October 19, 2010

Prop 19 health effects, pot and antidepressants, marijuana potency, stay high longer, CYP inhibitors, The Downside of High

I am not a doctor. I have no medical training. Medical information is provided with no guarantee of its accuracy. The information in this post was gathered online.

Let me start by saying this. The liver is a vital organ, necessary for survival. The liver is the organ that gets rid of most drugs and toxins and xenobiotics that people ingest. Cytochrome P450 (CYP) enzymes are the major enzymes involved in drug metabolism, accounting for about 75% of total drug metabolism. Most CYP enzymes catalyze the oxidation of organic substances. CYP enzymes in humans are located in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. CYP enzymes play an important role in the breakdown of drugs and toxins and are present in most tissues of the body. The smooth endoplasmic reticulum in liver cells is the main location of drug metabolism. There are at least 57 genes in humans that code for various CYP enzymes. CYP enzymes have been found in all kingdoms of life.

I mention a lot of different drugs in this blog post. Some people may be curious about experimenting with various drugs I mention. If you're planning on mixing drugs with marijuana (or mixing drugs in general) — know your dose, know your limits, know the drug interactions. Certain drug combinations or overdosing on certain drugs can cause hepatotoxicty and liver failure and death. Wikipedia says 50% of all acute liver failures and 5% of all hospital admissions are due to drug-induced liver injury. Acetaminophen (Tylenol, Paracetamol) is the most common cause of acute liver failure in the US, and causes three times as many cases of liver failure as all other drugs combined. While 25% of a liver can regenerate into a whole liver (the liver is the only internal organ in humans that can naturally regenerate lost tissue), a liver transplant is the only option for people with irreversible liver failure.

Using marijuana while taking a prescribed dose of one other medication may not cause liver injury, but there can definitely be unexpected side effects. Also, if someone uses marijuana and two or more additional substances, those substances could potentially cause liver injury. If you're taking medications or other drugs, research online, or better yet, ask a doctor or pharmacist before using marijuana (or any other drugs or substances -- even things like fruit juices can have harmful interactions with certain drugs).

Now that that's out of the way, back to my post.

Table of Contents
  1. Prop 19 health effects
  2. cannabinoids
  3. marijuana strains high in CBD
  4. marijuana strains high in THC
  5. marijuana concentrate potency
  6. THC metabolism
  7. stay high longer
  8. marijuana and antidepressants
  9. CYP inhibitors
  10. CYP2C9 inhibitors
  11. CYP2C19 inhibitors
  12. CYP2D6 inhibitors
  13. CYP3A4 inhibitors
  14. schizophrenia
  15. The Downside of High
  16. dronabinol
  17. dronabinol drug interactions
  18. other drugs that contian THC or CBD
  19. marijuana interactions
  20. experience reports
  21. search ideas
  22. books

Prop 19 health effects

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On October 5, 2010, an article about marijuana's health effects appeared in the Los Angeles Times, written by Itai Danovitch, a member of the California Society of Addiction Medicine's Committee on Public Policy, and assistant professor of psychiatry and behavioral neurosciences at Cedars-Sinai Medical Center.

He wrote that the health risks of marijuana are often overlooked in the debate over marijuana legalization. He referred to a RAND study which said legalization will almost certainly lead to a price drop for weed, and increased usage. He said increased use means increased health risks. The California Society of Addiction Medicine is concerned that the Prop 19 initiative spreads misinformation in its text. Prop 19 says, in the Findings section, that "Cannabis is not physically addictive, does not have long term toxic effects on the body..." Danovitch wrote that about 9% of adults who use cannabis develop an addiction to it (about 1/11 people). Among people who start smoking pot before 18, as much as 17% of them develop an addiction to it (about 1/6 people). Danovitch said that marijuana addiction doesn't cause dramatic physical dependence, but it can lead to problems regarding work, relationships, and education. Addiction is defined "by the inability to stop using despite recognition of harmful consequences."

Danovitch wrote that short-term, cannabis intoxication impairs memory and learning. It also causes a two to three-fold increase in accidents. He wrote "Though not as dramatic as the fifteenfold increase in accidents caused by alcohol intoxication, marijuana's impact on traffic safety does have significance." He said smoked marijuana can lead to respiratory inflammation and bronchitis. He said smoked cannabis has been linked to precancerous changes in the lungs, although it has not definitively been shown to cause cancer.

Danovitch wrote that long-term, marijuana use can reveal pre-existing vulnerabilities to schizophrenia. He said that there is evidence that over time, marijuana use may actually make anxiety and depression worse. He said the toll of long-term cannabis use appears to be the greatest among people who start smoking during adolescence, while the brain is still maturing. He wrote that there is evidence that brain processing of highly complex information is slowed. He said long-term marijuana users abstaining for 28 days and undergoing brain scans showed less activity in brain regions for learning and memory. Although long-term cannabis use hasn't been shown to reduce intelligence.

Danovitch said that there is widespread consensus among treatment professionals that incarcerating people for use/possession is wrong, and that a different policy is long overdue. But "we need to anticipate and deal with the consequences of our policy decisions." He wrote that with legalization, there will be an increased necessity for drug treatment services, drug education, and drug prevention programs.

He wrote that "although marijuana is less hazardous to health than many other legal or illegal drugs, it is not without risk, and voters and potential users need to fully understand this." He said voters need to vote based on accurate facts. He wrote that if Prop 19 passes, Californians should insist that revenue from weed taxes goes toward "any problems that arise from increased usage."

On October 9, 2010, an article by Shari Roan in the Los Angeles Times discussed the potential fallout on people's health if Prop 19 passes.

She wrote about Carol McDonald who was supposedly addicted to marijuana for 19 years. A few months after she smoked weed for the first time in 1969, she was smoking it every day. She smoked before going to work, she smoked if she was upset, she smoked for celebrations. Roan wrote that there has been scant "discussion on the potential fallout on people's health" if Proposition 19 passes. Roan wrote that addiction counselors in California are split on Prop 19, yet public health experts nationally are mostly against legalization (which they say will increase the number of addicts, contribute to more automobile accidents, and harm school performance).

People for and against legalization can both point to studies on marijuana's health effects that support their position. Roan wrote they agree that marijuana should be avoided during pregnancy (however, some pro-legalization advocates may point to a study on pregnant Jamaican mothers regarding that), and that marijuana is harmful for people with mental illness or who are at risk for developing a serious mental illness like schizophrenia. (However, some people tend to think that marijuana can help people with mental illnesses, or that people with mental illnesses or are pre-disposed to mental illnesses use marijuana to self-medicate.)

Roan said that federal data shows that marijuana is addictive for about 9% of adults who use it (vs 15% for people who use alcohol and 15% who use cocaine). She wrote that marijuana dependence is more common in America than addiction to cocaine or heroin because marijuana is the most widely used illegal substance in the country.

Roan wrote about a study published in 1998 by the National Highway Traffic Safety Administration which found that the effects of cannabis alone on driving "were small or moderate, but severe when combined with alcohol." But a study published in the journal Accident, Analysis and Prevention in 2004 showed "no increased risk of motor vehicle accidents causing traumatic injury among drivers using marijuana." [Anecdotally, many marijuana users say they drive better under the influence of marijuana.]

She said that experts widely disagree on the overall cognitive effects of marijuana. Dr. Tim Cermak said that among 14 and 15-year-olds who start smoking weed, 17% will be dependent within 2 years. Cermak said that adolescent marijuana use could impact their life permanently, saying "When you take a vacation from development in school for five years, you just don't get to the same endpoint that was available to you earlier in life."

Roan said that nobody knows how many more people will try weed if Prop 19 passes. She said some experts predict a 50% increase but others say the numbers are unlikely to increase since California's medical marijuana laws already make pot easy to get. Stephen Gutwillig, the California director of the Drug Policy Alliance, says "it's a vast exaggeration that more people will take this up." [But none of that speaks to increases in usage by people who reside outside of California, in the US and other countries.] Stephen Gutwillig also said you can't overdose on marijuana. [I think he meant to say that there have been no reported overdoses from people smoking unadulterated cannabis. However, it *is* possible to overdose on concentrated THC.]

Among the California Society of Addiction Medicine members, over 66% believe marijuana addiction will increase if Prop 19 passes. And nearly 70% believe there will be increased use by adolescents. The association takes no position on Prop 19, but their website lists controls that should be enacted if marijuana is legalized, such as: advertising/marketing rules, warning labels, fees and taxes from sales to fund marijuana addiction treatments, treatment instead of legal punishment for adolescent users, restrictions to minimize minors' access to marijuana, and periodic evaluation of the law's effects on public health and people driving intoxicated.

Cermak said Prop 19 lacks many of those safeguards and that the initiative's assertion that pot is not physically addictive is a myth.

Carol McDonald had a $5,000/year pot habit and chronic bronchitis. She tried to quit many times over the years but short periods of abstaining were following by relapses. After several months without using, her depression without marijuana was so great she tried to kill herself by taking "every pill in the house" at age 42. Five years later she checked into a rehab program in St. John's Hospital and smoked her last joint in the car on the way there.

Erowid lists several health effects of cannabis.

cannabinoids

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Wikipedia says the cannabis plant produces cannabinoids "when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBG (cannabigerol)."

This 2005 study cites a 1998 study that says CBGA, a precursor of THCA, is a product of the "alkylation of olivetolic acid with geranyl pyrophosphate by an enzyme called geranylpyrophosphate:olivatolate geranyltransferase."

Wikipedia says then two separate synthase enzymes convert CBG to either CBD or CBC. CBD is then enzymatically cyclized (undergoing a chemical reaction where one part of a molecule becomes linked to another to form a closed ring) to THC.

Wikipedia says CBD has shown sedative effects in animal tests, although some research shows CBD can increase alertness. CBD can relieve anxiety, nausea, convulsions, inflammation, and inhibit cancer growth. CBD can be used as an atypical antipsychotic to treat schizophrenia. CBD may also relieve dystonia (a movement disorder where sustained muscle contractions cause abnormal postures or twisting and repetitive moments). CBD can make people more sociable. CBD acts an an indirect antagonist of cannabinoid agonists and has no affinity for the CB1 or CB2 receptors. CBD has also been shown to act as a 5-HT1A receptor agonist, which gives it antidepressant, anti-anxiety, and neuroprotective effects. Wikipedia says under acidic conditions, CBD cyclizes to THC. Wikipedia says cannabis uses the same metabolic pathway to produce CBD and THC, until the last step when CBDA synthase performs catalysis instead of THCA synthase.

On October 11, 2010, an article by Jonah Lehrer was published on Wired.com entitled "Why Are the Effects of Marijuana So Unpredictable?". He wrote that cannabis "can trigger dramatically different symptoms depending on the strain and context" unlike alcohol, which has mostly predictable effects. He said that the THC/CBD ratio seems to be a key variable.

He linked to an article on Nature.com about a study published in the British Journal of Psychiatry which suggested that CBD can mitigate THC's impact on memory formation. People who smoked marijuana low in CBD (under 0.14%) were significantly worse at remembering text than when sober. People who smoked marijuana high in CBD (over 0.75%) showed no such impairment.

Lehrer wrote "it's very difficult to generalize about the effects of most drugs." He said marijuana can relax people, make them paranoid, cause uncontrollable laughter, lead to runaway anxiety. He said that one's mental state when using can profoundly influence the outcome. (Indeed. Timothy Leary coined the term "set and setting" in the 1969 book The Psychedelic Experience: A Manual Based on the Tibetan Book of the Dead.)

Lehrer also linked to research about endocannabinoids in rough-skinned newts. The researchers hypothesis was endocannabinoids "might be involved in coordinating multiple physiological and behavioral functions during acutely stressful events."

Lehrer wrote "Too often, we forget that drugs work their magic on a brain that's never the same", and concluded that it shouldn't be very surprising that cannabis (which has over 2,000 strains and) which has various THC/CBD ratios which act on "context-dependent neural pathways" would have such a wide variety of effects on people. Furthermore, at least 85 cannabinoids have been found in marijuana.

On a related note, in March 2010 an article appeared on webmd.com entitled Longtime Pot Smoking May Raise Psychosis Risk with the sub-title "Longtime Marijuana Users More Likely to Report Hallucinations." The article referred to a study published in the May 2010 issue of the Archives of General Psychiatry which involved 3,801 young adults. Researchers asked young adults up to 21 years old who were born between 1981 and 1984 about their pot use. 14.3% has smoked pot for 6 or more years. Researchers wrote that young adult who had 6 or more years since they first smoked weed were twice as likely to develop a non-affective psychosis (such as schizophrenia or delusional disorder) compared to those who had never used weed. Also, young adults who had at least 6 years since they first smoked weed were 4 times as likely to have high scores on a measure of delusionary experiences.

I've read elsewhere that THC can have psychotic effects and CBD can have anti-psychotic effects. I've read that Cannabis indica strains have higher CBD and lower THC levels than Cannabis sativa strains. Indica effects include a lethargic heavy body stone, a "couchlock" effect. I've read that CBD can have a sedative effect, and that CBD tends to postpone the beginning of a high but can make it last twice as long. A high THC content can cause a cerebral high, increased pulse, and lead to paranoia.

marijuana strains high in CBD

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Incidentally, Harborside Health Center in Oakland offers strains that are high in CBD for patients who want the anti-inflammatory and anti-spasm effects of cannabis but not the "high" that THC offers. (Elemental Wellness might also carry CBD-rich products.)

The following are advertised products at Harborside Health Center in Oakland with high CBD content (sorted by highest reported CBD %):
  • True Blueberry x OG Kush, 5.26%/12.75% THC/CBD as of 7/29; 5.26%/12.71% THC/CBD as of 7/29, 8/4, 8/6; 5%/12.5% THC/CBD for $17/g, $60/8th as of 7/30, 7/31; 4.9%/9.7% THC/CBD as of 5/19, 5/20, 5/21, 5/24
  • Harlequin, 5.72%/9.54% THC/CBD as of 8/19, 8/20, 8/23, 8/24, 8/25, 8/26, 8/27; 5.2%/8.4% THC/CBD as of 6/24, 6/28, 6/29, 6/30, 7/1, 7/2, 7/3, 7/5, 7/6, 7/7, 7/8, 7/9, 7/12
  • Incredible Romulan Rx, 4.84%/9.12% THC/CBD as of 7/13, 7/14, 7/15, 7/16, 7/19, 7/20, 7/21, 7/22, 7/23; 5.66%/6.97% THC/CBD as of 10/7, 10/8, 10/11, 10/12, 10/13, 10/14; 3.22%/5.59% THC/CBD for $13/g, $40/8th as of 9/16, 9/17, 9/20, 9/21
  • Incredible Romulan, 4.8%/9.4% THC/CBD as of 6/9, 6/10, 6/11, 6/14, 6/15, 6/16, 6/17, 6/18, 6/21, 6/22
  • Rx Red, 9.6%/9.04% THC/CBD as of 6/1, 6/2, 6/3, 6/4, 6/7, 6/8; 8.77%/7.57% THC/CBD as of 9/22, 9/23, 9/24, 9/28, 9/29, 10/1, 10/5, 10/6
  • Jamaican Lion, 5.54%/8.91% THC/CBD as of 6/15, 6/16, 6/17, 6/18, 6/21, 6/22, 6/23
  • Stinky Purple, 7.3%/8.1% THC/CBD for $13/g, $40/8th, $240/oz as of 7/1, 7/2, 7/3, 7/5
  • Rx (HHCSJ), 4.7%/7.75% THC/CBD for $15/g, $50/8th, and $325/oz as 10/11
  • Soma A+, 8.59%/7.25% THC/CBD as of 7/27, 7/28, 7/29, 7/30, 7/31; 6.6%/6.31% THC/CBD as of 5/24; ; 7.3%/4.88% THC/CBD as of 8/31, 9/1, 9/2, 9/3, 9/6, 9/7, 9/8, 9/9, 9/10
  • Trainwreck Bubble, 43.81%/5.8% THC/CBD for $25/g as of 7/20; 51.23% THC for $30/g as of 6/22, 6/23, 6/24, 6/28, 6/30, 7/1
  • CBD-Rich Glycerine Tincture for $20 as of 10/6, 10/7, 10/8

Romulan is a well-known medical marijuana strain. The "Incredible Romulan Rx" which Harborside sells might be Rx which is Romulan x Fucking Incredible. It might be Romulan x Rx.

On July 21, 2010, an article by Charles Manley entitled "Marijuana Facts: Health Impacts of California's Legalization Proposal" was published on Associated Content. Associated Content lets anyone publish their own original content on any topic. His article later appeared on Yahoo! News on October 14, 2010.

On September 20, 2010 a blog post by Matt Coker entitled "Dueling Sides on Prop 19 Trot Out Research" appeared on OC Weekly. He referred to statements by the Community Anti-Drug Coalitions of America, as well as statements by its chairman and CEO retired General Arthur T. Dean. The CADCA opposes Prop 19. CADCA said "After years of decline marijuana use among adolescents has been slowly climbing up again because fewer kids see it as harmful and more view it as socially acceptable." CADCA said "Since research shows a direct link between a decrease in perception of harm and social disapproval and an increase in drug use, there is no doubt that Proposition 19 will only lead to more marijuana use among youth." Dean said "Marijuana already costs the United States $181 billion annually in increased health care and treatment costs, crime and lost productivity. So any revenue gained by taxing marijuana would be far outweighed by the healthcare and criminal justice costs to the state."

The Marijuana Policy Project said the FBI's Uniform Crime Report shows that over half of all US drug arrests in 2009 were for marijuana. And that the National Survey on Drug Use and Health shows that 16.7 million people in the US used marijuana in the past month, an increase of 8%.

Coker wrote that MPP executive director Rob Kampia said "decades of law enforcement efforts have absolutely failed to reduce marijuana's use or availability, and that it's simply an exercise in futility to continue arresting hundreds of thousands of Americans for using something that's safer than alcohol."

Coker ends by noting that the California Beer and Beverage Distributors association, and the California Police Chiefs Association and the California Narcotics Officers Association, are opposed to Prop 19. Coker concludes "All they need now is for Mexican drug cartels to join them and the holy alliance will be complete." As far as I know, no drug cartels have come out in opposition to Prop 19, and a recent RAND study stated that Prop 19 would not cripple drug cartels (I'll write more on that in a later blog post).

On October 12, 2010, a blog post by Jann Gumbiner, Ph.D. appeared on Psychology Today entitled "Does Marijuana Impair Cognition? Implications for Prop 19".

She wrote that when deciding to vote yes on Prop 19, police consider criminal consequences, lawyers consider legal consequences, businesspeople consider financial consequences, and "I think through the health implications and even more specifically, the mental health implications." She wrote that cannabis has helped thousands of cancer patients cope with pain, eat better, and sleep better. Then asked "Does marijuana impair cognition?"

She referred to a 2001 study published in Nueropsychopharmacology by Hart, et al called Effects of Acute Smoked Marijuana on Complex Cognitive Performance. Experienced users were given single joints with 0% or 1.8% or 3.9% THC, provided by NIDA. The subjects then took a computerized test called The Micro-Cog, a standardized test that measures attention, memory, reaction time, digital recall, mental calculation, visuospatial processing, etc. Subjects given 0% or 1.8% or 3.9% THC were compared by cognitive ability. People who smoked 3.9% THC gave accurate math answers, but it took them longer. She said that "slowed reaction time is consistent with anecdotal observations."

Gumbiner wrote that smokers should not drive. [Prop 19 itself does not allow cannabis consumption by the operator of any vehicle while its being operated.] She did say that "this one small study implies that there are no serious cognitive effects to getting high" and that "I can find no health reason justifying criminalizing marijuana." But THC levels over 3.9% are quite common nowadays.

marijuana strains high in THC

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The following are reported THC levels for various cannabis strains according to various online seedbanks (I've linked to strain pages at Seedfinder, but THC % comes from seedbanks). These are the marijuana strains with the highest THC levels I could find:

Wikipedia says some strains of cannabis contain as much as 29% THC.

The following are some advertised THC levels for several cannabis strains via Twitter at Harborside Health Center in Oakland (and Harborside San Jose), which are lab tested by Steep Hill Lab (sorted by highest THC report):
  • 25.72% Strawberry Cough, as of 5/14; 16.59% as of 6/22; 16.50% as of 6/3, 6/4, 6/14; 14.26% as of 5/17, 5/18, 5/19, 5/20, 5/21
  • 24.40% Jack's Haze, as of 9/22; 15.54% as of 9/16, 9/17; 15.49% as of 9/2; 15.4% as of 7/14, 7/15, 7/16; 15.25% as of 7/31; 14.5% as of 5/18, 5/19; 13.31% as of 6/14, 6/15
  • 23.60% Super Silver Haze, as of 10/11; 19.19% as of 9/6; 18.89% as of 9/20; 18.09% as of 8/6; 16.79% as of 10/5, 10/6; 16.0% as of 6/28; 14.5% as of 5/24
  • 22.74% Chem Dawg 4, as of 7/12; 22.7% as of 7/7; 21.54% as of 6/23; 21.53% as of 6/7, 6/23; 19.8% as of 7/15; 18.7% as of 9/23; 18.5%
  • 22.50% Hawaiian Sativa, as of 5/18, 5/19
  • 19.65% Headband, as of 7/21; 17.8% as of 8/23, 8/24; 16.97% as of 5/28, 5/29; 16.63% as of 7/1, 7/2; 16.05% as of 6/28, 6/29; 15.5% as of 9/2, 9/3, 9/6; 14.2% as of 6/18; 14% as of 7/12; 13.31% as of 6/21, 6/23; 11.6% as of 5/21
  • 19.63% XJ-13, as of 9/23, 9/29; 16.58% as of 10/11, 10/12; 14.8% as of 8/31, 9/1, 9/2, 9/3; I've also seen 16.6% and 15.9% on budreviews.com
  • 19.24% Tahoe OG, as of 5/20; 18.49% as of 9/24; 16.83% as of 6/3, 6/4; 16.73% as of 10/1, 10/5, 10/6; 16.56% as of 7/7, 7/8; 16.53% as of 6/8; 15.00% as of 6/11; 14.9% as of 6/21
  • 19.21% Chem Dawg '91, as of 9/9, 9/10; 16.55% as of 7/21; 14.25% as of 6/18
  • 18.50% Dream Queen, as of 9/23; 16% as of 9/16; 15.22% as of 6/3; 13.4% as of 8/19; 12.2% as of 5/17; (I've read this is also known as Green Crack)
  • 18.40% Velvet Kush, as of 6/23
  • 17.60% Sour Headband, as of 7/20, 7/21; 16.5% as of 6/2, 6/3, 6/4
  • 17.51% White Rhino, as of 10/6, 10/7; 16.13% as of 9/9, 9/10; 16.08% as of 9/22, 9/23; 15% as of 7/14
  • 17.36% OG Kush, as of 8/20; 16.86% as of 9/21; 16.62% as of 8/27; 16.30% as of 7/27, 7/28; 16.27% as of 9/16, 9/17; 16.5% as of 7/30, 7/31; 15.86% as of 6/24; 15.37% (Fire OG Kush) as of 7/14; 14.80% as of 6/1, 6/12; 14.0% (Intensive Care OG Kush) as of 9/28; 13.94% as of 6/18; 13.76% as of 5/28, 5/29; 13.4% as of 6/17; 13.18% as of 10/7, 10/8
  • 17.30% Skywalker OG, as of 6/9, 6/10; 15.76% as of 9/1, 9/2, 9/3; 15.21% as of 9/21, 9/22, 9/23
  • 17.24% The White, as of 9/17; 15.96% as of 8/31, 9/1
  • 17.24% Pineapple Kush, as of 6/24; 16.8% as of 6/1, 6/2; 16.32% as of 5/26; 14.53% as of 7/7, 7/9, 7/13; 14% as of 9/24, 10/1, 10/5
  • 17.21% Ultraviolet, as of 7/23
  • 17.04% Dutch Treat, as of 10/7; 17.03% as of 7/13, 7/14; 15.79% as of 9/20, 9/21; 15.37% as of 9/29; 14.50% as of 5/26, 5/27; 13.81% as of 5/13, 5/14
  • 16.80% Jack Pot (Jack Herer x Super Silver Haze), as of 6/24; 15.2% as of 7/28
  • 16.45% Blackberry Kush, as of 8/27; 15% as of 7/27, 7/28, 7/29; 14.4% as of 6/7, 6/8; 11.6% as of 5/13, 5/13, 5/17
  • 16.20% Spicy Jack, as of 10/5, 10/6, 10/7
  • 16.17% Double Sour Diesel, as of 7/15; 16.16% as of 10/13, 10/14; 15% as of 7/31; 12.8% as of 7/30
  • 16.04% Tangerine Kush, as of 9/20, 9/21, 9/22; 14.62% as of 10/1, 10/5
  • 15.62% East Coast Sour Diesel, as of 10/1; 15.34% as of 9/20, 9/21, 9/22, 9/23, 9/24; 15% as of 6/8; 12.56% as of 5/26, 5/27, 5/28, 5/29
  • 14.73% Grape, as of 6/28, 6/29, 6/30; 14.7% as of 6/21, 6/22; 14.53% 9/20, 9/21, 9/22, 9/23, 9/24; 13.45% as of 6/8, 6/9, 6/10, 6/11; 12.56% as of 7/9; 12.4% as of 5/13, 5/14, 5/17
  • 14.46% Master Kush, as of 6/22, 6/23; 13.01% (Intensive Care Master Kush) as of 9/1, 9/2, 9/3
  • 13.92% 707 Headband, as of 6/3, 6/4; 13.26% as of 8/31, 9/1

Those are all strains that Harborside patients grew at home and sold to Harborside.

marijuana concentrate potency

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The following are some advertised THC levels for several concentrates, hash, oil, melts, and other products via Twitter at Harborside Health Center in Oakland (and Harborside San Jose), which are lab tested by Steep Hill Lab:
  • 74.69% Chem Dawg Oil, $40/g as of 9/1, 9/2, 9/3
  • 71.72% Chem Dawg 4 Oil, $30/g as of 9/22, 9/23, 9/24; 69.05% $30/g as of 9/17; 68.68% $50/g as of 6/2, 6/3; 68.68% $50/1.4g as of 6/4, 6/7, 6/8, 6/9, 6/10, 6/11
  • 71.02% Purple Oil, $30/g as of 9/6, 9/7, 9/8; 51.36% $40/g as of 10/14
  • 69.21% THC Gold, $35/0.5g or $60/g as of 6/17, 6/18, 6/21, 6/22, 6/23, 6/24, 6/28, 6/29, 6/30, 7/1, 8/31, 9/1, 9/2, 9/3, 9/6, 9/7, 9/8, 9/9, 9/10, 9/17, 9/20, 9/21, 9/22, 9/23, 9/24, 9/28, 9/29, 10/1; 61.82% $30/0.5g or $60/g as of 7/8, 7/9, 7/12, 7/13, 7/14, 7/15, 7/16, 7/19, 7/20, 7/21, 7/22, 7/23, 7/27, 7/28, 8/4, 8/19, 8/20, 8/23, 8/24, 8/25, 8/26, 8/27
  • 69.06% Purple Dream Oil, $30/g as of 10/5, 10/6, 10/7, 10/8
  • 67.95% Blackberry Kush Oil, $30/g as of 10/11, 10/12, 10/13, 10/14
  • 66.43% MK ULTRA Oil (SJ), $30/g as of 10/10
  • 66.27% Purple Oil (SJ), $30/g as of 10/10
  • 65.19% Dream Queen Oil, $40/g as of 9/17, 9/20, 9/21, 9/22, 9/23, 9/24, 9/28, 9/29
  • 63.44% Skywalker CO2 Melt (SJ), $45/g as of 10/10
  • 61.17% Blue Dream Super Melt, $50/g as of 8/24, 8/25, 8/26, 8/26; 54.74% $50/g as of 10/5, 10/6, 10/7, 10/8
  • 60.30% Jack Herer Super Melt, $50/g as of 6/1, 6/2, 6/3; $45/g as of 6/4, 6/7, 6/8, 6/10, 6/10, 6/14, 6/15, 6/16, 6/17, 6/18, 6/21, 6/22, 6/23, 6/24
  • 59.00% Headband Super Melt, $40/g as of 6/17, 6/18; 52.51% $40/g as of 7/8, 7/9, 7/12, 7/13, 7/14
  • 57.46% Velvet Kush Bubble, $30/g as of 8/4
  • 56.93% Afgooey Super Melt, $50/g as of 6/17, 6/18, 6/21, 6/23, 6/24, 6/28, 6/29, 6/30, 7/1, 7/2, 7/5, 7/6, 7/7, 7/8, 7/9, 7/12, 7/13, 7/14, 7/15, 7/16, 7/19, 7/20, 7/21, 7/22, 7/23, 7/27, 7/28, 8/4 ($35/g), 8/19, 8/20; 51.11% $45/g as of 10/11, 10/12, 10/13, 10/14
  • 56.09% Velvet Kush Hash, $20/g as of 10/5; 44.56% and $25/g as of 10/14
  • 54.37% Nitro Gold, $50/g as of 9/20, 9/21, 9/22, 9/23, 9/24, 9/28, 9/29, 10/1, 10/5, 10/6, 10/7, 10/8, 10/11, 10/12, 10/13, 10/14; 50% $50/g as of 6/29, 6/30, 7/1, 7/2, 7/6, 7/7, 7/8, 7/9
  • 54.26% Jack Flash Super Melt, $45/g as of 10/5, 10/6, 10/7, 10/8, 10/11, 10/12, 10/13, 10/14
  • 54.07% Space Queen & Pandora's Box Super Melt, $50/g as of 9/20, 9/21, 9/22, 9/23, 9/24
  • 53.90% Master Kush Oil, $35/g as of 8/4
  • 53.37% Kushage Full Melt, $35/g as of 9/17, 9/20, 9/21, 9/22, 9/23, 9/24, 9/28, 9/29, 10/1
  • 52.61% Blackberry Kush Super Melt, $50/g as of 9/28, 9/29, 10/1
  • 52.57% Kush Bubble Hash, $20/g as of 9/21, 9/22, 9/23, 9/24
  • 52.50% Headband Oil, $40/g as of 7/28
  • 52.10% OG Kush Bubble, $20/g as of 7/27; 47.37% $30/g as of 9/9
  • 51.44% Headband Bubble Hash, $25/g as of 9/28
  • 50.52% Skywalker OG Bubble, $25/g as of 8/31
  • 50.52% OG Kush x Sweet Tooth Full Melt, $35/g as of 9/20, 9/21, 9/22, 9/23, 9/24
  • 50.06% Durban Bubble, $30/g as of 9/28, 9/29, 10/1, 10/5
  • 48.60% Super Silver Haze Bubble, $20/g as of 9/1
  • 48.35% Sour Cream Oil (SJ), $35/g as of 10/10
  • 48.18% Headband Full Melt, $30/g as of 10/8, $35/g as of 10/12
  • 47.73% Purple Dream Queen Oil, (tastes like ruby red grapefruit), $40/g as of 8/19, 8/20, $35/g as of 9/7, 9/8, 9/9, 9/10
  • 46.56% Blackberry Kush Full Melt, $35/g as of 5/19
  • 46.21% Master Kush Bubble Hash, $25/g as of 9/29
  • 45.42% Dream Queen Hash, $15/g as of 7/23
  • 45.16% U2 Melt (SJ), $35/g as of 10/10
  • 45.15% Headband Hash, $10/g as of 9/22, 9/23, 9/24; 40.36% $25/g as of 10/5, 10/6, 10/7, 10/8, 10/11, 10/12, 10/13; 40.36% $20/g as of 10/13; 38.39% $15/g as of 9/2, 9/3; 36.16% $15/g as of 8/26, 8/27
  • 44.91% Purple Dragon Bubble Hash, $25/g as of 10/11
  • 44.03% OG Kush Full Melt, $35/g as of 5/19
  • 44.03% Chocolate Chunk Melt (SJ), $35/g as of 10/10
  • 42.13% GDP Hash, $10/g as of 9/29; 37.73% $15/g as of 10/11, 10/12, 10/13, 10/14; 37.44% $15/g as of 7/5; 34.44% $15/g as of 7/3; 29.35% $15/g as of 7/13, 7/14; 27.57% $15/g as of 10/5, 10/6, 10/7, 10/8
  • 41.60% AK-47 Hash, $15/g as of 9/23, 9/24; 37.79% $10/g as of 10/5
  • 38.96% OG Kush Kief, $10/g as of 10/14
  • 36.63% White Rhino Gold Bud, (bud covered in concentrate), as of 8/27
  • 33.64% Headband Honey Bud, $35/g as of 7/8, 7/9
  • 25.70% Chem Dawg 4 Kief, $15/g as of 10/6, 10/7, 10/8
  • 23.60% Super Silver Haze Hash, $15/g as of 10/11

Harborside buys concentrates from patients who make them at home (although I suppose it's possible that Harborside might also make concentrates).

Percentages may vary from plant to plant, grower to grower, sample to sample, and concentrate to concentrate. Harborside buys product from various patient homegrowers (I've read maybe 400). Oils and melts and hashes are not standardized.

Are there any scientific studies on the effects of cannabis concentrates in animals or humans? There are published LD50 levels for THC in mice, rats, dogs, and monkeys. For dogs, the LD50 of oral THC is 525mg/kg. So if 10 six-pound (2.72kg) chihuahuas each eat 1.428 grams of THC, at least 5 will die. (1.428g of THC can be found in 1.93g of 74% THC hash oil, or 5.71g of 25% THC bud (about 1/8th plus 2/3rds of an 8th)).

Wikipedia says metabolism of THC occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4.

At least 85 cannabinoids have been found in cannabis. I would be interested in finding out which CYP enzymes metabolize each of those cannabinoids, as well as which substances act as inhibitors of those CYP enzymes.

I would also be interested in learning about marijuana contraindications (factors that increase the risks involved in using a particular drug). Google cannabis contraindications and marijuana contraindications. I'd also like to learn more about adverse drug reactions related to marijuana. How many substances can you combine with marijuana? How many combinations can be made with various substances and over 2,000 marijuana strains? Could one substance react one way with one certain strain, and another way with another certain strain? Could Prozac have 2,000 slightly different effects when used with 2,000 different marijuana strains?

THC metabolism

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I've noticed on Google Scholar that THC is "metabolized by CYP3A4, CYP2C11, and to a lesser extent CYP2C9." (Google CYP3A4 THC.) I've read that THC is rapidly metabolized in the liver to an active metabolite (11-hydroxy THC) which is then converted to inactive metabolites and excreted in urine/stool. That site mentions CYP3A3, CYP3A4, CYP2C9, and CYP2C6.

In biochemistry, a substrate is a molecule upon which an enzyme acts. Wikipedia lists THC as a minor substrate of CYP3A4. THC is also a substrate of CYP2C19.

This study says the CYP3A4 enzyme is the most active metabolizer of 7a and 7ß-hydroxy-delta8-THC.

stay high longer

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I've read that consumption of marijuana along with Cytochrome P450 2C9 inhibitors (aka CYP2C9 inhibitors) leads to extended intoxication.(source) If that's true, that means that people using marijuana along with CYP2C9 inhibitors can stay high longer or stay stoned longer. (Also see this Google Scholar search for Cytochrome P450 2C cannabis, and this Google Scholar search for CYP2C9 cannabis.)

[Speaking of enzyme inhibition, earlier this month I blogged about URB937 (Google URB937) which inhibits FAAH, therefore boosting andandamide, an endocannabinoid neurotransmitter discovered in 1992. Or as another website put it: URB937 kills pain like marijuana without getting you stoned.]

marijuana and antidepressants

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Speaking from personal experience, the first time I smoked marijuana I was intoxicated for more than 48 hours but less than 72 hours. I wouldn't exactly call it a pleasant experience. Looking back, I would say that I experienced prolonged mania, psychosis, and delirium. Incidentally, the Wikipedia article for delta-9-tetrahydrocannabinol lists a half-life (the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity) for THC of up to 59 hours. At the time I first smoked marijuana I was taking either Prozac (fluoxetine), or Paxil (paroxetine), or Effexor (venlafaxine) (possibly Effexor XR). I've had prescriptions for and have taken all three of those drugs before but I currently don't recall which one I was taking at the time (or had possibly discontinued days before). I would actually recommend that people NOT smoke weed while taking antidepressants. Don't smoke marijuana on antidepressants.

Fluoxetine (Prozac) is a selective serotonin reuptake inhibitor (SSRI) as well as a strong CYP2D6 inhibitor, a CYP2C19 inhibitor, a CYP3A4 inhibitor, and one of the drugs patients should tell their doctor they're taking before taking dronabinol (capsules containing THC). CYP2D6 metabolizes fluoxetine into the biologically active metabolite norfluoxetine. Wikipedia says fluoxetine and it's active metabolite norfluoxetine are both potent CYP2D6 inhibitors, as well as mild to moderate CYP1A2 inhibitors, CYP2B6 inhibitors, CYP2C9 inhibitors, CYP2C19 inhibitors, and CYP3A4 inhibitors. Fluoxetine and norfluoxetine also inhibit the activity of P-glycoprotein (aka permeability glycoprotein, P-gp, Pgp, ABCB1, MDR1, PGY1, CD243), an ATP-binding cassette transporter, which transports drugs across extra- and intra-cellular membranes. P-glycoprotein also functions as a transporter in the blood-brain barrier. ABCB1 transports various substrates across the cell membrane. It's involved in regulating the distribution and bioavailability of drugs, and the removal of toxic metabolites and xenobiotics from cells into urine, bile, and the intestine. Google prozac marijuana.

Paroxetine (Paxil) is a selective serotonin reuptake inhibitor (SSRI) as well as a strong CYP2D6 inhibitor. Google paxil marijuana.

Venlafaxine (Effexor) is a serotonin-norepinephrine reuptake inhibitor (SNRI) as well as a substrate of CYP2D6, meaning that the CYP2D6 enzymes metabolizes it. Wikipedia says venlafaxine is extensively metabolized in the liver via CYP2D6 to desvenlafaxine, which is just as potent an SNRI as venlafaxine. Google effexor marijuana.

On January 24, 2001, there was an article in USA Today called "Marijuana and antidepressants don't mix" by Mike Falcon and Stephen A. Shoop, MD. It mentioned that Mike Tyson told reporters five weeks before "his most recent bout" that he was taking Zoloft, an SSRI. The Detroit News quoted a member of the Michigan Board in Control of Athletics who said that Mike Tyson's October 2000 post-fight urine sample tested positive for marijuana. Tyson claimed he discontinued Zoloft before fights, but USA Today said that doctors say the combination of marijuana and antidepressants, even if separated by weeks, "could make even the toughest customer punchy or worse."

Dr. Gabriel Nahas, editor of Marijuana and Medicine, and pharmacology research professor at NYU Medical Center, said the combination of cannabis and antidepressants "is a cocktail which can confound and confuse even the most determined and experienced psychiatrist." Nahas said "the effects on the patient can be very confusing, disorienting, and dangerous."

Dr. Abraham Kryger, a family physician in Monterey, California, said the combination of antidepressants and marijuana is probably severely under-reported. There are patients who have been prescribed antidepressants who don't tell their physicians they smoke pot, even if their doctor asks them. So physicians see side effects "which may or may not be due to the anti-depressant alone." In 2001, USA Today said cannabis contains at least 66 cannabinoids (the number is at least 85 as of 2010). USA Today said "It's therefore impossible to precisely define the effects produced by cross-medicating marijuana with antidepressants."

USA Today said there are many studies proving marijuana's effectiveness "in treating nausea, glaucoma and intra-ocular eye pressure, migraine headaches, suppressed appetite in AIDS patients, and specific types of pain. Some studies also suggest applications in movement and neurologic disorders."

Nahas said marijuana's drawbacks include addictive effects ("Nobody can argue that habitual use of marijuana does not exist"), memory impairment, distance and time distortion, behavioral responses, amotivational syndrome (caused by temporary low levels of testosterone according to Istvan Boksay), and disease. Nahas said marijuana can destroy gametes in both men and women, changing reproductive systems irreversibly.

USA Today wrote that Marijuana and Medicine has shown possible interactions between marijuana and antidepressants such as additive tachycardia, accelerated heartbeat, hypertension, drowsiness, transient delirium, cognitive problems with tricylic antidepressants; and severe mania with psychosis on fluoxetine (Prozac, which USA Today incorrectly calls Luvox; Luvox is fluvoxamine). Marijuana and Medicine said THC may inhibit serotonin uptake and increase it's synthesis. Istvan Boksay, a research pharmacologist at NYU Medical Center, and chief of psychiatry at the Aging and Dementia Research Center, said cannabinoid receptors in the brain are not SSRI-mediated and not serotonin-mediated. But marijuana can affect dopamine and norepinephrine.

USA Today said not all SSRIs are affected equally by cannabis. Prozac and Paxil have "greater inhibitory effects" on P450 enzymes which metabolize many drugs. The paper said that taking SSRIs "could prolong the excretion of marijuana from the body."

Dr. Lester Lee, director of Arista Medical in Huntington Beach, California and the former head of the US Olympic Committee's drug-testing arm, said SSRIs are excreted before THC so SSRIs "can and will elevate levels of THC in urine."

USA Today concludes "Taking prescription antidepressants and simultaneously self-medicating with marijuana is not a good idea. And not telling the physician who prescribes your antidepressants that you use marijuana is simply a poor and potentially dangerous decision."

In July 2007, CNN reported that the CDC said antidepressants were the most prescribed drugs in the US. The U.S. Centers for Disease Control and Prevention examined 2.4 billion drugs prescribed in 2005. 118 million were for antidepressants. CNN said that adult usage of antidepressants almost tripled between 1988-1994 and 1999-2000. The CDC reported that the use of antidepressants rose 48% between 1995 and 2002.

Dr. Kelly Posner, an assistant professor at Columbia University College of Physicians and Surgeons, said 8% of adolescents will have a major depressive episode in their lifetime, and 25% of adults will. Posner said 55% of African-Americans who have depression don't seek treatment for it. Posner thinks depression is driving the number of prescriptions but Dr. Robert Goodman says marketing by pharmaceutical companies to doctors and consumers is the real driving force.

I don't know how many Californians currently have antidepressant prescriptions, but suppose the number of antidepressant prescriptions in California was relative to the proportion of California population to the total US population. As of October 19, 2010 the US Population Clock estimates the US population at 310,518,117. California is the most populous state in the US, with an estimated 36,961,664 people in 2009. That's 11.9% of the US population. 11.9% of 118 million antidepressant prescriptions (in 2005) is a potential 14.042 million antidepressant prescriptions in California. If any of those millions of people in California currently taking antidepressants start using marijuana, they may soon discover that marijuana use with antidepressants has unique side effects.

The CDC also has stats on drug use in the US here. From 2003 to 2006, 47% of Americans used at least one prescription drug in the past month.

CYP inhibitors

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CYP2C9 inhibitors

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Going back to CYP2C9 inhibitors, which Wikipedia says can lead to extended marijuana intoxication, most inhibitors of CYP2C9 are competitive inhibitors.(source) In competitive inhibition, when the inhibitor binds to the active site on the enzyme, it prevents binding of the substrate and vice versa.

Noncompetitive inhibitors of CYP2C9 include:
  • 6-hydroxyflavone (found in the leaves of Barleria prionitis (aka the porcupine flower)
  • medroxyprogesterone acetate (aka MPA; a synthetic variant of the human hormone progesterone; used as a contraceptive and in hormone replacement therapy) (Depot medroxyprogesterone acetate (DMPA), also known as Depo-Provera, is a hormonal contraceptive birth control drug injected every 3 months. Wikipedia says a depot injection is an injection, usually subcutaneous or intramuscular, of a pharmacological agent which releases its active compound in a consistent way over a long period of time.)
  • nifedipine (a dihydropyridine calcium channel blocker used as an antianginal and antihypertensive; also used for premature labor, esophageal spasms, and Raynaud's phenomenon)
  • phenethyl isothiocyanate (no WP page) (aka PEITC; an anti-carcinogen found in cabbages and other cruciferous vegetables) (Google search)
  • tranylcypromine (which acts as a non-selective and irreversible MAOI; used as an antidepressant and anxiolytic; aka Parnate, Jatrosom)

Strong CYP2C9 inhibitors include:

Weak CYP2C9 inhibitors include:
  • amiodarone (an antiarrhythmic medication used for irregular heart beat)
  • chloramphenicol (a bacteriostatic antimicrobial; a broad-spectrum antibiotic; may cause bone marrow toxicity)
  • cimetidine (a H2-receptor antagonist used to treat heartburn and peptic ulcers, marketed as Tagamet, Tagamet HB, Tagamet HB200)
  • fenofibrate (a fibrate used to reduce cholesterol levels, reduce LDL, reduce VLDL, increase HDL; marketed as Tricor, Trilipix, Lipofen, Lofibra, Lipanthyl, Lipidil, Supralip, Fenocor-67, Fenogal, and Antara)
  • flavones (a class of flavonoids). Natural flavones include (some of these could be exceptions):
  • flavonols (a class of flavonoids present in many fruits and vegetables). Flavonols include (some of these could be exceptions):
  • fluvastatin (a statin used to treat hypercholesterolemia and prevent cardiovascular disease; marketed as Lescol, Canef, Vastin
  • fluvoxamine (an SSRI antidepressant marketed as Luvox, Fevarin)
  • isoniazid (a first-line anti-tuberculosis medication; marketed as Laniazid, Nydrazid)
  • lovastatin (a statin used to treat hypercholesterolemia and prevent cardiovascular disease; naturally found in oyster mushrooms and red yeast rice; sold under the brand names Mevacor, Altocor, Altoprev, Stratosan, and Advicor (combined with niacin)
  • probenecid (a uricosuric drug that increases uric acid excretion; used to treat gout and hyperuricemia)
  • setraline (an SSRI antidepressant sold under the brand names Zoloft, Selectra, Eleva)
  • sulfamethoxazole (a sulfonamide bacteriostatic antibiotic; abbreviated SMX; often combined with trimethoprim as SMX-TMP, known as Bactrim, Septrin, Septra, Biseptol)
  • teniposide (a podophyllotoxin derivative used to treat childhood acute lymphocytic leukemia; known as Vumon, VM-26)
  • voriconazole (a triazole anti-fungal medication generally used to treat serious, invasive fungal infections; known as VFEND)
  • zafirlukast (a leukotriene receptor antagonist (LTRA) for the maintenance treatment of asthma; marketed as Accolate, Accoleit, Vanticon) [Singulair is another LTRA]

CYP2C19 inhibitors

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Regarding CYP2C19, about 15-20% of Asians and 3-5% of Caucasians are poor metabolizers with no CYP2C19 function. (Although this site says the poor metabolizer CYP2C19 genotype occurs in 1-3% of Caucasians.) Wikipedia says that THC is a substrate of CYP2C19 (meaning, the CYP2C19 enzyme metabolizes THC).

Strong CYP2C19 inhibitors include:
  • moclobemide (an MAOI used to treat depression and social anxiety; tradenames Aurorix, Manerix; not approved for use in US)
  • fluvoxamine (an SSRI antidepressant marketed as Luvox, Fevarin)
  • chloramphenicol (a bacteriostatic antimicrobial; a broad-spectrum antibiotic; may cause bone marrow toxicity)

Other CYP2C19 inhibitors include:
  • cimetidine (a H2-receptor antagonist used to treat heartburn and peptic ulcers, marketed as Tagamet, Tagamet HB, Tagamet HB200)
  • felbamate (an anticonvulsant used to treat partial seizures and epilepsy; increases risk of aplastic anemia and/or liver failure; brandname Felbatol)
  • fluoxetine (aka Prozac, Sarafem; an SSRI antidepressant)
  • indometacin (aka indomethacin) (an NSAID (non-steroidal anti-inflammatory drug) used to reduce fever, pain, stiffness, swelling; tradenames Indocin, Indocid, Indochron E-R, Indocin-SR)
  • ketoconazole (an antifungal drug used to treat skin and fungal infections; tradenames Nizoral, Sebizole; been largely replaced by fluconazole and itraconazole)
  • lansoprazole (a proton-pump inhibitor which prevents the stomach from producing gastric acid; brandnames Prevacid, Helicid, Zoton, Inhibitol; available as a generic)
  • modafinil (an analeptic drug used to treat narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea; tradenames Provigil, Alertec, Modavigil, Modalert, Modafinilo, Carim, Vigia; is unapproved for but may be effective in treating depression and schizophrenia)
  • omeprazole (a proton pump inhibitor used to treat dyspepsia, peptic ulcer disease, gastroesophageal reflux disease (GERD), laryngopharyngeal reflux, and Zollinger-Ellison syndrome; tradenames Losec, Prilosec, Antra, Gastroloc, Mopral, Omepral, Zegerid, Prilosec OTC, Zegerid OTC, Segazole, OMEZ, Ulcozol, Xelopes)
  • oxcarbazepine (an anticonvulsant and mood stabilizing drug used to treat epilepsy; also anxiety and mood disorders, benign motor tics; tradename Trileptal)
  • probenecid (a uricosuric drug that increases uric acid excretion; used to treat gout and hyperuricemia)
  • ticlopidine (an antiplatelet drug and adenosine disphosphate receptor inhibitor; may increase risk of thrombotic thrombocytopenic purpura and neutropenia, so largely replaced by the drug clopidogrel)
  • topiramate (an anticonvulsant drug used to treat epilepsy; brandname Topamax)

CYP2D6 inhibitors

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(The Wikipedia page for poor metabolizer currently redirects to CYP2D6, although it should probably redirect to drug metabolism. This website has a good overview of the difference between poor metabolizers, rapid metabolizers, and ultra-rapid metabolizers.)

Due to genetic polymorphism, CYP2D6 shows the largest phenotypical variability among the CYP enzymes. People with the poor metabolizer CYP2D6 genotype have little or no CYP2D6 function.

About 6-10% of whites and 2% of Asians have the poor metabolizer CYP2D6 genotype. The frequency of poor metabolizers is greater in blacks than whites. CYP2D6 ultrarapid metabolizers is greater among Middle Eastern and North Africa populations.

Substrates of CYP2D6 (substances that CYP2D6 metabolizes) include beta-blockers, antiarrythmics, all tricyclic antidepressants, most SSRIs, venlafaxine (Effexor) (an SNRI), opioids, antipsychotics, DXM, etc.

Strong CYP2D6 inhibitors include:
  • SSRIs
    • citalopram (aka Celexa, Cipramil; an SSRI used for depression, and off-label for anxiety)
    • fluoxetine (aka Prozac, Sarafem; an SSRI antidepressant)
    • paroxetine (aka Paxil, Aropax, Seroxat; an SSRI used to treat depression, OCD, panic/social anxiety/anxiety disorders)
  • Other antidepressants
    • bupropion (aka Wellbutrin, Zyban, Voxra, Budeprion, Aplenzin; a dopamine reuptake inhibitors and nicotinic acetylcholine receptor antagonist; used as antidepressant and smoking cessation aid)
    • duloxetine (brandnames Cymbalta, Yentreve; an SNRI (serotonin-norepinephrine reuptake inhibitor) used for major depressive disorder and generalized anxiety disorder; also relieves pain related to fibromyalgia and diabetic neuropathy)
  • terbinafine (a synthetic allylamine antifungal; sold as Lamisil, Corbinal, Zabel, Sebifin, Zimig)
  • quinidine (a stereoisomer of quinine originally derived from cinchona tree bark; acts as a class I antiarrhtymic agent)
  • MDMA (aka ecstasy, E, X; a recreational empathogen which can induce euphoria, a sense of intimacy with others, diminished anxiety and depression; may be effective in the treatment of PTSD and anxiety associated with terminal cancer; possibility of neurotoxic damage to the central nervous system)

Weak CYP2D6 inhibitors include:
  • buprenorphine (tradenames Subutex, Temgesic, Buprenex, Suboxone; a semi-synthetic opioid that is used in lower doses to control moderate pain in non-opioid tolerant individuals and in higher doses to treat opioid addiction)

Other CYP2D6 inhibitors include:
  • amiodarone (an antiarrhythmic medication used for irregular heart beat)
  • dronedarone (aka SR33589, Multaq; an antiarrhythmic used for irregular heart beat; used to treat atrial fibrillation and atrial flutter)
  • anti-histamines
    • chlorphenamine (a 1st generation alkylamine antihistamine; aka chlorpheniramine; available in chlorphenamine maleate as Chlor-Trimeton, Piriton, Chlor-Tripolon, HISTA-12; relatively weak sedative effects vs other 1st gen antihistamines; may be effective for depression and anxiety)
    • diphenhydramine (aka DPH, DHM, Benadryl, Dimedrol; found in Nytol, some Unisom products, Tylenol PM, Midol PM, Advil PM; a 1st gen anti-histamine in the ethanolamine class of antihistaminergic agents; used to treat allergies; has a powerful hypnotic effect, can be used as sleep aid and anxiety relief; antiemetic; can be used to treat side effects such as tremors of many antipsychotics)
  • antipsychotics
    • chlorpromazine (aka Thorazine, Largactil, CPZ (chlorpromazine hydrochloride); an typical anti-psychotic synthesized in 1950; a prototype for phenothiazine drugs; has anticholinergic, antidopaminergic, anxiolytic, antihistaminic, and weak antiadrenergic effects; its anticholinergic effects include constipation, sedation, hypotension, nausea relief; its antidopaminergic effects include restlessness, dystonia; can cause tardive dyskinesia which can be irreversible; has been largely superseded by newer atypical antipsychotics)
    • haloperidol (a typical antipsychotic in the butyrophenone class; used to treat schizophrenia, acute psychotic states, delirium; tradenames Haldol, Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol, Einalon S, Eukystol, Halosten, Keselan, Linton, Peluces, Serenace, Serenase, Sigaperidol)
  • celecoxib (NSAID) (aka Celebrex, Celebra, Onsenal; a sulfa NSAID used to treat osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, reduce numbers of colon and rectum polyps in familial adenomatous polyposis) (Wikipedia says it's metabolized mainly by CYP2C9)
  • cimetidine (a H2-receptor antagonist used to treat heartburn and peptic ulcers, marketed as Tagamet, Tagamet HB, Tagamet HB200)
  • clomipramine (a tricyclic antidepressant developed in the 1960s; aka Anafranil)
  • chloramphenicol (a bacteriostatic antimicrobial; a broad-spectrum antibiotic; may cause bone marrow toxicity)
  • cocaine (a crystalline tropane alkaloid found in coca leaves; a central nervous system stimulant, appetite suppressant, topical anesthetic; a serotonin-norepinephrine-dopamine reuptake inhibitor; addictive) (Wikipedia mentions metabolism by CYP3A4)
  • doxorubicin (aka hydroxydaunorubicin; sold as Adriamycin, Adriamycin PFS, Adriamycin RDF, Rubex; a photosensitive anthracycline antibiotic used in chemotherapy; used to treat hematological malignancies, many carcinomas, and soft tissue sarcomas; can cause heart damage) (Wikipedia mentions metabolism by CYP3A4)
  • metoclopramide (an antiemtic and gastroprokinetic agent, used to treat nausea/vomiting, migraine headaches, facilitate gastric emptying for gastroparesis; tradenames Maxolon, Reglan, Degan, Maxeran, Primperan, Pylomid, Cerucal, Pramin; the most common cause of drug-induced movement disorders)
  • methadone (a synthetic opioid used as an analgesic, antitussive, and maintenance anti-addictive for patients on opioids; developed in Germany in 1937; acts on opioid receptors and produces many same effects; used in managing chronic pain; used to treat opioid dependence, mitigate opioid withdrawal syndrome; high doses can block euphoric effects of heroin, morphine, similar drugs; found in levomethadone, Polamidone, Heptadon, found in Methadose)
  • moclobemide (an MAOI used to treat depression and social anxiety; tradenames Aurorix, Manerix; not approved for use in US)
  • quinidine (a stereoisomer of quinine originally derived from cinchona tree bark; acts as a class I antiarrhtymic agent)
  • ranitidine (a histamine H2-receptor antagonist that inhibits stomach acid production; used to treat peptic ulcer disease, GERD; used along with fexofenadine to treat hives; brandnames Zantac, Zinetac)
  • ranolazine (antianginal) (an antianginal medication used to treat chronic angina pectoris; aka Ranexa, Ranozex)
  • ritonavir (tradename Norvir; an anti-retroviral drug used to treat HIV and AIDS)
  • doxepin (a drug with tricyclic antidepressant and anxiolytic properties; aka Aponal, Adapine, Deptran, Sinquan, Sinequan, found in creams to treat dermatological itch (Zonalon, Xepin); used to treat insomnia (Silenor))
  • halofantrine (a drug used to treat malaria; marketed as Halfan) (Wikipedia says it is CYP3A4 mediated)
  • imipramine (a tricyclic antidepressant of the dibenzazepine group; used to treat major depression, enuresis (the inability to control urination); sold as Antideprin, Deprimin, Deprinol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil; aka melipramine; may be effective for panic disorder)
  • levomepromazine (an aliphatic phenothiazine neuroleptic drug; an antipsychotic about half as potent as chlorpromazine with strong analgesic, antiemetic properties; known as methotrimeprazine in the US; sold as Nosinan Nozinan, Levoprome; marketed as Neurocil, Nozinan in Europe, Canada; serious side effects include tardive dyskinesia, akathisia, potentially fatal neuroleptic malignant syndrome; known as a "dirty drug") (marijuana is also known as a "dirty drug")
  • pimozide (aka Orap; an antipsychotic drug of the diphenylbutylpiperidine class; high potency vs chlorpromazine; based on weight even more potent than haloperidol; has special neurologic indications for Tourette syndrome and resistant tics; side effects include akathisia, tardive dyskinesia; rarely neuroleptic malignant syndrome and long QT syndrome)
  • thioridazine (aka Mellaril, Novoridazine, Thioril; an antipsychotic drugs in the phenothiazine group; previously widely used to treat schizophrenia and psychosis; now reserved for patients who fail to respond to or have contraindications for other antipsychotics due to concerns about cardiotoxicity and retinopathy; can cause potentially fatal neuroleptic malignant syndrome)

Doctorfungus.org says although 14 families of CYP enzymes have been found in humans, about 95% of all drug oxidation is done by 6 CYP enzymes: CYP3A4/5, CYP2D6, CYP2C8/9, CYP1A2, CYP2C19, and CYP2E1. That site says CYP enzyme activity may vary in people based on medical, environmental, and dietary factors; as well as different racial populations. That site has a pie chart that shows the percentage of drugs metabolized by CYP enzymes:
  • 36% CYP3A4/5
  • 19% CYP2D6
  • 16% CYP2C8/9
  • 11% CYP1A2
  • 08% CYP2C19
  • 04% CYP2E1
  • 03% CYP2A6
  • 03% CYP2B6

CYP3A4 inhibitors

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Wikipedia says in humans, the CYP3A4 protein is encoded by the CYP3A4 gene, which is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. It also says CYP3A4 is absent in fetal liver but increases to approximately 40% of adult levels in the 4th month of life and 72% at 12 months. CYP3A4 has also been found in the brain. Wikipedia says CYP3A4 is involved in the metabolism of approximately half the drugs which are used today.

Strong/moderate CYP3A4 inhibitors include:

Weak CYP3A4 inhibitors include:
  • cimetidine (a H2-receptor antagonist used to treat heartburn and peptic ulcers, marketed as Tagamet, Tagamet HB, Tagamet HB200)
  • buprenorphine (tradenames Subutex, Temgesic, Buprenex, Suboxone; a semi-synthetic opioid that is used in lower doses to control moderate pain in non-opioid tolerant individuals and in higher doses to treat opioid addiction)
  • cafestol (a diterpene molecule in unfiltered coffee; has anticarcinogenic properties in rats; may inhibit the progress of Parkinson's disease)

Other CYP3A4 inhibitors include:
  • amiodarone (an antiarrhythmic medication used for irregular heart beat)
  • ciprofloxacin (antibiotic)
  • ciclosporin (an immunosuppressant)
  • diltiazem (a calcium channel blocker)
  • imatinib (an anti-carcinogen)
  • echinacea (an immunostimulator)
  • enoxacin (an antibacterial)
  • ergotamine
  • metronidazole (an antibacterial)
  • mifepristone (an abortifacient)
  • norfloxacin (an antibiotic)
  • tofisopam (an anxiolytic)
  • non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  • gestodene (a hormonal contraceptive)
  • mibefradil
  • saquinavir (a protease inhibitor; an antiretroviral drug used in HIV therapy; tradenames Invirase, Fortovase; a component in highly active retroviral therapy)
  • selective serotonin reuptake inhibitors (SSRIs) (used as antidepressants, to treat anxiety disorders, some personality disorders, premature ejaculation, some cases of insomnia)
    • fluoxetine (aka Prozac, Sarafem; an SSRI antidepressant)
    • fluvoxamine (an SSRI antidepressant marketed as Luvox, Fevarin)
  • carambola (aka star fruit; the fruit of the Averrhoa carambola tree native to Philippines, Indonesia, India, and Sri Lanka)
  • piperine (the alkaloid responsible for the pungency of black pepper and long pepper; used in traditional medicine and as an insecticide; long pepper has 1-2%, white and black pepper has 5-9%; can be extracted from black pepper using dichloromethane)
  • milk thistle (a flowering plant of the daisy family native to Mediterranean regions of Europe, North Africa and the Middle East; seeds have been used as liver tonics for centuries; used to treat liver cirrhosis, chronic hepatitis, toxin induced liver damage, and gallbladder disorders)

schizophrenia

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On June 24, 2010 Jessica Ward Jones MD, MPH wrote that marijuana use appears to worsen the symptoms of schizophrenia. She referred to a study in the June 2010 issue of the British Journal of Psychiatry entitled "Psychosis reactivity to cannabis use in daily life: an experience sampling study." Schizophrenics display symptoms such as hallucinations, delusions, disorganized behavior, sometimes a flattened affect (where they show little emotion), lack of motivation, alogia (lack of additional information in responses), and lack of desire to form relationships.

In June 2010, JR Minkel of LiveScience wrote about the same study in an article entitled "Marijuana Worsens Schizophrenia" (although the article refers to 48 patients and 47 healthy people).

Dr. Cecile Henquet of Maastricht University Medical Center in the Netherlands followed a group of 42 people with schizophrenia who were daily marijuana users and 38 healthy people, and asked what they were doing and how they felt 12 times a day for 6 days.

The schizophrenics reported a significantly increased feeling of well being and improved mood after using pot than healthy subjects. But hours later, the schizophrenics had a decreased mood, more hallucinations, increased vulnerability to psychosis, and overall worsening of symptoms compared to healthy people. The study concluded that "Patients with psychosis are more sensitive to both the psychosis-inducing and mood-enhancing effects of cannabis."

THC was suspected as the chemical responsible for the worsened symptoms. A previous study published online in January 2005 ("Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction") concluded that THC was associated with "transient exacerbation in core psychotic and cognitive deficits in schizophrenia" and might "differentially affect schizophrenia patients relative to control subjects." Schizophrenics had "enhanced sensitivity to the cognitive effects" of THC.

Also in January 2005, a study by Henquet's team was published in the British Medical Journal ("Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people"). Study participants included 2,437 people aged 14 to 24-year-old with and without predisposition for psychosis, and were followed for 4 years. The study concluded that "Cannabis use moderately increases the risk of psychotic symptoms in young people but has a much stronger effect in those with evidence of predisposition for psychosis." Jones also wrote that "Additional research by Henquet showed that both genetic and environmental factors play a role in this predisposition."

A study by researchers at the University of Pittsburgh School of Medicine appeared in the July 2008 issue of Archives of General Psychiatry. David A. Lewis, MD, said that heavy marijuana use, especially in adolescence, appeared to be "associated with an increased risk for the later development of schizophrenia, and the course of illness is worse for people with schizophrenia who use marijuana." Regarding the study, Rick Nauert, PhD wrote that the brains of schizophrenics have significantly reduced expression of cannabinoid receptor type 1. He wrote that reduced GABA is known to be present in schizophrenics. GABA is the chief inhibitory neurotransmitter in the mammalian central nervous system. He wrote that marijuana use by schizophrenics appears to worsen the deficit in GABA synthesis since activation of the CB1 receptor impairs signaling by GABA.

Wikipedia says schizophrenia is a mental illness with a global lifetime prevalence of about 1.5%, meaning about 1 in 67 people will get schizophrenia in their lifetime, worldwide. California has a population of over 36.9 million people. 1.5% of 36.9 million is 553,500 people. Schizophrenia commonly manifests as bizarre or paranoid delusions (that are often persecutory), disorganized thinking and speech, auditory hallucinations, and is accompanied by significant occupational and social dysfunction. People with schizophrenia are likely to have additional conditions such as depression and anxiety disorders. Social problems like homelessness, poverty, and long-term unemployment are common. The suicide rate of schizophrenics is about 5% higher than others. The lifetime occurrence of substance abuse is about 40%. Contributing factors to schizophrenia include genetics, early environment, psychological and social processes, and neurobiology. Some drugs appear to cause or worsen symptoms.

On July 21, 2010, an article by Maia Szalavitz appeared on TIME.com entitled A Complex Link Between Marijuana and Schizophrenia.

Szalavitz said studies have repeatedly found that people with schizophrenia are about twice as likely to smoke pot as those without. But also, studies suggest that people who smoke pot are twice as likely to develop schizophrenia as non users. A 2007 review of research concluded that smoking pot just once was associated with a 40% increase in risk of psychotic disorders. But schizophrenia rates in the US have remained the same or possibly decreased. Schizophrenia has been found to affect about 1% of people.

She wrote that maybe people who are genetically predisposed to schizophrenia also happen to especially enjoy marijuana. Some studies suggest smoking pot can trigger schizophrenia earlier in people who are predisposed, yet overall schizophrenia rates are not increasing, and the average age of onset is not decreasing. [This is just a guess, but perhaps many people are going undiagnosed.]

She wrote than genes and family history account for 50% of the risk for schizophrenia. And that "about 10% of healthy people have personality features that, when intensified, may characterize schizophrenia", like paranoia.

She also referred to the Henquet study which found that schizophrenics who smoked pot experienced stronger mood-lifting effects than non schizophrenics. They also had less anxiety, and were less socially withdrawn.

In July 2010, a study by researchers at the Feinstein Institute for Medical Research in Long Island was published in Schizophrenia Research. The research on 455 people with schizophrenia showed that those who smoked pot had better memory, greater verbal ability, and faster brain processing speed than those who didn't smoke. Pamela DeRosse said "in order to go out to even find cannabis, enough to become dependent or abuse it, requires that you be more cognitively intact than the average patient with schizophrenia."

Szalavitz wrote that "many schizophrenia patients who smoke pot smoke enough to become addicted." Henquet said schizophrenics "are apparently more sensitive to the addictive potential than other people" because they experience short-term gain associated with pot, but long-term troubles seem unrelated.

Szalavitz wrote that that THC in marijuana is known to cause hallucinations in high doses and can even make healthy people have brief psychotic episodes or feel paranoia. But CBD in marijuana has anti-psychotic effects.

Onset of symptoms peak in late adolescence and early adulthood. Among people diagnosed with schizophrenia, 40% of men and 23% of women are diagnosed before age 19. Symptoms lasting less than a month may be diagnosed as brief psychotic disorder. Various psychotic conditions may be classified as psychotic disorder not otherwise specified. Symptoms lasting over a month but under six months will be diagnosed as schizophreniform disorder. Symptoms that are continuous for at least six months will be diagnosed as schizophrenia according to DSM-IV-TR.

There is sometimes confusion when diagnosing psychotic symptoms. Psychotic symptoms can also be present in drug-induced psychosis, drug intoxication, bipolar disorder, and borderline personality disorder. Delusions can also occur in avoidant personality disorder, social anxiety disorder, delusional disorder, and schizotypal personality disorder. It can be difficult to distinguish delusions of schizophrenia from obsessions that occur in obsessive-compulsive disorder.

The Downside of High

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The Nature of Things with David Suzuki is Canada's longest running documentary series. This year the series featured a documentary called The Downside of High, written and directed by Bruce Mohan. It was produced by Sue Ridout for Dreamfilm Productions of Vancouver, and story-produced by Maureen Palmer. A MetaFilter post said the documentary aired January 28, 2010 on CBC, and that Bruce Mohan decided to make the film after his nephew became mentally ill. The CBD site also said the documentary aired August 26, 2010 on CBC TV and September 2, 2010 on CBC News. The 45-minute film can also be watched online .

The film follows three young adults from British Columbia who believe (along with their doctors) that their schizophrenia was triggered by marijuana use. All of them spent months in psych wards and still struggle with mental illness. In the documentary, some of the world's top schizophrenia experts conclude that teens who start smoking pot before age 16 are 4 times more likely to become schizophrenic. They also said that for all young adults, smoking pot nearly doubles the risk of developing paranoia, hallucinations, and recurring psychosis -- which are symptoms of schizophrenia. Cannabis high in THC may be a big part of the problem. But breeders have also been breeding out CBD which buffers the effects of THC. So much of today's marijuana contains more psychosis-inducing THC and less protective CBD.

Facts in the film, according to the CBC site, include the following. A 2009 UN Drug Report said that marijuana is the most widely used illegal drug in the world. Over 31 million people in North America use pot at least once a year, or about 10% of people age 15 to 64; in Europe, it's 5.2%. In Canada, the average use is 14.1%. British Columbia has the highest usage in Canada, with 16.8% of people over age 15 using (about 1/6 people). RCMP said that according to Health Canada, marijuana confiscated in 1988 had an average THC level of 4.8% and in 2008 had an average level of 11.1%. THC triggers an increase in dopamine, which leads to heightened awareness, which can lead to paranoia and hallucinations associated with schizophrenia. Dr. Jim Van Os said people who use pot before 16 are 4 times as likely to become schizophrenic. And that regular pot smokers have double the chance of becoming schizophrenic as non users. A report by the Schizophrenia Society of Canada said over 230,000 people in Canada have schizophrenia and that 1 in 100 people will develop schizophrenia in their lifetime. [I have seen schizophrenia rates reported as 1% and also 1.5% of global population. As of October 14, 2010, the world population clock estimated global population at 6,875,096,753 people. 1% would be 68,750,967.53 or 68.75 million schizophrenics worldwide. 1.5% would be 103,126,451.295 or 103.12 million schizophrenics worldwide.]

Risk factors for schizophrenia include a history of childhood trauma, a psychosis-prone personality, family history of mental illness, and environment (people living in urban areas have higher rates of schizophrenia). Scientists believe that any substance that interferes with neural pruning in teens can have potentially devastating and long-lasting psychological effects. Evidence suggests that marijuana use precedes schizophrenia, but also people with pre-existing mental instability may self-medicate.

On September 7, 2010, ScienceDaily reported on a study on the association between psychotic disorders and urban living. It was supported by the National Assembly for Wales and Swedish Research Council for Working Life and Social Research. The study, "Individuals, Schools, and Neighborhood: A Multilevel Longitudinal Study of Variation in Incidence of Psychotic Disorders", appeared in the September 2010 issue of Archives of General Psychiatry. The study looked at 203,829 people: everyone born in Sweeden in 1972 and 1977. Researchers concluded that "The association between urbanicity and psychosis appears to be a reflection of increased social fragmentation present within cities." It said "certain characteristics that define individuals as being different from most other people in their local environment may increase risk of psychosis." The study also said that "being raised in more urbanized areas was associated with an increased risk of developing any nonaffective psychotic disorder."

Speaking of population and urban areas, California is the most populous state in the US with over 36.9 million people, it has 8 of America's 50 most populous cities, and it has the 2nd and 6th biggest census statistical areas in the US. If California was a country, it would be the 35th most populous country on Earth, after Poland. Los Angeles County alone is more populous than 42 US states. Here is a list of urban areas in California by population. Also, the UN Food and Agriculture Organization said that over 50% of the planet's 6.9 billion people already live in cities. And that by 2050, about 6.6 billion of Earth's 9.2 billion people will be living in cities, or over 70%. Wikipedia says if population trends continue, the world's urban population will double in size every 38 years.

The CBC site also said a gene called COMT which regulates dopamine levels was discovered in 2002. (This is inaccurate. I've read that COMT is an enzyme that degrades dopamine; the COMT gene encodes the COMT enzyme. However, there was study in 2002 among Ashkenazi Jews entitled "A highly significant association between a COMT haplotype and schizophrenia" that "found a highly significant association between schizophrenia and a COMT haplotype." The study mentioned a microdeletion on chromosome 22q11. (There is also a syndrome called 22q11.2 deletion syndrome, and microdeletions on 22q11.2 are associated with a 20 to 30 times increased risk of schizophrenia. Most people with 22q11.2 deletion syndrome are missing about 3 million base pairs of DNA on one copy of chromosome 22 in each cell of their body.) Perhaps it would be more accurate to say that a COMT gene variant was discovered in 2002.) The CBC sites said the COMT gene has 2 variants, and one's susceptibility to marijuana-induced psychosis depends on the combination of variants a person has. (Google Scholar search for COMT haplotype) (Google Scholar search for COMT allele.) Also Google COMT val158met schizophrenia. Val158Met is also known as rs4680, a genetic variant and single nucleotide polymorphism in the COMT gene.

Wikipedia says that COMT (catechol-O-methyltransferase) is one of several enzymes that degrade catecholamines like dopamine, epinephrine, and norepinephrine. The enzyme was discovered in 1957 by Julius Axelrod.

The CBC website also said in the 1960s, marijuana had less THC but also more CBD, which buffers psychotic effects. CBD was discovered in the 1930s. In the 1970s, studies found that CBD could reduce convulsion in rats. So marijuana contains a substance that can trigger psychosis and another substance that can treat it. Dr. Robin Murray said that extreme beliefs about marijuana -- that pot is the work of the devil, and that pot is a sacred herb -- are not practical. He said people need to know that if they smoke a lot of pot, or very potent pot, they're more likely to go psychotic.

The MetaFilter post about the film The Downside of High said that experts estimate that 8% to 13% of all schizophrenia cases are linked to marijuana use during teenage years.

In January 2010, an article by Vanessa Richmond on The Tyee talked about The Downside of High. (The article also appeared on Huffington Post.) One of the main researchers in the documentary is Dr. Robin Murray of the Institute of Psychiatry at the University of London. He said that the vast majority of people have nothing but enjoyment from cannabis. But he was convinced after reading a Swedish study that followed 50,000 military recruits over 15 years.

Dr. Jim Van Os of the University of Maastricht said by the mid 1980s, "we started to observe that 80 to 85% of people who came in with their first psychotic episode were smoking marijuana."

Murray said "everyone varies in their genetic susceptibility. Some of us can happily take cannabis without developing a problem; others of us are more prone."

One of the teens profiled in The Downside of High is Ben, who said most of his friends smoked pot regularly with no problems. But at 16 he starting fearing demons, little men with knives, and anacondas in his house. (Had he seen The Exorcist, Cat's Eye, and Anaconda?) He jumped off the roof twice and stayed in a hospital for over a year.

A psychiatrist at B.C.'s Children's Hospital, Dr. Shimi Kang, said they're seeing more and more problems with pot than ever before. Teens say their parents smoked weed and were fine, and wonder why they're having problems. Corporal Richard DeLong of the Royal Canadian Mounted Police said THC levels in the 60s and 70s were 1 to 3%. But in labs today, THC is showing as 18 to 25%. Also, marijuana usage in North American doubled in the 90s.

Narrator David Suzuki said in some people too much THC in the brain can trigger too much heightened awareness, anxiety, and cause them to attribute too much meaning to mundane events. The film says that increased dopamine levels conclusively lead to psychosis and schizophrenia.

dronabinol

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Dronabinol (aka Marinol) is an oral capsule that contains THC. I've read that Marinol caps contain 2.5 mg of pure THC.

In contrast, a single joint with 1g of 25% THC bud contains 250mg of THC (100x more THC), plus other cannabinoids. A single joint with 400mg of 5% THC bud contains 20mg of THC (8x more THC), plus other cannabinoids. Inhaling marijuana smoke can produce a different experience than orally consuming marijuana (although I've heard that oral consumption can lead to a longer high). In The Biotechnology of Cannabis sativa it says that burning THCA (delta 1-tetrahydrocannabinolic acid) produces THC; burning THCA causes a decarboxlyation reaction converting THCA to the psychoactive THC molecule. Wikipedia says the same thing. In 2003, Ed Rosenthal in Cannabis Culture magazine said when marijuana is smoked, the carboxyl group (COOH) is released from THCA as CO2 and water vapor producing the psychoactive THC molecule.

Dronabinol is used to treat nausea and vomiting caused by chemotherapy. It's also used to increase appetite. Dronabinol may be habit forming. Patients suddenly stopping dronabinol may experience withdrawal symptoms like irritability, insomnia, restlessness, hot flashes, sweating, runny nose, diarrhea, hiccups, and loss of appetite.

Before taking dronabinol, patients should tell their doctor if they are taking:

Patients should also tell their doctors if they've ever used marijuana or other illegal drugs, if they drink or have ever drunk large amounts of alcohol, if they have or have ever had high blood pressure, seizures, heart disease, dementia, a mental illness such as mania, depression, or schizophrenia. Mothers should not breastfeed when taking dronabinol. Users should not drive a car or operate machinery until they know how dronabinol affects them. Alcohol can make the side effects of dronabinol worse.

dronabinol drug interactions

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Drugs.com lists some drug interactions between dronabinol (THC) and Prozac. In addition, Dronabinol interacts with over 460 drugs. There are 5 drugs with minor interections with dronabinol. There are 452 drugs with moderate interactions with dronabinol. Drugs.com says 5 drugs are known to have major interactions with dronabinol:

The following is a list of all 462 drugs that interact with dronabinol (THC) according to Drugs.com. All the following substances have moderate interactions with dronabinol except the 10 that have "(major interaction)" or "(minor interaction)" on the line. Presumably, all of these drugs interact with marijuana as well. [In other words, at least 420 drugs interact with marijuana. Coincidentally, 462 is 420 + 42 (10% of 420).]

Dronabinol may cause the following side effects:
  • anxiety
  • confusion
  • dizziness
  • feeling like you are outside of your body
  • hallucinations
  • high or elevated mood
  • memory loss
  • nausea
  • sleepiness
  • stomach pain
  • strange or unusual thoughts
  • sudden warm feeling
  • unsteady walking
  • vomiting
  • weakness

Dronabinol may cause other side effects, and some side effects can be serious:
  • fast or pounding heartbeat
  • seizures

Symptoms of dronabinol overdose include:
  • changed awareness of time
  • constipation
  • decreased coordination
  • difficulty speaking clearly
  • difficulty urinating
  • dizziness or fainting when standing up too fast
  • drowsiness
  • extreme tiredness
  • fast heartbeat
  • feeling that you are outside of your body
  • inappropriate happiness
  • memory problems
  • mood changes
  • red eyes
  • sharper senses than usual

I would think that many precautions and side effects of dronabinol could also apply to marijuana. Wikipedia also has an article on the effects of cannabis.

other drugs that contain THC or CBD

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Cannador is an oral capsule with a standardized THC and CBD content, in a THC/CBD ratio of about 2 to 1. Cannador is used as a painkiller after major surgery. One study used Cannador capsules that contained 2.5mg THC and about 1.25mg CBD.

Nabilone (marketed as Cesamet) is a synthetic THC analogue that binds to the CB1 receptor. It's used to treat vomiting and nausea caused by chemotherapy, as well as other conditions.

Sativex is a mouth spray with a THC/CBD ratio of 1:1. Minor cannabinoids and terpenoids are also present. Sativex was approved in Canada as an adjunctive treatment for neuropathic pain in adults with MS, and for cancer pain. Wikipedia says each spray of Sativex contains 2.7mg THC and 2.5mg CBD.

I've also found the following: Review on clinical studies with cannabis and cannabinoids 2005-2009

marijuana interactions

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WebMD lists several drug interactions with marijuana.

WebMD says do not take the following drug combinations. Major marijuana interactions include:
  • marijuana and barbituates or sedatives might cause too much sleepiness
  • marijuana and sedatives (CNS depressants) might cause too much sleepiness. Sedatives include
  • marijuana and theophylline might decrease the effects of theophylline (aka dimethylxanthine; used to treat COPD and asthma; trace amounts found in tea; also found in Chuao cocoa beans)

WebMD says be cautious with the following drug combinations. Moderate marijuana interactions include:
  • marijuana and Antabuse (disulfiram). Using marijuana and disulfiarm can cause "irritability, agitation, trouble sleeping."
  • marijuana and Prozac (fluoxetine) (aka Sarafem) might cause people to feel "irritated, nervous, jittery, and excited. Doctors call this hypomania."

WebMD says be watchful with the following drug combinations. Minor marijuana interactions include:
  • marijuana and warfarin might increase the effects of warfarin, might increase the chance of bruising and bleeding. Warfarin is a vitamin K antagonist and a synthetic derivative of dicoumarol; is the most widely prescribed anticoagulant drug in North America; it was originally used as a rodent poison; found to be effective and safe for preventing thrombosis and embolism; many drugs and some foods (like plant-based food containing vitamin K) interact with warfarin; brandnames Coumadin, Jantoven, Marevan, Lawarin, Waran)

I'll repeat this again: Certain drug combinations or overdosing on certain drugs can cause hepatotoxicty and liver failure. Wikipedia says 50% of all acute liver failures and 5% of all hospital admissions are due to drug-induced liver injury.

experience reports

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Google searches for the following will show experience reports for people under the influence of marijuana and additional substances:

search ideas

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For more information, try Googling the following (also make sure you check Google Scholar and Google Books):

Also Google marijuana and (other CYP inhibitors I've listed above).

books

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The following books/resources maybe be useful in further research:

Again, I am not a doctor. I have no medical training. This information is provided with no guarantee of its accuracy, although I've tried my best to present it accurately. Reader beware.
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