A preclinical study found that repeated CBG treatment prevented a long-term recognition memory impairment induced by MK-801 in male rats, an experimental model used to study cognitive deficits relevant to schizophrenia. The effect did not appear to involve restoring reduced BDNF protein levels, though changes in TrkB messenger RNA point to a possible mechanism that will require further research.
CBG (cannabigerol), the precursor molecule from which THC and CBD are formed in the cannabis plant, and a cannabinoid far less studied than either of them, has just given researchers another reason to pay attention.
A preclinical study published online ahead of print by Pharmacology Biochemistry and Behavior found that CBG prevented a long-term memory deficit in male rats treated with MK-801, a compound commonly used in experimental models of cognitive impairments associated with schizophrenia.
Does that mean CBG improves memory in people with schizophrenia? No, but the results offer an interesting clue about a problem for which there are still no approved treatments: the cognitive deficits that can accompany the disorder.
CBG and a Memory Problem
Schizophrenia affects about 23 million people worldwide, or roughly one in 345, according to the World Health Organization, and can cause persistent difficulties across a range of cognitive functions.
These impairments can affect memory, attention, learning and executive function, and can have real-world consequences for a person’s ability to study, work, maintain relationships or live independently. The authors of the new study describe the pharmacological options for treating them as limited, note that some research finds all antipsychotics have minimal effect on cognitive function, and cite estimates that 30% to 35% of patients with schizophrenia are treatment-resistant.
That’s where the new study comes in. It was carried out by researchers at the Instituto de Investigaciones Biológicas Clemente Estable and the Universidad de la República, in Uruguay, together with colleagues at Phytoplant Research, the Universitat de Vic-Universitat Central de Catalunya, the University of Barcelona and Spain’s Biomedical Research Networking Center in Mental Health.
To study CBG’s potential effects, the researchers used MK-801, a substance that blocks certain NMDA receptors in the brain. In animals, this compound can cause cognitive impairments that mimic some of the deficits observed in schizophrenia, which is why it is commonly used as an experimental model.
The study used 67 adult male Wistar rats, bred and housed at the institute’s facilities in Montevideo. The researchers gave them repeated doses of CBG at 10 mg/kg, and some of the animals then received a single 0.1 mg/kg dose of MK-801, while others received a control solution. Then came the test.
Did the Rats Remember What They Had Seen?
To measure memory, the researchers used a fairly intuitive test known as novel object recognition.
First, the rats are exposed to certain objects. The following day, one of them is replaced with a new one.
Normally, if an animal remembers what it saw before, it spends more time exploring the new object. If it fails to distinguish between the old and new objects, that may indicate impaired recognition memory.
That is exactly what happened in the rats that received only MK-801: they stopped showing a preference for the new object.
By contrast, the rats that had received CBG retained that ability, even after receiving MK-801.
According to the authors, CBG prevented the long-term recognition memory impairment caused by the experimental compound.
The researchers also had to rule out a much less exciting explanation: that the treated rats were simply moving around more and therefore spent more time exploring. According to the study, neither MK-801 nor CBG nor the combination affected locomotor activity. MK-801 did reduce rearing, the behavior of standing up on the hind legs, but the authors report that this did not change how long the animals spent exploring the objects.
Things Got a Little Stranger Inside the Brain
The researchers also tried to determine how that effect might be occurring.
One of the main suspects was BDNF, a protein associated with brain plasticity, learning and memory.
MK-801 reduced BDNF protein levels in two regions involved in these processes: the hippocampus and the medial prefrontal cortex. If CBG was preventing the cognitive impairment, one logical possibility was that it might also restore those BDNF levels. But it didn’t.
Even though the rats maintained their performance on the memory test, CBG did not restore the BDNF protein levels reduced by MK-801.
Then another clue emerged: the combination of CBG and MK-801 significantly increased messenger RNA expression for TrkB, a receptor closely involved in BDNF signaling, in the medial prefrontal cortex.
In very simplified terms, CBG appeared to influence part of the molecular machinery involved in memory, but not through the most obvious mechanism the researchers expected to find.
The authors suggest that TrkB signaling may contribute to the observed effect through a mechanism independent of direct changes in BDNF.
Promising, Yes; a Treatment, Not Yet
The study was conducted exclusively in male rats. The researchers did not test different CBG doses or dosing schedules, and they have not yet confirmed whether the changes observed in TrkB messenger RNA extend to the protein level.
Also, MK-801 does not give rats “schizophrenia.” It is an experimental tool that mimics certain cognitive deficits relevant to the study of specific aspects of the disorder.
For that reason, the results do not show that CBG treats schizophrenia, improves memory in human patients or should be used clinically for that purpose.
What they do show is something much narrower and, for that very reason, still interesting: in this preclinical model, CBG was able to preserve a form of memory that MK-801 had impaired.
And for a cannabinoid that remains far less studied than its more famous relatives, that is enough to justify a second look.
Disclosure: the study was funded by Uruguayan public science programs, including MEC-DICYT and PEDECIBA. The cannabigerol was donated by Phytoplant Research S.L.U., a Spanish cannabis research company, and two of the paper’s authors, Carlos Ferreiro-Vera and Verónica Sánchez de Medina, work for the company, according to its competing interest declaration.
Editor’s note: this article describes findings in animals. Preclinical research is an early step and does not establish that a compound is safe or effective in people. Nothing here is medical advice, and no one should change or stop a prescribed treatment based on it.
