Cannabis Research A-Z

 On October 15, 2004, the FDA has concluded that antidepressant medications increase the risk of suicidal thinking and behavior in children and adolescents with depression and other psychiatric disorders. If you have questions or concerns, discuss them with your health care provider

"What I remember most about being depressed was always being exhausted. I could never get to sleep at night, and when I did, I had nightmares. Then I'd wake up in the morning and have to drag myself to work. And in all that time—four or five years, I guess—I never once enjoyed anything. I was actually planning my own suicide when my doctor referred me to a psychiatrist who put me on imipramine. For the first time in years, I finally began to get some pleasure out of life."

—Sam, 43

Before the SSRIs, tricyclics were the first line of defense against encroaching depression, and had been ever since imipramine's release in 1958 under the brand name Tofranil.

Today, tricyclics are a less popular choice than the new generation of antidepressants, but they're still an important weapon in the antidepressant arsenal for a subset of people who don't respond to anything else.

Before tricyclics were developed, psychiatrists treating severely depressed clients had only two real choices: amphetamines or electroshock therapy.

Imipramine was discovered by Swiss scientists searching for a successful schizophrenia treatment; it turned out that imipramine didn't do much for schizophrenia at all. What it did do very well was perk up depressed patients.

Common Cyclic Antidepressants

Lower doses are used with elderly patients)

With the discovery of imipramine, doctors finally had a drug that relieved a person's underlying depression.

When scientists realized how effective imipramine was—about 70 percent of depressed patients responded to this drug—they flocked to the laboratories in search of similar drugs based on imipramine's three-ring ("tricyclic") antihistaminic chemical structure.

Before long, laboratories all over the country began churning out tricyclic clones, each one a little different from, but none any better than, imipramine itself.

A later-developed drug in this class, maprotiline (Ludiomil), had four rings and was therefore called "tetracyclic." Taken together, the tricyclics and tetracyclics are known as "heterocyclics" or "cyclics."

But while all these cyclics were effective, not one provided the perfect solution to depression for which scientists had been searching.

 Ankara, Turkey: Cannabinoids, when administered in combination with non-steroidal anti-inflammatory drugs (NSAIDS), produce a synergistic analgesic effect, according to preclinical data published in the February issue of the journal Anesthesia & Analgesia.

A research team at the Trakya University in Turkey investigated the analgesic interaction between cannabinoids and NSAIDS in mice. "Analysis showed additive interactions between [cannabinoids] and [NSAIDS] when they were co-administered systematically in an inflammatory visceral pain model," investigators concluded. "The combination of cannabinoids and NSAIDS may have utility in the pharmacotherapy of pain."

http://www.norml.org/index.cfm?Group_ID=6819

Cox ML, Haller VL, Welch SP

Eur J Pharmacol 2007 Apr 20.

We have shown in past isobolographic studies that a small amount of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) can enhance morphine antinociception in mice. However, previous studies of the Delta(9)-THC/morphine interaction were performed using normal mice or rats and evaluated acute thermal antinociception.

Less is known about cannabinoid and opioid interactions involved in mechanical nociception and in chronic inflammatory pain models, such as Freund's complete adjuvant-induced arthritic model. One fixed-ratio combination was chosen for testing the interaction between Delta(9)-THC and morphine in the Freund's adjuvant-induced arthritic model.

This combination represented a 1:1 ratio of the drugs and thus consisted of equieffective doses ranging from 0.1 to 5 mg/kg Delta(9)-THC and from 0.1 to 5 mg/kg morphine. The combination ED(50) value for the fixed ratios (total dose) in relation to the ED(50) value of the drugs alone was determined.

The isobolographic analysis indicated a synergistic interaction between Delta(9)-THC and morphine in both the non-arthritic and the arthritic rats.

Since Freund's adjuvant-induced alteration in endogenous opioid tone has been previously shown, our data indicate that such changes did not preclude the use of Delta(9)-THC and morphine in combination. As with acute preclinical pain models in which the Delta(9)-THC/morphine combination results in less tolerance development, the implication of the study for chronic pain conditions is discussed.

Dumont G, Kramers C, Sweep F, Touw D, van Hasselt J, de Kam M, van Gerven J, Buitelaar J, Verkes R 

Clin Pharmacol Ther 2009 May 13.

This study assessed the acute physiologic effects over time of (co)administration of Delta9-tetrahydrocannabinol (Delta9-THC) (the main psychoactive compound of cannabis) and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") in 16 healthy volunteers.

Pharmacokinetics and cardiovascular, temperature, and catecholamine responses were assessed over time.

Both single-drug conditions robustly increased heart rate, and coadministration showed additive effects.

MDMA increased epinephrine and norepinephrine concentrations, whereas THC did not affect the catecholamine response.

Coadministration of MDMA and THC attenuated the increase of norepinephrine concentrations relative to administration of MDMA alone.

These results show that THC mediates heart rate increase independent of sympathetic (catecholaminergic) activity, probably through direct cannabinoid receptor type 1 (CB(1)) agonism in cardiac tissue. Furthermore, THC coadministration did not prevent MDMA-induced temperature increase, but it delayed the onset and prolonged the duration of temperature elevation.

These effects may be of particular relevance for the cardiovascular safety of ecstasy users who participate in energetic dancing in nightclubs with high ambient temperature.Clinical Pharmacology & Therapeutics (2009); advance online publication 13 May 2009. doi:10.1038/clpt.2009.62.

Author(s)

Abstract

Δ⁹-Tetrahydrocannabinol (THC) is the active metabolite of cannabis, which has demonstrable cytotoxic activity in vitro.
In support of our previously published data, we have investigated the interactions between THC and anti-leukemia therapies and studied the role of the signalling pathways in mediating these effects.

Results showed clear synergistic interactions between THC and the cytotoxic agents in leukemic cells.

Additionally, exposure of cells to sub lethal levels of THC (1 μM) sensitised cells to these cytotoxic agents, by reducing IC₅₀ values by ∼ 50%. Sensitisation appeared to be dependent upon the ability of THC to down regulate phosphorylated ERK, as cells dominantly expressive of MEK were not sensitised to the cytotoxic drugs by equi-molar amounts of THC.

Overall, these results demonstrate for the first time that a combination approach with THC and established cytotoxic agents may enhance cell death in vitro. Additionally the MAPK/ERK pathway appears responsible in part for these effects.

Journal Title

Source / Source

2008, vol. 49, n^o9, pp. 1800-1809 [10 page(s) (article)]

Flisberg P, Paech MJ, Shah T, Ledowski T, Kurowski I, Parsons R 
Support, Non-U.S. Gov't]
Eur J Anaesthesiol 2009 Mar; 26(3):192-5.

BACKGROUND AND OBJECTIVE: An estimated 150 million people worldwide use cannabis.

The effect of cannabis on anaesthetic requirements in humans does not appear to have been studied.

METHODS: In this prospective, randomized, single-blinded study, 30 male patients using cannabis more than once per week (group C) and 30 nonusers (group NC), aged 18-50 years, were induced with propofol 1.5, 2, 2.5, 3 or 3.5 mg kg.

Additional doses were given when required. The primary outcome was the 50% effective dose of propofol and successful induction was determined by loss of consciousness with a bispectral index value of less than 60 and satisfactory insertion of a laryngeal mask. Propofol requirements to achieve these outcomes were recorded.

RESULTS: The dose required to achieve the target bispectral index value was not significantly higher in group C, but group C required a significantly higher propofol dose to achieve laryngeal mask insertion (314.0 +/- 109.3 vs. 263.2 +/- 69.5 mg, P < 0.04). The estimated effective propofol induction dose in 50-95% of patients did not significantly differ between groups.

CONCLUSION: We conclude that cannabis use increases the propofol dose required for satisfactory clinical induction when inserting a laryngeal mask.

More from this journalEuropean journal of anaesthesiolog

April 13, 2009 -- People who smoke both cigarettes and marijuana have a greater risk for developing the progressive lung disease COPD than cigarette smokers who don't smoke pot, a new study shows.

Smokers in the study who reported using both tobacco and marijuana were three times as likely as nonsmokers to have clinically confirmed COPD (chronic obstructive pulmonary disease); people who smoked only cigarettes had a slightly lower risk.

The study is among the first to suggest a synergistic relationship between marijuana and tobacco use among older people who are most at risk for COPD.

"This effect suggests that smoking marijuana may act as a primer, or sensitizer, in the airways to amplify the adverse effects of tobacco on respiratory health," says study researcher Wan C. Tan, MD, of the University of British Columbia and St. Paul's Hospital in Vancouver, Canada.

COPD Risk

About 12 million Americans are currently living with a diagnosis of COPD; an equal number are believed to have the disease and not know it, according to the National Heart, Lung and Blood Institute.

In the U.S, the term COPD includes both emphysema and chronic bronchitis. With COPD, breathing becomes more difficult over time.

Largely caused by cigarette smoking, COPD is the fourth leading cause of death in the U.S.

While the link between tobacco and COPD is well established, far less is known about the impact of marijuana use on the lungs.

Some studies have found that even short-term heavy marijuana smoking can worsen lung function, while others have not shown this association.

Even less is known about the combined effects of smoking cigarettes and pot, Tan tells WebMD.

The study by Tan and colleagues included 878 residents of Vancouver, Canada participating in a larger investigation examining COPD prevalence.

Participants were considered tobacco smokers if they had smoked at least 365 cigarettes in their lifetime, and were considered marijuana smokers if they reported having ever smoked pot. The researchers defined "substantial" marijuana use as having smoked at least 50 marijuana cigarettes.

The average cigarette smoker in the study had smoked for 16 years, while the self-described pot smokers had smoked an average of 84 marijuana cigarettes.

When COPD was clinically confirmed though a diagnostic method known as spirometric testing:

• The incidence of COPD among participants who smoked cigarettes alone was 2.7 times higher than among nonsmokers.
• The incidence of COPD was 2.9 times higher among participants with a history of smoking both cigarettes and pot, even after controlling for other risk factors for the pulmonary disease.
• COPD risk among people who smoked marijuana, but not tobacco, was slightly higher than among nonsmokers, but the increase was not statistically significant.

The study appears in the April 14 issue of the Canadian Medical Association Journal.

Yamreudeewong W, Wong HK, Brausch LM, Pulley KR 
Probable Interaction Between Warfarin and Marijuana Smoking (July/August). [JOURNAL ARTICLE]
Ann Pharmacother 2009 Jun 16.

OBJECTIVE: To report a probable interaction between warfarin and marijuana smoking, resulting in increased international normalized ratio (INR) values and bleeding complications.

CASE SUMMARY: A 56-year-old white male had been receiving chronic warfarin therapy for 11 years after mechanical heart valve replacement. He was admitted to the hospital with a diagnosis of upper gastrointestinal bleeding. Upon admission, his INR value was supratherapeutic at 10.41, and his hemoglobin level was 6.6 g/dL.

He received 4 units of fresh frozen plasma and one 10-mg dose of oral vitamin K; his INR was 1.8 the next day. He was discharged 7 days after admission. Fifteen days after hospital discharge, he was readmitted with a constant nosebleed and increased bruising.

His INR value was 11.55. After treatment, he was discharged with an INR value of 1.14. The patient smoked marijuana more frequently throughout the period of these 2 hospitalizations due to his depression.

He was counseled by the pharmacist on the potential interaction of warfarin and marijuana. The patient decided to stop smoking marijuana after the third counseling session. During the 9 months that he did not smoke marijuana, his INR values ranged from 1.08 to 4.40 with no significant bleeding complications.

DISCUSSION: Marijuana may increase warfarin anticoagulant effect by inhibiting its metabolism, and to a lesser extent, displacing warfarin from protein-binding sites. Other causes (eg, nonadherence) of the patient's increased INR were ruled out. Using the Horn Drug Interaction Probability Scale, our patient's warfarin- marijuana interaction appeared to be probable.

CONCLUSIONS: To our knowledge, there have been no other reported cases of warfarin-marijuana interaction.

While more clinical reports would be useful to confirm this interaction, clinicians should be aware of its probability so as to manage patients appropriately.

The Annals of pharmacotherapy [Ann Pharmacother]

Clin Pharmacol Ther. 2009 Aug;86(2):160-6. Epub 2009 May 13

Int Rev Psychiatry. 2009 Apr;21(2):143-51

Abstract

Flisberg P, Paech MJ, Shah T, Ledowski T, Kurowski I, Parsons R 
Research Support, Non-U.S. Gov't]
Eur J Anaesthesiol 2009 Mar; 26(3):192-5.

BACKGROUND AND OBJECTIVE:

An estimated 150 million people worldwide use cannabis. The effect of cannabis on anaesthetic requirements in humans does not appear to have been studied.

METHODS:

In this prospective, randomized, single-blinded study, 30 male patients using cannabis more than once per week (group C) and 30 nonusers (group NC), aged 18-50 years, were induced with propofol 1.5, 2, 2.5, 3 or 3.5 mg kg.

Additional doses were given when required. The primary outcome was the 50% effective dose of propofol and successful induction was determined by loss of consciousness with a bispectral index value of less than 60 and satisfactory insertion of a laryngeal mask.

Propofol requirements to achieve these outcomes were recorded.

RESULTS:

The dose required to achieve the target bispectral index value was not significantly higher in group C, but group C required a significantly higher propofol dose to achieve laryngeal mask insertion (314.0 +/- 109.3 vs. 263.2 +/- 69.5 mg, P < 0.04).

The estimated effective propofol induction dose in 50-95% of patients did not significantly differ between groups.

CONCLUSION:

We conclude that cannabis use increases the propofol dose required for satisfactory clinical induction when inserting a laryngeal mask.

 European journal of anaesthesiology