
  2. Little binding affinity at CB1; mildly antagonizes THC
  3. Reduces anxiety, paranoia, tachycardia, hunger, sedation
  4. Analgesic; neuro-protective antioxidant; anticonvulsant, anti-nausea; antagonizes TNF-alpha; anti-MRSA; agonistic at 5HT1a (anti-anxiety)
  5. Cytotoxic to many cancer cell line- cytopreserative to normal cells
  6. Improves cognition in animal models of hepatic encephalopathy
A Little History

In the late 1800s through the early 1900s both Lilly & H.K. Mulford Co. (USA Based Companies) developed, manufactured, processed and distributed a wide variety of Cannabis based products for treatment of a wide variety of ailments.

Click the following Link for a full Chronology of Cannabis:

http://idrasilrx.com/patient-info/ailments/cannibis-chronology/

Insurance Information for Doctors

The following Insurance Information for Doctors and their staff is designed to help them better understand how health insurance is billed for Idrasil™. If you have any specific questions please contact Patient Services at (855) IDRASIL or Services@IdrasilRx.com

Is Idrasil™ reimbursable by a patients medical insurance?

Yes. Idrasil™ is reimbursable by private insurance, HMO or better. No MediCaid, No MediCal, no Kaiser.

How does the patient submit the insurance claim?

They do not, C3 Patients Association™ does!

  • Simply write the patient a prescription for Idrasil 25mg, PRN / Qd on the doctors prescription pad and give it to the patient.
  • The Patient will then, if they have not already, Become A Member with C3 Patients Association™, supply their information (Prescription etc, and C3 Patients Association™ will Submit the Insurance Claim for them.

Idrasil Interactions

Cannabinoid Opioid Interactions

1. Initially thought to to act on same pathways to produce their pharmacologic actions

2. In mice and rats, THC greatly enhances analgesic effects of morphine in a synergistic fashion

3. Increased potency of other mu opioids (hyrdomorphone and oxymorphone) seen with oral-r-9-THC in mouse models

4. Possibilities of enhanced and persistent analgesic effect at lower opioid doses

5. Share several pharmacologic properties

→ Antinociception

→ Hypothermia

→ Sedation

→ Hypotension

→ Inhibition of intestinal mobility and locomotion

Cannabis Opioid Conclusions

1. Co-administration of cannabis with oral sustained release opioids is safe

2. Co-administration of cannabis in subjects on stable doses of morphine or oxycodone appears to enhance analgesia

3. Co-administration of cannabis trends towards lowering concentration of the opioids

→ The PK effects would be expected to reduce the analgesic effects of the opioids

→ The effect of cannabis to enhance opioid analgesia occurs by a pharmacodynamic, not a pharmacokinetic mechanism

Cannabis-Drug Interactions

Constituents

Cannabis herb contains a wide range of cannabinoids, which are the major active compounds. The main psychoactive constituent is delta9-tetrahydrocannabinol (THC; dronabinol), and it is the cause of many of the pharmacological effects elicited by the consumption of cannabis. However, other cannabinoids, which do not possess psychoactive properties, such as cannabidiol, cannabinol (a decomposition product of delta9-tetrahydrocannabinol), cannabigerol and cannabichromene, are increasingly being investigated for their pharmacological and therapeutic properties. Cannabinoids are often found in the plant as their acid metabolites, e.g. ll-nor-9-carboxy-delta9-tetrahydrocannabinol, cannabidiol acid and others, especially if the plant has been grown in a cooler climate. These decarboxylate to the parent cannabinoid at high temperatures, such as during smoking. Most medicinal cannabis products have been heat treated to ensure that the cannabinoids are present only in the non-acid form.

Use and Indications

Cannabis has no current established use in herbal medicine because of its legal position in most parts of the world. However, medicinal cannabis is increasingly being used to treat chronic conditions, as an adjunct, or where other treatments may be inadequate. For example, a buccal spray preparation of cannabis, containing mainly dronabinol (the medicinal name for delta9-tetrahydrocannabinol) with cannabidiol, is available as an adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis in adults. It is also being investigated for use as an analgesic in other disease states such as diabetic neuropathy and rheumatoid arthritis, and to relieve spasticity in multiple sclerosis and spinal cord injury. Dronabinol and nabilone (a synthetic cannabinol) are used as antiemetics in patients receiving cancer chemotherapy, and dronabinol has been used as an appetite stimulant in AIDS. Cannabis is a widely used illicit drug because of its psychoactive properties, and has a long history of such use, including by those with chronic illnesses.

Varieties of Cannabis sativa that contain very little cannabinoids (often referred to as hemp) have been cultivated for their fiber and seeds, and these, and the oil derived from the seeds, may be found in some herbal products.

Pharmacokinetics

The most important pharmacokinetic effects of cannabis depend on whether the herb (or its extracts) are smoked or taken orally. When smoked, cannabinoid acids are decarboxylated by the high temperature, and reach the lung as active free cannabinoids. Psychotropic effects start from within seconds to a few minutes, reach a maximum after 20 to 30 minutes, and taper off within 3 to 4 hours. If the same preparation were to be taken orally, however, cannabinoid acid absorption would be lower and much less predictable, with psychotropic effects starting after a delay of 30 to 90 minutes, reaching their maximum after 2 to 4 hours and lasting for about 6 hours.

The metabolism of cannabis is complex, resulting in both active and inactive compounds. The cannabinoids are extensively metabolized by cytochrome P450, in particular, by the isoenzyme CYP2C9 and CYP3A4.2 Smoking cannabis may induce CYP1A2, see theophylline, and also clozapine. Dronabinol has also been shown to inhibit CYP1A1, despite increasing its expression. Cannabis also induces the expression of CYP2E1 and CYP2D6 in mice.

Research suggests that some constituents of cannabis can affect others. Cannabidiol, an active but non-psychotropic cannabinoid, has been shown to partially inhibit the hydroxylation of dronabinol, probably by CYP2C. There is limited evidence that some cannabinoids might inhibit P-glycoprotein or reduce P-glycoprotein expression.

Interactions Overview

Most of the drug interaction data relate to smoking cannabis. Smoking cannabis has been shown to decrease levels of theophylline, chlorpromazine and probably clozapine. Use of transdermal nicotine with cannabis enhances tachycardia, and increases the stimulant effect of cannabis. Tachycardia has also been seen with combined use of tricyclic antidepressants and cannabis. Cannabis might increase the effects of opioids such as morphine. Isolated cases of hypomania have been seen when cannabis was used with disulfiram and with fluoxetine, and a man taking cannabis and sildenafil had a myocardial infarction. Another case report describes a fatal stroke in a young man who received cisplatin and smoked cannabis. Indomethacin might antagonize some of the effects of smoking cannabis. Smoking cannabis does not appear to affect the pharmacokinetics or antiviral efficacy of indinavir or nelfmavir, and oral cannabis does not appear to affect the pharmacokinetics of Docetaxel or Irinotecan.

Cannabis + Alcohol

The detrimental effects of drinking alcohol and smoking cannabis may be additive on some aspects of driving performance. However, there is some evidence that regular cannabis use in itself does not potentiate the effects of alcohol. Smoking cannabis may alter the bioavailability of alcohol.

Evidence and Mechanism

(a) CNS effects

Simultaneous use of alcohol and oral delta9-tetrahydrocannabinol (THC, the major active ingredient of cannabis) reduced the performance of psychomotor tests, suggesting that those who use both drugs together should expect the deleterious effects to be additive. In a further placebo-controlled study, subjects smoked cannabis containing 100 or 200 micrograms/kg of delta9-tetrahydrocannabinol and drank alcohol (to achieve an initial blood level of 70mg%, with further drinks taken to maintain levels at 40mg %) 30 minutes before driving. They found that cannabis, even in low-to-moderate doses, negatively affected driving performance in real traffic situations. Further, the effect of combining moderate doses of both alcohol and cannabis resulted in dramatic performance impairment as great as that observed with blood-alcohol levels of 140 mg% alone. Similar results (including a suggestion of a synergistic impairment of performance) have been found in a number of other studies, including different doses of cannabis and regular cannabis users.

A study in 22 healthy subjects, who occasionally used cannabis cigarettes and drank moderate amounts of alcohol, found that the number of euphoric events in response to a cannabis cigarette was greater after alcohol ingestion, and the duration of euphoric events was longer. The speed of onset of the effects of cannabis was also faster when it was smoked after the ingestion of alcohol.

One study in 14 regular cannabis users (long-term daily use) and 14 infrequent cannabis users found that regular use reduced the disruptive effects of alcohol on some psycho-motor skills relevant to driving, whereas infrequent use did not have this effect. In this study, neither group had smoked any cannabis in the 12 hours before the alcohol test. Another study found that moderate doses of alcohol and cannabis, consumed either alone or in combination, and did not produce significant behavioral or subjective impairment the following day.

A study in 12 healthy subjects who regularly used both cannabis and alcohol found that alcohol 0.5 g/kg significantly increased break latency without affecting body sway, whereas cannabis given as a cigarette containing tetrahydrocannabinol 3.33%, increased body sway but did not affect brake latency. There were no significant additive effects on brake latency, body sway or mood when the two drugs were used together. A population-based study of 2,777 drivers involved in fatal road crashes, who drank alcohol and/or used cannabis, found that, although both cannabis and alcohol increased the risk of being responsible for a fatal crash, no statistically significant interaction was observed between the two drugs.

(b) Pharmacokinetic studies

Fifteen healthy subjects given alcohol 0.7 g/kg developed peak plasma alcohol levels of about 78 mg% at 50 minutes, but, if they smoked a cannabis cigarette 30 minutes after the drink, their peak plasma alcohol levels were only 55mg% and they occurred 55 minutes later. In addition, their subjective experience of the drugs decreased when used together. However, another study found that smoking cannabis 10 minutes before alcohol consumption did not affect blood-alcohol levels. A further study found that blood-alcohol levels were not affected by delta9-tetrahydrocannabinol given orally one hour before alcohol. A study in 22 healthy subjects, who occasionally used cannabis cigarettes and drank moderate amounts of alcohol, found that plasma delta9-tetrahydrocannabinol levels were higher when alcohol was consumed before smoking a cannabis cigarette.

Importance and Management

Several studies have found that cannabis and alcohol produce additive detrimental effects on driving performance, but other studies have not found any potentiation. This is probably due to the variety of simulated driving tests used and possibly the time lag between the administration of alcohol and cannabis; behavioral impairment after cannabis has been reported to peak within 30 minutes of smoking. Nevertheless, both drugs have been shown to affect some aspects of driving performance and increase the risk of fatal car accidents. Concurrent use of cannabis and alcohol before driving should therefore be avoided.

 

Cannabis + Chlorpromazine

Smokers of cannabis may possibly need larger doses of chlorpromazine than non-smokers.

Clinical Evidence

A study in 31 patients found that the clearance of chlorpromazine was increased by 38% by tobacco smoking, by 50% by cannabis smoking, and by 107% when both tobacco and cannabis were smoked.

Experimental Evidence

No relevant data found.

Mechanism

Not established. The probable reason is that some of the components of tobacco smoke act as enzyme inducers, which increase the rate at which the liver metabolizes chlorpromazine, thereby reducing its serum levels and clinical effects.

Importance and Management

Established interactions but of uncertain clinical importance. Be alert for the need to increase the dosages of chlorpromazine and related antipsychotics in patients who smoke, and reduce the dosages if smoking is stopped.

Cannabis + Cyclosporine

Cannabidiol, an important constituent of cannabis, may increase cyclosporine levels. This interaction is based on experimental evidence only.

Clinical Evidence

No interactions found.

Experimental Evidence

An in vitro study found that the incubation of human and mouse liver microsomes with cannabidiol, an active but non-psychoactive constituent of cannabis, resulted in inhibition of cyclosporine metabolism. The production of cyclosporine metabolites was reduced by 73 to 83%. Similar results were found in studies in mice)

Mechanism

Cannabidiol may inhibit the cytochrome P450 subfamily CYP3A, and so increase cyclosporine levels. However, cannabis does not affect the metabolism of other CYP3A4 substrates, see Cannabis + Irinotecan.

Importance and Management

These preclinical data suggest that one constituent of cannabis might possibly raise cyclosporine levels. These data require confirmation in humans. Until such data are available, bear in mind the possibility that irregular use of cannabis might be a factor in unstable cyclosporine levels. It might be unwise for patients taking cyclosporine to use cannabis.

Cannabis + Cisplatin

A case report describes a fatal stroke when a young man receiving cisplatin smoked cannabis.

Evidence, Mechanism, Importance and Management

A 27-year-old man who smoked cannabis and tobacco daily developed tinnitus and paresthesia after receiving the first course of chemotherapy consisting of cisplatin, etoposide and bleomycin for testicular cancer. Following the second course of chemotherapy, the patient reported distal paresis of the right arm and, 2 days later, about 30 minutes after cannabis inhalation, he developed headache, paresis of his right leg and aphasia. A large thrombus was found in the carotid artery. The patient died the next day. He had no cardiovascular risk factors apart from the smoking (about 4 cigarettes per day).

Cisplatin is known to carry a small risk of stroke, and cases have also been reported for cannabis smoking alone. In this case it was suggested that the use of cannabis may have also contributed to the adverse outcome in this patient. It might be prudent for patients receiving cisplatin to avoid smoking cannabis.

Cannabis + Clozapine

Patients who give up smoking cannabis may develop higher blood levels of clozapine and be at risk of adverse reactions, since plasma levels of clozapine are lower in smokers than in non-smokers.

Clinical Evidence

A 37-year-old man who smoked both tobacco and cannabis daily, and took clozapine 700 mg daily, experienced elevated clozapine plasma levels and signs of clozapine toxicity, one month after he stopped smoking both tobacco and cannabis. One week after reducing the dose of clozapine to 500 mg daily, his psychotic symptoms disappeared and plasma levels returned to normal.

Experimental Evidence

No relevant data found.

Mechanism

Tobacco smoke contains aromatic hydrocarbons that are potent inducers of the cytochrome P450 isoenzyme CYP1A2, by which clozapine is metabolized. The contribution of cannabis smoking to this case is unknown, but cannabis smoking alone is also known to induce CYP1A2, independent of tobacco. See Cannabis + Theophylline.

Importance and Management

It is known that patients who smoke tobacco may experience lower serum clozapine levels and, although there is no direct evidence, this may equally apply to cannabis smoking. Irregular smoking of cannabis might cause fluctuations in clozapine levels.

Cannabis + Disulfiram

Two isolated case reports describe hypomanic-like reactions when patients taking disulfiram used cannabis, whereas no unusual interaction with the combination was seen in other subjects.

Evidence, Mechanism, Importance and Management

A man with a 10-year history of drug abuse (alcohol, amphetamines, cocaine, cannabis) taking disulfiram 250 mg daily, experienced a hypomanic-like reaction (euphoria, hyperactivity, insomnia, irritability) on two occasions, associated with the concurrent use of cannabis. The patient said that he felt as though he had been taking amphetamine. One other similar case has been reported. The reason for this reaction is not understood. In a randomized study in alcohol-dependent subjects who had previously used cannabis, no unusual interaction effects were found in a group of 11 subjects receiving disulfiram and smoking cannabis twice weekly for 4 weeks. Therefore the interaction described in the two case reports would not appear to be of general significance.

Cannabis + Docetaxel

The pharmacokinetics of Docetaxel are not altered by an herbal tea containing cannabis.

Clinical Evidence

In a study investigating the effects of cannabis on Docetaxel pharmacokinetics, 12 patients were given 200 mL of an herbal tea containing cannabis 1 g/L each day for 15 days. The tea was prepared from medicinal-grade cannabis (Cannabis sativa L. Flos, Bedrocan®) containing the cannabinoids delta9-tetrahydrocannabinol 18% and cannabidiol 0.8%. The clearance and the AUC of Docetaxel given on day 12 of the cannabis tea were not significantly altered, when compared with Docetaxel given before the cannabis tea. The dose of Docetaxel used was 180 mg, reduced to 13 5 mg in 3 patients who experienced dose-related Docetaxel toxicity.

Experimental Evidence

No relevant data found.

Mechanism

Docetaxel is metabolized by the cytochrome P450 isoenzyme CYP3A4, and this does not appear to be affected by oral cannabis.

Importance and Management

This study suggests that cannabis taken orally will not affect the pharmacokinetics of Docetaxel. No dosage adjustments are likely to be needed if Docetaxel is given with cannabis tea. It is not known if this applies to other drugs metabolized by CYP3A4, or to other preparations and routes of administration of cannabis, but see also Cannabis + Cyclosporine, and Cannabis + Irinotecan, below.

Cannabis + Ecstasy

The information regarding the use of cannabis with ecstasy is based on experimental evidence only.

Evidence, Mechanism, Importance and Management

An animal study found that pretreatment with cannabidiol, a major constituent of cannabis, did not affect the levels of ecstasy (MDMA, methylenedioxymethamfetamine) in the brain of mice.

Cannabis + Fluoxetine

An isolated report describes mania when a patient taking fluoxetine smoked cannabis.

Evidence, Mechanism, Importance and Management

A 21-year-old woman with a 9-year history of bulimia and depression was taking fluoxetine 20 mg daily. A month later, about 2 days after smoking two ‘joints’ of cannabis (marijuana), she experienced a persistent sense of well-being, increased energy, hyper sexuality and pressured speech. These symptoms progressed into grandiose delusions, for which she was hospitalized. Her mania and excitement were controlled with lorazepam and perphenazine, and she largely recovered after about 8 days. The reasons for this reaction are not understood but the authors of the report point out that one of the active components of cannabis, dronabinol (delta9-tetrahydrocannabinol), is, like fluoxetine, a potent inhibitor of serotonin uptake. Thus a synergistic effect on central serotonergic neurons might have occurred. This seems to be the first and only report of an apparent adverse interaction between cannabis and fluoxetine, but it emphasizes the risks of concurrent use.

Cannabis + Food

No interactions found.

Cannabis + Herbal medicines

No interactions found.

Cannabis + Irinotecan

The pharmacokinetics of Irinotecan are not altered by an herbal tea containing cannabis.

Clinical Evidence

In a crossover study, 24 patients were given intravenous Irinotecan 600 mg before and 12 days after starting a 15-day course of 200 mL daily of a herbal tea containing cannabis 1 g/L. This was prepared from medicinal-grade cannabis (Cannabis sativa L. Flos, Bedrocan®) containing the cannabinoids delta9-tetrahydrocannabinol 18% and cannabidiol 0.8%. The clearance and the AUC of Irinotecan and its metabolites, SN-38 and SN-38G, were not significantly altered by the presence of cannabis.

Experimental Evidence

No relevant data found.

Mechanism

Irinotecan is metabolized by cytochrome P450 isoenzyme CYP3A4, and this does not appear to be affected by oral cannabis.

Importance and Management

This study suggests that cannabis taken orally will not affect the pharmacokinetics of Irinotecan. No dosage adjustments are likely to be needed if Irinotecan is given with cannabis tea. It is not known if this applies to other drugs metabolized by CYP3A4, or to other preparations and routes of administration of cannabis, but see also Cannabis + Cyclosporine, and Cannabis + Docetaxel.

Cannabis + Nicotine

The effects of transdermal nicotine and cannabis smoking on increasing the heart rate are additive, and nicotine increased the stimulant effect of cannabis. Combined use might increase the addictive potential of both drugs.

Clinical Evidence

In a study in 20 healthy subjects who smoked either a low-dose or a high-dose cannabis cigarette 4 hours after the application of a placebo or a 21 mg nicotine patch, nicotine enhanced the maximum increase in heart rate seen with cannabis. The increase in heart rate for nicotine alone was between 10 and 15 bpm, for cannabis alone 32 and 42 bpm, for women and men, respectively, and, for the combination, 45 and 58bpm, respectively. In addition, the duration of tachycardia after smoking the low-dose cannabis was prolonged by 30 minutes by nicotine, but was not changed after the high-dose cannabis. Nicotine increased the subjective stimulant effects of cannabis, but the reported duration of effects of cannabis were shortened by nicotine. Plasma levels of nicotine and delta9-tetrahydrocannabinol (THC) did not differ on concurrent use. The cannabis cigarettes were standardized to 1.99% THC (low dose) and 3.51% THC (high dose).

Experimental Evidence

Studies in mice found that nicotine enhanced the effects of delta9-tetrahydrocannabinol in terms of hypolocomotion, hypothermia and antinociceptive responses. Somatic signs of withdrawal from delta9-tetrahydrocannabinol were more severe in mice that had received nicotine.

Mechanism

Unknown. The additive effect on heart rate may be due to sympathetic activity of both drugs, and might also involve cannabinoid receptors.

Importance and Management

Cannabis is often smoked with tobacco. The findings of the clinical study show that transdermal nicotine has additive effects with cannabis on heart rate, and increased the stimulant effect of cannabis. The clinical significance of these findings is uncertain.

Cannabis + NSAIDs

Indomethacin appears to antagonize some of the effects of cannabis, and cannabis might antagonize the analgesic efficacy of NSAIDs.

Clinical Evidence

Four healthy subjects were given placebo or indomethacin 25 mg three times daily for one day, and then a single-dose 2 hours before smoking cannabis 400 micrograms/kg on the following day. Indomethacin did not alter the pharmacokinetics of delta9-tetrahydrocannabinol. Subjective measures of heart rate acceleration and intoxication were modestly attenuated by indomethacin. Subjects also reported that the effects of marihuana on time perception were antagonized by indomethacin.

Experimental Evidence

In a study rabbits received placebo or 2% indomethacin applied topically to both eyes one hour prior to an intravenous injection of delta9-tetrahydrocannabinol. The fall in intraocular pressure caused by delta9-tetrahydrocannabinol was inhibited by topical indomethacin.

In an animal model of analgesia, chronic treatment with delta9-tetrahydrocannabinol markedly reduced the efficacy of aspirin, celecoxib, indomethacin, ketorolac and naproxen, and reduced the potency of diclofenac and paracetamol (acetaminophen).

Mechanism

It is suggested that prostaglandins have some part to play in some of the effects of cannabis, and that these are antagonized by indomethacin, which is a prostaglandin inhibitor. Similarly, cannabis antagonizes the effects of NSAIDs.

Importance and Management

The effects of indomethacin on the subjective measures and intraocular pressure-lowering effects of delta9-tetrahydrocannabinol are probably not of clinical significance. However, the relevance of the finding that chronic use of delta9-tetrahydrocannabinol might result in reduced efficacy and potency of NSAIDs requires further study.

Cannabis + Opioids

Low doses of cannabis enhanced the effect of morphine in three patients. Animal studies have shown that cannabinoids may enhance the potency of opioids.

Evidence, Mechanism, Importance and Management

A report of 3 patients with chronic pain (due to multiple sclerosis, HIV-related peripheral neuropathy and lumbar spinal damage) found that small doses of smoked cannabis potentiated the antinociceptive effects of morphine. The patients were able to decrease the dose of opioid by 60 to 100%. Studies in animals have shown that delta9-tetrahydrocannabinol, the major psychoactive constituent of cannabis, enhances the potency of opioids such as morphine, codeine, hydromorphone, methadone, oxymorphone and pethidine (meperidine). It has been suggested that low doses of delta9-tetrahydrocannabinol given with low doses of morphine may increase opioid potency without increasing adverse effects. Cannabis use in methadone-maintained patients did not appear to affect treatment progress, although some psychological difficulties were slightly more prevalent. However, other workers have suggested that heavy cannabis use is associated with poorer progress when methadone is given in the treatment of opioid addiction.

Cannabis + Phencyclidine

The interaction between cannabis and phencyclidine is based on experimental evidence only.

Clinical Evidence

No interactions found.

Experimental Evidence

An animal study found that pretreatment with cannabidiol significantly increased the levels of phencyclidine in the brain and blood of mice. Behavioral tests indicated that the increase in brain levels led to an increase in intoxication caused by phencyclidine. When the study was repeated using delta9-tetrahydrocannabinol in doses of 120 mg/kg, the brain levels of phencyclidine were increased twofold. Lower doses of delta9-tetrahydrocannabinol did not result in such an effect.

Mechanism

Unknown.

Importance and Management

This preclinical study provides some evidence that cannabis might increase the abuse potential of phencyclidine.

Cannabis + Phenytoin

There is one in vitro study suggesting that delta9-tetrahydrocannabinol, a major constituent of cannabis, might induce phenytoin metabolism. Note that, in clinical use dronabinol has induced seizures.

Clinical Evidence

No interactions found.

Experimental Evidence

In an in vitro study in which human liver microsomes were incubated with phenytoin alone, or phenytoin and delta-tetrahydrocannabinol, a major constituent of cannabis, the rate of metabolism of phenytoin was slightly increased in a dose-dependent manner. The rate of metabolism of delta9-tetrahydrocannabinol to its 11-hydroxy metabolite was not altered by phenytoin.

Various cannabinoids have shown antiepileptic effects in animal studies. In one study, the antiepileptic effect of phenytoin was increased when combined with cannabidiol.

Mechanism

The in vitro data suggest that delta9-tetrahydrocannabinol induces the cytochrome P450 isoenzyme CYP2C9.

Importance and Management

This appears to be the only evidence that cannabis might affect phenytoin levels, and is only in vitro data. As such, it requires confirmation before any recommendations can be made. Note also that there are no reports in the literature of cannabis use affecting phenytoin levels. Note that oral dronabinol (delta9-tetrahydrocannabinol) has caused seizures in clinical use, and the manufacturer recommends caution in those with a seizure disorder.

Cannabis + Protease Inhibitors

The short-term use of cannabis cigarettes or dronabinol (delta9-tetrahydrocannabinol) did not appear to adversely affect indinavir or nelfinavir levels or viral loads in HIV-positive patients.

Clinical Evidence

In 9 HIV-positive patients on a stable regimen containing indinavir (mostly 800 mg every 8 hours), smoking a cannabis cigarette (3.95% tetrahydrocannabinol) three times daily before meals for 14 days resulted in a median 14% decrease in AUC and maximum level and a 34% decrease in minimum indinavir level. However, only the change in maximum level was statistically significant. Similarly, dronabinol (delta9-tetrahydrocannabinol) 2.5 mg three times daily for 14 days had no significant effect on indinavir pharmacokinetics.

In another 11 patients on a stable regimen containing nelfinavir 750 mg three times daily, there was a non-significant 10% decrease in AUC, 17% decrease in maximum level and 12% decrease in minimum nelfinavir level after 14 days of cannabis cigarettes. Similarly, dronabinol 2.5 mg three times daily for 14 days had no significant effect on nelfinavir pharmacokinetics.

There was no adverse effect on viral load or CD4 count in the patients receiving cannabis cigarettes or dronabinol.

Experimental Evidence

No relevant data found.

Mechanism

No mechanism expected.

Importance and Management

Short-term use of cannabis cigarettes or dronabinol does not appear to have any important effect on levels of indinavir or nelfinavir, nor on markers of HIV infection.

Cannabis + Sildenafil

Myocardial infarction occurred in a man who had smoked cannabis and taken a tablet of sildenafil.

Clinical Evidence

A 41-year old man with no history of cardiac disease experienced a myocardial infarction after smoking cannabis and recreationally taking a tablet of sildenafil (strength not specified). Later tests showed that he had no evidence of inducible ischemia.

Experimental Evidence

No relevant data found.

Mechanism

Myocardial infarction is a rare adverse effect of sildenafil alone. It was suggested that the metabolism of sildenafil by cytochrome P450 isoenzyme CYP3A4 might be inhibited by constituents of cannabis such as cannabidiol, thereby increasing the risk of adverse events. However, in clinical studies, oral cannabis did not alter levels of other CYP3A4 substrates. These included Cannabis + Irinotecan, and Cannabis + Docetaxel.

Importance and Management

The vasodilatory effects of sildenafil necessitate caution in its use in patients with cardiovascular disease; myocardial infarction has rarely been associated with its use. The contribution of an interaction to this case is unclear, but bear the possibility in mind in the event of adverse effects on concurrent use.

Cannabis + Theophylline

Cannabis smokers may need more theophylline than non-smokers to achieve the same therapeutic benefits, because the theophylline is cleared from the body more quickly.

Evidence, Mechanism, Importance and Management

One study found that tobacco or cannabis smoking similarly caused higher total clearances of theophylline (given as oral aminophylline) than in non-smokers (about 74mL/kg per hour compared with 52 mL/kg per hour), and that clearance was even higher (93 mL/kg per hour) in those who smoked both. A later analysis by the same authors, of factors affecting theophylline clearance, found that smoking two or more joints of cannabis weekly was associated with a higher total clearance of theophylline than non-use (82.9 mL/kg per hour versus 56.1 mL/kg per hour).

Tobacco and cannabis smoke contain polycyclic hydrocarbons, which act as inducers of the cytochrome P450 isoenzyme CYP1A2, and this results in a more rapid clearance of theophylline from the body.

Little is known about the effects of smoking cannabis on theophylline levels, but be alert for the need to increase the theophylline dosage in regular users. Note that irregular cannabis use might cause fluctuations in theophylline levels.

Cannabis + Tricyclic Antidepressants

Tachycardia has been described when patients taking tricyclic antidepressants smoked cannabis.

Evidence, Mechanism, Importance and Management

A 21-year-old woman taking nortriptyline 30 mg daily experienced marked tachycardia (an increase from 90 to 160 bpm) after smoking a cannabis cigarette. It was controlled with propranolol. A 26 year old complained of restlessness, dizziness and tachycardia (120 bpm) after smoking cannabis while taking imipramine 50 mg daily. Four adolescents’ aged 15 to 18 taking tricyclic antidepressants for attention-deficit hyperactivity disorder had transient cognitive changes, delirium and tachycardia after smoking cannabis.

Increased heart rates are well-documented adverse effects of both the tricyclic antidepressants and cannabis, and what occurred was probably due to the additive beta-adrenergic and antimuscarinic effects of the tricyclic’s, with the beta-adrenergic effect of the cannabis. Direct information is limited but it has been suggested that concurrent use should be avoided.