RESEARCH ROUND-UP Highlights from clinical

trials on cannabis science

By Liam Drew

SPASTICIT Y

Cannabinoid hope
for MND
A clinical trial of a cannabi-
noid oral spray that is used
to treat people with multiple
sclerosis (MS) suggests that
the treatment could also
ease the symptoms of motor
neuron disease (MND).
The treatment targets
spasticity, a condition caused
by the permanent contraction
of muscles, which impedes
a person’s movement. It is
a prominent symptom of
both MND and MS. In 2010,
after a long history of people
with MS using cannabis to
self-medicate, a cannabis-
based treatment to manage
spasticity associated with MS
was approved in the United
Kingdom. Giancarlo Comi
at Vita-Salute San Raffaele
University in Milan, Italy, and
his colleagues now suggest
that this same cannabinoid
preparation can ease spasticity
in people with MND. decreased people’s reported psychosis — a condition in of strains containing less than
In a double-blind, rand- pain levels. Future studies which a person’s perception of 10% THC. But using strains
omized phase II trial, 30 people might more finely distinguish reality is distorted. that contained more than 10%
received a placebo and 29 peo- the treatment’s efficacy in two The researchers surveyed THC made the probability of
ple were given the cannabinoid forms of MND: amyotrophic 901 people with psychotic developing psychosis almost
spray — a solution containing lateral sclerosis, in which spas- disorders, who had been five times higher than that of
roughly equal amounts of tet- ticity varies in its prevalence admitted into psychiatric care non-users.
rahydrocannabinol (THC) and and intensity, and the less com- at 10 sites in Europe and one Incidence of psychosis
cannabidiol (CBD), the main mon primary lateral sclerosis, in Brazil, about their present varied considerably between
psychoactive and non-psycho- which is often accompanied by and past cannabis consump- sites, and correlated with
active components, respec- severe spasticity. tion. Their responses were both the availability of high-
tively, of cannabis. Participants Lancet Neurol. 18, 155–164 then compared with those of potency cannabis and the
spent two weeks finding a (2019) 1,237 people without psychiat- number of people who used
dosage with which they were ric diagnoses. cannabis daily. These findings
happy, and then maintained M EN TA L H EA LTH Consistent with previous suggest that potency contrib-
that dose for four weeks. Spas- studies, psychosis was three utes considerably to regional
ticity was measured before and Potent pot linked times more common in people variations in the prevalence of
after treatment.
Whereas spasticity wors-
to psychosis who used cannabis daily than
in people who had never used
psychosis. By looking at where
highly potent cannabis was
ened slightly in the group that High-potency cannabis might the drug. The researchers most available, the research-
received a placebo, it improved carry greater risks to mental then grouped the participants ers calculated that if daily
in those who received the health than do less powerful according to whether they use were accepted as causing
cannabinoid treatment. Of strains. An international study used strains of cannabis that psychosis, eliminating its use
the participants who received led by Marta di Forti at King’s are particularly rich in THC. would reduce psychosis rates
cannabinoids, 55% reported College London suggests that Compared with non-users of in London by 30% and in
feeling better, compared with people who use strains that cannabis, the odds of develop- Amsterdam by 50%.
only 13% of those given a contain large amounts of THC ing psychosis were more than Lancet Psychiatry 6, 427–436
placebo. The cannabinoids also are more likely to develop twice as high for daily users (2019)

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PAIN
Cannabinoids’
analgesic promise
The case of a 66-year-old
woman who feels only mini-
mal pain might have revealed a
new path to pain relief. Investi-
gators think that inhibiting the
breakdown of anandamide, a
fatty-acid amide that interacts
with cannabinoid receptors,
could provide long-term pain
relief.
The woman came to doc-
tors’ attention when, following
an operation on her arthritic
thumb, she required almost
no pain relief. Her medical
records revealed that after
a hip replacement the year
before she had similarly taken
only paracetamol.
James Cox at University
College London, Devjit
Srivastava at Raigmore Hos-
pital in Inverness, UK, and
their colleagues surveyed the
woman’s genome in search
of a genetic basis for her pain
insensitivity. They discovered
two genetic changes affecting
an enzyme called fatty-acid
amide hydrolase (FAAH).
FAAH degrades a number of
fatty-acid amides, including
anandamide — an activator of
the cannabinoid receptor CB1.
One of the genetic changes
was a common mutation
that gives rise to a form of
FAAH with low activity. The
other was the deletion of a
short region of DNA next to
the gene encoding FAAH,
which removed a gene that
closely resembles FAAH. The
researchers proposed that
combining these changes
would cause a person to
exhibit low FAAH activity
and, therefore, a build up of
anandamide. The woman’s
blood samples confirmed this.
The work suggests that an
increased level of anandamide
provides long-term suppres-
sion of pain signalling, and
seems to clinically validate
FAAH as a drug target — a
development that might
encourage more work on
strategies aimed at dampening
FAAH activity.
Br. J. Anaesth. 123, e249–e253
(2019)
CANNABIS OUTLOOK
I M M UN O LO GY clinical trials in several rare a firm mechanistic footing.
autoimmune diseases, includ- Hepatology 69, 1535–1548 (2019)
Inflammatory ing lupus, but the compound
inhibition might also be useful for more
common inflammatory condi-
M E NTA L H E A LTH
A compound that targets the tions such as arthritis. CBD might bring
cannabinoid receptor CB2 can
powerfully suppress inflamma-
Clin. Pharmacol. Ther. 104,
675–686 (2018)
psychosis relief
tion in humans. The drug can- The psychotic effects of canna-
didate, ajulemic acid, has no W E I G H T LOSS bis are commonly attributed to
psychotropic side effects, and its THC content. Conversely,
strengthens the idea that CB2 Safer target for CBD seems to have anti-
activators offer an alternative
way of stopping inflammation.
hunger blockers psychotic properties. A small
clinical trial indicates that
CB2 is almost absent from Drugs that suppress appetite CBD can relieve changes in
neurons in the central nervous and promote weight loss by brain activity that are associ-
system, so activating the recep- blocking the cannabinoid ated with psychosis.
tor causes no psychotropic receptor CB1 could be back To probe CBD’s mecha-
effects. It is, however, abun- on the menu, more than a nism of action, Sagnik
dantly expressed on circulating decade after such a drug was Bhattacharyya at King’s Col-
immune cells, and researchers withdrawn owing to its severe lege London and his colleagues
have known since the 1990s psychiatric side effects. used functional magnetic
that activating CB2 in rodents Rimonabant, approved in resonance imaging (fMRI) to
can suppress inflammation. Europe for use as an anti- see how the drug affected the
Last year, Derek Gilroy at obesity drug in 2006 before brain activity of medication-
University College London and being withdrawn two years free young adults who had
his colleagues, in collaboration later, targets CB1 in the part of sought psychiatric help and
with Corbus Pharmaceuticals the brain that controls hunger. who were considered at high
in Norwood, Massachusetts, Blocking the receptor reduced risk of developing psychosis.
showed that ajulemic acid appetite, but also interfered Participants were given
(developed by Corbus as with other brain functions. either a dose of CBD or a
Lenabasum) also dampened Fresh findings suggest that placebo. The two groups were
inflammation in humans. drugs that block CB1 found then compared with healthy,
only in peripheral organs such age-matched individuals as
“Altered brain as the liver could suppress they all performed a verbal
function in people hunger without inducing learning task. Brain activity
experiencing psychotropic side effects. was recorded using fMRI at the
psychosis could be A study in mice, led by Jie baseline and during memory
modified by a single Liu and George Kunos at the encoding and memory recall.
dose of CBD.” US National Institute on Alco- Compared with healthy
hol Abuse and Alcoholism in people, the brains of those at
Escherichia coli bacteria Bethesda, Maryland, pinpoints high risk of psychosis showed
killed with ultraviolet light two distinct pathways by diminished activation of the
were injected into the skin of which CB1 in the liver affects striatum during encoding,
healthy volunteers to generate metabolic processing. In mice and of the medial temporal
inflammation. Participants fed a high-fat diet, CB1 activa- lobe and midbrain during
were then given a placebo, a tion inhibited three inter- recall. CBD seemed to par-
widely used anti-inflamma- linked intracellular signalling tially reverse those changes:
tory steroid or ajulemic acid. components in the liver, which activation of the areas was
The researchers found that was associated with excess still depressed compared with
both the drug candidate and glucose and insulin in the healthy individuals, but higher
the steroid led to a dramatic blood. Drugs that block CB1 than that in people at high risk
decrease in the number of interfered with this pathway who were given a placebo.
neutrophils that infiltrated and helped to normalized The study suggests that
the injection site, as well as a glucose and insulin levels. altered brain function in people
decrease in the production The researchers also found experiencing psychosis could
of certain pro-inflammatory that such drugs could reverse be modified by a single dose of
lipid signalling molecules. fat accumulation in the livers CBD, supporting the molecule’s
But ajulemic acid also seemed of mice fed a high-fat diet further development as an anti-
to promote clearance of the through a second pathway that psychotic compound.
bacteria and, at higher doses, increases fatty-acid oxidation. JAMA Psychiatry 75, 1107–1117
to stimulate the body’s natural The findings confirm a (2018)
mechanisms for resolving central role for CB1 in regulat-
inflammation — effects that ing liver metabolism and put NATURE.COM
the steroid did not have. the clinical exploration of For the latest Research Highlights
Ajulemic acid is now under- CB1 blockers that are confined published by Nature Research visit:
going phase II and phase III solely to peripheral organs on http://go.nature.com/2xyawlx
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