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MARIJUANA TERPENES ARE ‘AS EFFECTIVE AS MORPHINE’ FOR PAIN RELIEF AND HAVE FEWER
SIDE EFFECTS, NEW STUDY FINDS
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SCIENCE & HEALTH
MARIJUANA TERPENES ARE ‘AS EFFECTIVE AS MORPHINE’ FOR PAIN RELIEF AND HAVE FEWER
SIDE EFFECTS, NEW STUDY FINDS
Published
3 seconds ago
on
May 30, 2024
By
Ben Adlin
A new federally funded study into the effects of cannabis terpenes suggests that
the compounds could be “potential therapeutics for chronic neuropathic pain,”
finding that an injected dose of the compounds produced a “roughly equal”
reduction in pain markers when compared to a smaller dose of morphine. Terpenes
also appeared to enhance the efficacy of morphine when given in combination.
Unlike with morphine, however, none of the studied terpenes produced a
meaningful reward response, the research found, indicating that “terpenes could
be effective analgesics with no rewarding or dysphoric side effects.”
Notably, terpenes that were vaporized or administered orally seemed to have
little impact on pain.
Marijuana Helps People Quit Using Prescription Sleep Aids
Marijuana Helps People Quit Using Prescription Sleep Aids
A recent survey among individuals using cannabis for sleep problems revealed a
preference for marijuana over other sleep aids. Particularly, smoking or vaping
products containing THC, CBD, and myrcene terpene were popular choices.
Respondents noted feeling more refreshed, focused, and capable the morning after
cannabis use compared to traditional sleep aids. Additionally, they reported
better outcomes the next morning and fewer side effects, such as fewer headaches
and less nausea. “In general, the use of cannabis for sleep-related issues was
perceived as more advantageous than over-the-counter medications or prescription
sleeps aids,” Carrie Cuttler, a WSU professor and one of the study co-authors,
said in a press release on Monday. “Unlike long-acting sedatives and alcohol,
cannabis was not associated with a ‘hangover’ effect.” However, some users
reported side effects such as morning grogginess, anxiety, and irritability.
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The paper, “Terpenes from Cannabis sativa induce antinociception in a mouse
model of chronic neuropathic pain via activation of adenosine A2A receptors,”
was published this month in PAIN, the journal of the International Association
for the Study of Pain. The 14-author team behind the report includes researchers
from the University of Arizona’s Comprehensive Center for Pain and Addiction as
well as the National Institutes of Health (NIH).
“A question that we’ve been very interested in is could terpenes be used to
manage chronic pain?” lead researcher John Streicher, a professor of
pharmacology at the University of Arizona’s College of Medicine in Tucson, said
in a press release about the study. “What we found is that terpenes are really
good at relieving a specific type of chronic pain with side effects that are low
and manageable.”
Authors note that while primary chemical components in marijuana, like THC and
CBD, have been shown in some studies to be effective in managing chronic pain,
“their efficacy is generally moderate, and THC is burdened by unwanted
psychoactive side effects.”
“These limits have focused attention on other potentially therapeutic components
of Cannabis,” they wrote, “including minor cannabinoids, flavonoids, and
terpenes.”
> “Cannabis sativa terpenes were as effective as morphine at reducing chronic
> neuropathic pain and a combination of the two analgesics further enhanced pain
> relief without negative side effects.”
While many plants produce terpenes—the terpene pinene, for example, is made not
only by cannabis but also pine and cedar trees, oranges and rosemary—the study
explains that cannabis is an outlier in its chemical creation.
“While most other plants have 2 dominating terpene species, Cannabis contains up
to 150 terpenes, with multiple terpenes acting as the dominant species,” the
study says, adding that the “complexity of the Cannabis chemovar may determine
the different biological effects caused by different strains of Cannabis.”
The newly published research looked at five terpenes—alpha-humulene,
beta-caryophyllene, beta-pinene, geraniol and linalool—which authors said “are
found in moderate to high levels within Cannabis.”
Solution of terpenes were injected into mice to test how they influenced
measures of both peripheral neuropathic pain and inflammatory pain, which were
induced in the mice through chemotherapy drugs and injections in the animals’
hind paws, respectively. Terpenes were also given to the mice orally and via
vaporization.
Each terpene was tested individually “along with a morphine comparison for
efficacy,” authors explained. Terpenes dosages were 200 mg/kg, while the
morphine comparison was 10 mg/kg.
> “Terpenes are efficacious in producing antinociception in a mouse model of
> neuropathic pain.”
The goal of the study was not only to measure whether terpenes relieved pain in
mice but also the mechanism behind any pain relief. That meant not only
observing the animals’ behavior but also evaluating cell function by, for
example, flash-freezing skin from mouse paws and evaluating its mRNA.
Findings showed that all the tested terpenes seemed to reduce markers of
neuropathic pain, while all terpenes except pinene appeared to treat
inflammatory pain.
“Taken together, this evidence suggests that all terpenes produce robust
antinociception,” the study says of the results for neuropathic pain. For
inflammatory pain, it continues, “all terpenes except b-pinene are effective
antinociceptive agents in this second, different pathological type pain.”
Combining even lower doses of both cannabis terpenes and morphine, meanwhile,
seemed to produce an even stronger pain-relieving effect.
“This brings up the idea that you could have a combination therapy, an opioid
with a high level of terpene, that could actually make the pain relief better
while blocking the addiction potential of opioids,” Streicher said. “That’s what
we are looking at now.”
> “Terpenes produce comparable antinociceptive tolerance to morphine in
> chemotherapy-induced peripheral neuropathy.”
As for whether or not terpenes have “reward liability,” researchers found that
“Crucially, both geraniol and linalool showed neutral conditioning, neither
preference nor aversion, suggesting they do not cause reward or dysphoria.”
“When combined with our pain data above,” they said of the two terpenes, “this
suggests these terpenes could be effective analgesics with no rewarding or
dysphoric side effects.”
“In contrast, both a-humulene and b-caryophyllene showed a significant place
aversion, suggesting they may be dysphoric under these treatment conditions,”
results showed, while beta-pinene also indicated “potential aversive/dysphoric
side effects.”
“Overall, these results suggest that no terpene has reward liability, some have
neither reward nor aversive liability, while some have aversive liability,”
authors wrote. “These observations are crucial when evaluating the potential
clinical utility of these ligands as pain drugs.”
As Streicher explained, “What we found was, yes, terpenes do relieve pain, and
they also have a pretty good side effect profile.”
The method of application also mattered. The study focused on injected terpenes,
which authors acknowledged “is not very translationally relevant” to human use.
However, terpenes given to mice orally and through vaporization had little
observed impact on pain markers, and in some they cases produced modest side
effects, such as hypothermia. Researchers concluded that terpenes administered
orally or through inhalation “have limited bioavailability.”
“A lot of people vape or smoke terpenes as part of cannabis extracts that are
available commercially in states where cannabis use is legal,” Streicher said in
the university release. “We were surprised to find that the inhalation route
didn’t have an impact in this study, because there are a lot of at least
anecdotal reports saying that you can get the effects of terpenes whether taken
orally or inhaled. Part of the confounding factor is that terpenes smell quite
nice and it’s hard to disguise that aroma, so people could be kind of having the
psychosomatic placebo-style effect.”
Examination of how the terpenes worked on a mechanistic level suggested that
terpenes may play an anti-inflammatory role in addition to interacting directly
with some receptors in nervous system.
The findings “suggested that the terpenes are A2AR agonists, as they evoked cAMP
accumulation by the A2AR. However, the exact nature of that agonism is not
clear,” the study says. “The terpenes did not compete with an orthosteric
radioligand (similar to our results with the CBR1), suggesting that they might
be allosteric agonists. However, our modeling studies suggested a mechanism for
the terpenes to bind and activate the A2AR in the orthosteric site.”
“Future work will need to disentangle these mechanisms of selective receptor
engagement in different pain sites,” it adds.
As for how the research translates to pain treatment in humans, authors said the
findings are promising but also demonstrate the need for further study.
“Overall, our observations support the translational utility of terpenes as
potential treatments for neuropathic pain and have identified a novel
A2AR-mediated mechanism, with some terpenes activating this receptor in the
spinal cord,” they wrote. “Further work will be needed to overcome the
translational hurdles identified, such as limited oral/inhaled bioavailability
and antinociceptive tolerance. We also propose to further explore the
antinociceptive mechanisms of action of these ligands, which may pave the way
for development as new clinical therapies.”
As the University of Arizona noted in its release, the findings build on prior
research in which Streicher’s team found that some terpenes mimicked the effects
of cannabinoids, “including a reduction in the sensation of pain, in animal
models of acute pain.”
Though the bulk of cannabis research has centered on primary cannabinoids such
as THC and CBD, terpenes and other minor chemical components of the plant have
become an increasing hot area of study. Another recent study, for example,
published in the Journal of Molecular Sciences, found that the interaction
between cannabinoids and terpenes offers hope for novel therapeutic treatments.
“The plant Cannabis exhibits an effect called the ‘entourage effect’, in which
the combined actions of terpenes and phytocannabinoids results in effects that
exceed the sum of their separate contributions,” the study says. “This synergy
emphasizes how important it is to consider the entire plant when utilizing
cannabinoids medicinally as opposed to just concentrating on individual
cannabinoids.”
Another study published earlier this year looked at the “collaborative
interactions” between cannabinoids, terpenes, flavonoids and other molecules in
the plant, concluding that a better understanding of the relationships of
various chemical components “is crucial for unraveling cannabis’s complete
therapeutic potential.”
Other recent research funded by the National Institute on Drug Abuse (NIDA)
found that a citrusy-smelling terpene in marijuana, D-limonene, could help ease
anxiety and paranoia associated with THC. Researchers similarly said the finding
could help unlock the maximum therapeutic benefit of THC.
A separate study last year found that cannabis products with a more diverse
array of natural cannabinoids produced stronger psychoactive experiences in
adults, which also lasted longer than the high generated by pure THC.
And a 2018 study found that patients suffering from epilepsy experience better
health outcomes—with fewer adverse side effects—when they use plant-based CBD
extracts compared to “purified” CBD products.
Scientist last year also discovered “previously unidentified cannabis compounds”
called flavorants that they believe are responsible for the unique aromas of
different varieties of marijuana. Previously, many had thought terpenes alone
were responsible for various smells produced by the plant.
Similar phenomena are also beginning to be recorded around psychedelic plants
and fungi. In March, for example, researchers published findings showing
that use of full-spectrum psychedelic mushroom extract had a more powerful
effect than chemically synthesized psilocybin alone. They said the findings
imply that mushrooms, like cannabis, demonstrate an entourage effect.
> Lawmakers Push To Let VA Doctors Recommend Medical Marijuana And End THC
> Testing For Federal Job Applicants
Photo courtesy of Kimzy Nanney.
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Ben Adlin
Ben Adlin, a senior editor at Marijuana Moment, has been covering cannabis and
other drug policy issues professionally since 2011. He was previously a senior
news editor at Leafly, an associate editor at the Los Angeles Daily Journal and
a Coro Fellow in Public Affairs. He lives in Washington State.
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