Origins of THC, CBD and CBC in cannabis revealed by resurrecting extinct ancestral enzymes active millions of years ago

Amazing stuff! Reconstructing extinct enzymes could have wide ranging applications in the future.

"... Researchers ... have experimentally demonstrated for the first time how cannabis acquired the ability to produce these cannabinoids. In the process, they also developed enzymes that show promise for the biotechnological production of cannabinoids for medicinal applications. ...

the researchers reconstructed extinct enzymes that were active millions of years ago in ancestors of the cannabis plant. In cannabis, enzymes play a key role in the production of cannabinoids—bioactive compounds with, among other things, medicinal potential. ..."

"... The researchers used a technique known as ancestral sequence reconstruction. Based on DNA from modern plants, this method makes it possible to infer what enzymes looked like millions of years ago. These ‘ancestral enzymes’ were then resurrected in the laboratory and experimentally tested. The study provides the first experimental evidence that the biosynthesis of cannabinoids such as THC originated within a relatively recent ancestor of cannabis and subsequently became increasingly refined. ..."

From the abstract:

"Cannabinoids, such as tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) and cannabichromenic acid (CBCA), are bioactive and medicinally relevant compounds found in the cannabis plant (Cannabis sativa L.).

These three compounds are synthesised from a single precursor, cannabigerolic acid (CBGA), through regioselective reactions catalysed by different cannabinoid oxidocyclase enzymes. Despite the importance of cannabinoid oxidocyclases for determining cannabis chemotype and properties, the functional evolution and molecular mechanism of this enzyme family remain poorly understood.

To address this gap, we combined ancestral sequence reconstruction and heterologous expression to resurrect and functionally characterise three ancestral cannabinoid oxidocyclases.

Results showed that the ability to metabolise CBGA originated in a recent ancestor of cannabis and that early cannabinoid oxidocyclases were promiscuous enzymes producing all three THCA, CBDA and CBCA.

Gene duplication and diversification later facilitated enzyme sub functionalisation, leading to extant, highly-specialised THCA and CBDA synthases.

Through rational engineering of these ancestors, we designed hybrid enzymes which allowed identifying key amino acid mutations underlying the functional evolution of cannabinoid oxidocyclases.

Ancestral and hybrid enzymes also displayed unique activities and proved to be easier to produce heterologously than their extant counterparts.

Overall, this study contributes to understanding the origin, evolution and molecular mechanism of cannabinoid oxidocyclases, which opens new perspectives for breeding, biotechnological and medicinal applications."

Origins of THC, CBD and CBC in cannabis revealed

Origins of THC, CBD and CBC in cannabis revealed (original news release) "Where do the well-known cannabis compounds THC, CBD and CBC come from? Researchers ... have experimentally demonstrated for the first time how cannabis acquired the ability to produce these cannabinoids. In the process, they also developed enzymes that show promise for the biotechnological production of cannabinoids for medicinal applications."

Resurrected Ancestral Cannabis Enzymes Unveil the Origin and Functional Evolution of Cannabinoid Synthases (open access)

Fig. 5 Major modifications in the substrate binding region of ancestral and hybrid cannabinoid oxidocyclases.

Consuming cannabis while pregnant appears to increase the risk of preterm birth, low birth weight, and infant death

Bad news! But to be expected! Cannabis consumption is not harmless not even in states like Oregon, where cannabis use is largely legitimized!

Why the certainty of evidence for risks in previous studies was classified as "very-low-to-low" is a mystery to me and casts some doubt about this meta study! That should have been a red flag immediately that something is wrong with the study!

"... “Patients are coming to me in their prenatal visits saying, ‘I quit smoking and drinking, but is it safe to still use cannabis?’” said lead author Jamie Lo, M.D., M.C.R., associate professor of obstetrics and gynecology (maternal-fetal medicine) ...

In fact, cannabis remains one of the most common substances used in pregnancy that’s still illegal under federal law, and, unlike declines in prenatal use of alcohol or nicotine, cannabis use is continuing to increase. Lo said many of her patients are reluctant to give up cannabis during pregnancy because it helps to reduce common prenatal symptoms such as nausea, insomnia and pain. ...

The researchers found eight new studies since their previous update, raising the certainty of evidence from “very-low-to-low” to “moderate” for increased odds of low birth weight, preterm birth and babies being small for their gestational age. ..."

From the key points and abstract:

"Key Points

Question  Is cannabis use in pregnancy associated with neonatal outcomes?

Findings  In this updated systematic review and meta-analysis of 51 studies, prenatal cannabis use was associated with increased odds of preterm birth, small for gestational age, low birth weight, and perinatal mortality.

Meaning  Using cannabis in pregnancy was associated with increased risk of adverse neonatal outcomes; health care professionals should include this in their patient counseling, and increased public health measures are needed to raise awareness on safety of use.

Abstract

Importance  Prenatal cannabis use continues to increase, and cannabis remains the most commonly used illegal substance in pregnancy. Accumulating evidence suggests potential adverse effects on fetal and neonatal outcomes following cannabis use in pregnancy.

Objective  To update a living systematic review and meta-analysis to provide a timely understanding regarding cannabis use in pregnancy and fetal and neonatal outcomes.

Data Sources  The previous review was updated by searching bibliographic databases MEDLINE, CINAHL, PsycInfo, Global Health, and Evidence-Based Medicine Reviews Cochrane Database of Systematic Reviews from November 1, 2021, through April 4, 2024.

Study Selection  Cohort or case-control studies comparing pregnancies with and without prenatal cannabis use on prespecified fetal or neonatal outcomes with adjustment for confounders, such as co-use of tobacco products, were included. Two independent reviewers screened studies, with disagreements resolved through discussion.

Data Extraction and Synthesis  Included studies were extracted by 1 reviewer and confirmed by a second. Risk of bias was assessed with the Newcastle-Ottawa Scale. Random-effects meta-analyses of unadjusted and adjusted odds ratios (ORs) were performed for all primary outcomes. Results were synthesized using the Grading of Recommendations Assessment, Development, and Evaluation approach.

Main Outcomes and Measures  Primary outcomes were preterm birth (PTB; <37 weeks of gestation), small for gestational age (SGA), low birth weight (LBW; <2500 g), and perinatal mortality.

Results  For this update, 8 new studies with 1 709 998 participants were added, for a total of 51 studies synthesized (N = 21 146 938). From meta-analyses of adjusted effect sizes, moderate-certainty evidence indicated that cannabis use in pregnancy was associated with increased odds of LBW (20 studies; OR, 1.75; 95% CI, 1.41-2.18), PTB (20 studies; OR, 1.52; 95% CI, 1.26-1.83), and SGA (12 studies; OR, 1.57; 95% CI, 1.36-1.81), and low-certainty evidence indicated that it was associated with greater odds of perinatal mortality (6 studies; OR, 1.29; 95% CI, 1.07-1.55). Previously, the evidence was rated as very low or low certainty.

Conclusions and Relevance  Cannabis use in pregnancy was associated with greater odds of PTB, SGA, and LBW even after adjusting for co-use of tobacco products, and confidence in these findings increased from low in the prior review to moderate in the current meta-analysis. The findings of this study may help inform patient counseling and future public health policies."

Global Health NOW: Redrawing Battle Lines in the AIDS Fight; Twists in Abortion Lawsuit; and The Lifesaving Potential of Self-Driving Cars

Evidence review raises concern about cannabis use in pregnancy (original news release) "OHSU research team finds moderate risk for preterm birth, low birth weigh"

Prenatal Cannabis Use and Neonatal Outcomes / A Systematic Review and Meta-Analysis (no public access)

The Hazy Evolution of Cannabis

Very recommendable! Amazing stuff! Very funny! "Plate tectonics gave us weed!" I think, the host of this show Kallie Moore had tasted some cannabis herself before the show started. 😊

Cannabis is probably the oldest domesticated plant in the world! Wow!

China not only invented the printing press and gun powere among other things, but also rituals involving inhaling cannabis about 2500 years ago!

Animals and humans have developed this system! It dates back maybe hundreds of millions of years.

Finding re-leaf in Tucson

Feeling better now? 😊 Is that why the Beatles mentioned Tucson in one of their famous songs Get Back ("Jojo left his home in Tucson, Arizona For some California grass")?

 

High levels of dangerous metals like lead and cadmium found in exclusive marijuana users

Recreational poisoning!

"... cannabis plant is known to accumulate metals found in water, soil, fertilizers and pesticides. ...
After adjusting for age, sex, race and ethnicity and education, the researchers found higher levels of cadmium and lead in the blood and urine of participants reporting exclusive marijuana use when compared with non-marijuana/non-tobacco use. Cadmium and lead levels were also higher in exclusive marijuana users who’d reported using the drug within the last seven days, with metal levels falling with increased time since last use. ...
In terms of limitations, the researchers recognize that their study did not include how the marijuana was used, such as vape, combustibles and edibles, so they were unable to determine the difference in metal concentrations by method of use. ..."

"... Marijuana is the third most commonly used drug in the world behind tobacco and alcohol. As of 2022, 21 states and Washington D.C., covering more than 50 percent of the U.S. population, have legalized recreational use of marijuana; and medical marijuana is legal in 38 states and Washington D.C. However, because marijuana is still illegal at the federal level, regulation of contaminants in all cannabis-containing products remains piecemeal and there has been no guidance from federal regulatory agencies like the FDA or EPA. As of 2019, 48.2 million people, or 18 percent of Americans, report using marijuana at least once in the last year.
While 28 states regulate inorganic arsenic, cadmium, lead, and total mercury concentrations in marijuana products, regulation limits vary by metal and by state. ..."

From the abstract:

"Abstract

Background:

Marijuana is the third most used drug in the world.

Objectives:

Because the cannabis plant is a known scavenger of metals, we hypothesized that individuals who use marijuana will have higher metal biomarker levels compared with those who do not use.

Methods:

We combined data from the National Health and Nutrition Examination Survey (2005–2018) for 7,254n=7,254

 participants, classified by use: non-marijuana/non-tobacco, exclusive marijuana, exclusive tobacco, and dual marijuana and tobacco use. Five metals were measured in blood and 16 in urine using inductively coupled plasma mass spectrometry; urinary metals were adjusted for urinary creatinine.

Results:

Participants reporting exclusive marijuana use compared with non-marijuana/non-tobacco use had statistically significantly higher mean cadmium levels in blood [1.22 micrograms per liter1.22μg/L (95% CI: 1.11, 1.34); less than 0.001p<0.001] and urine [1.18 micrograms per gram1.18μg/g (95% CI: 1.0, 1.31);  0.004p=0.004] and statistically significantly higher mean lead levels in blood [1/27 micrograms per deciliter1.27μg/dL  (95% CI: 1.07, 1.50); 0.006p=0.006 ] and urine [1.21 micrograms per gram1.21μg/g  (95% CI: negative 0.006−0.006, 1.50); 0.058p=0.058].

Discussion:

Our results suggest marijuana is a source of cadmium and lead exposure. Research regarding cannabis use and cannabis contaminants, particularly metals, should be conducted to address public health concerns related to the growing number of cannabis users. https://doi.org/10.1289/EHP12074"

High levels of dangerous metals found in exclusive marijuana users A new study has found that people who exclusively use marijuana have higher levels of potentially dangerous metals in their blood and urine than those who don’t. The findings suggest that marijuana may be an overlooked source of metal exposure, an important consideration given the rise in its use.

Blood and Urinary Metal Levels High among Exclusive Marijuana Users

Blood and Urinary Metal Levels among Exclusive Marijuana Users in NHANES (2005–2018) (open access)

18 States that eased marijuana laws see more impaired driving and fatalities, report says

Definitely a cause for concern. Now we have THC and alcohol impaired drivers on the road.

Perhaps, we need more self driving cars soon! 😊

It looks like many users are also clueless about the potency and quantity of THC they are consuming. E.g. many THC containing products (e.g. gummy bears, cookies) are not labeled as to how much THC they contain. 

Another issue: How much THC ends up with minors?

"The Drug Free America Foundation released a new report showing that states that have legalized or weakened restrictions around high-THC marijuana, either for medical or recreational use, saw 32% more marijuana-impaired driving than states that have not adopted the same policies. ..."

"Adding to the concern is the fact that fatalities in the U.S. from marijuana-impaired drivers have risen dramatically between 2000 and 2018, rising from 9 percent of all fatal crashes to 21.5 percent."

"Simultaneously, marijuana potency has also grown exponentially, from the “Woodstock Weed” that contained THC levels of 1-3 percent to the modern commercial marijuana that averages THC levels of between 19.2 and 21.5 percent. ..."

States that eased marijuana laws see more impaired driving, report says | Just The News Study also warns that the potency of marijuana has skyrocketed in recent decades.

DFAF study reveals marijuana-impaired driving more dangerous in states where the drug is more permissive

New study released coincides with Labor Day impaired driving crackdown, reveals marijuana-impaired driving more dangerous in states where the drug is more permissive

The Effect of Cannabis Legalization on Driving Under the Influence of Cannabis (DUIC)

Marijuana and hallucinogen use, binge drinking, reach historic highs among adults 35-50 in the U.S.

Perhaps this is just story enriched with alarmism and hysteria to fill the summer slump! Or should we be concerned!

Is this just some testing and sampling by young adults or is there more to it?

How much of this increase can be attributed to the Covid-19 pandemic? How much of it is temporary?

Will the U.S. become a nation of addicts?

"Americans, from college to middle age, have a newfound taste for drugs, and are smoking marijuana and taking psychedelics at unprecedented rates. 

That’s according to the Monitoring the Future survey, which has tracked, among other topics, American substance use since the mid-1970s. The latest figures for MTF’s adult cohort, reported in the New Scientist, indicate that roughly a quarter of adults aged 35-50, and almost half of adults aged 19-30, said they had used marijuana in the past 12 months. About 4% of older adults, and 8% of younger adults, reported past-year use of psychedelics like LSD and MDMA. ..."

"... While binge drinking has generally declined for the past 10 years among younger adults, adults aged 35 to 50 in 2022 reported the highest prevalence of binge drinking ever recorded for this age group, which also represents a significant past-year, five-year and 10-year increase. ...

For example, 44% of young adults reported using marijuana in the past year, more than 1 in 10 reported using marijuana almost every day, and more than 1 in 5 have vaped marijuana. Nicotine vaping has nearly doubled in this age group since it was first measured in 2017 (from 14% to 24% in 2022). Hallucinogen use has more than doubled in 10 years, now at 8% in 2022 (compared to 3% in 2012).

Among midlife adults aged 35 to 50, marijuana and hallucinogen use have also been increasing. In the past year, 28% have used marijuana and 4% have used hallucinogens. Nearly 30% of adults reported having five or more drinks in a row in the past two weeks. ...
Hallucinogen use: Among adults aged 19 to 30, 8% reported past-year use of hallucinogens, significantly higher than five years ago (5% in 2017) and 10 years ago (3% in 2012). ...

The study also showed that past-year use of cigarettes, sedatives and nonmedical use of opioid medications (narcotics other than heroin) showed a 10-year decline for both adult age groups. Reports of past-year amphetamine use continued a 10-year decrease among 19-to-30-year-olds and a 10-year increase among 35-to-50-year-olds.  ..."

Beware America's recreational drug boom - The Post A record number of adults are using marijuana and psychedelics

Appetite for mind-altering substances is booming among US adults Rates of cannabis and psychedelic use among adults in the US reached record highs in 2022, part of a decade-long upswing in the use of mind-altering drugs

Marijuana and hallucinogen use, binge drinking, reach historic highs among adults 35-50

Dümmer durch Kiffen: Cannabis schädigt das Gehirn

Wurde schon seit Jahrzehnten oft behauptet. Vielleicht ist doch was dran! Meistens wurde diese Behauptung als eine Art Abschreckung abgetan.

Dümmer durch Kiffen: Cannabis schädigt das Gehirn Cannabis kann immer häufiger legal gekauft werden. Das erleichtert auch die Forschung zur Wirkung der Substanz. Und es wird bekannt, wie häufiges Kiffen auf die grauen Hirnzellen wirkt – nämlich verheerend.

Exercise releases cannabis-like chemicals that fight and reduce chronic inflammation

Good news! Do we need to smoke more pot now or can we get some pills?Can we get the positive effects of cannabinoids without becoming stoned?

"... found that the patients who exercised reported less pain and had more microbes in their guts that produce anti-inflammatory compounds. They also had lower levels of cytokines, which are molecules that allow your cells to talk to each other, and are crucial for healthy immune system function. Cytokines are often responsible for triggering inflammation in the body, which can be critical to our survival when the body is infected but can cause a ‘pointless’ kind of inflammation when they go overboard.

Exercise also increased the levels of endocannabinoids, which was strongly associated with the changes in the beneficial gut microbes and the anti-inflammatory substances they produce. According to the study published in the journal Gut Microbes, at least a third of the anti-inflammatory effects of the gut microbes were due to endocannabinoids. ..."

Unfortunately, the abstract of this research paper is loaded with minute details unlike what is common practice!

Exercise releases cannabis-like chemicals that fight and reduce chronic inflammation: Researchers have found a surprising link between endocannabinoids and gut microbes in reducing inflammation.

I presume this is the research paper the above article is referring to:

The anti-inflammatory effect of bacterial short chain fatty acids is partially mediated by endocannabinoids (No public access. Courtesy of Semantic Scholar here is the link to the PDF file)

Cannabis Increases Propensity for False Memories

If confirmed, then the legalization of Cannabis is obviously not as simple as many want us to believe! What about driving under the influence?



What should be the sentencing be for harming others or causing damage while intoxicated?



Cannabis Increases Propensity for False Memories | The Scientist Magazine® Virtual reality experiments reveal that the popular drug may make the brain more open to misremembering.