New evidence revealed in a study from Spain (titled: Cannabidiol Induces Rapid-Acting Antidepressant-Like Effects and Enhances Cortical 5-HT/Glutamate Neurotransmission: Role of 5-HT1A Receptors) provides evidence that the cannabinoid CBD (cannabidiol) may be an effective treatment for depression. The study was published in Volume 103 of the Journal of Neuropharmacology (2016).

Depression affects nearly fifteen million adults across the United States. Every year, roughly $42 billion dollars are spent on prescription medicines for depression and anxiety, including brands like Prozac, Zoloft, and Wellbutrin. This new evidence indicates that CBD could be an effective alternative to these pharmaceutical approaches.

Materials and Methods Used in the Study

The study examined three month old mice (C57BL/6, 25-30mg) after undergoing either an olfactory bulbectomy, or a sham-operation. The mice that received the olfactory bulbectomy procedure are referred to throughout the study as OBX mice.

C57BL/6 Mice (source)

C57BL/6 Mice (source)

The olfactory bulbectomy has been proposed and secured as a model of depression used in clinical studies. After the operation, mice exhibit hyperactivity in enclosed arenas, nocturnal hyperactivity, memory deficits, changes in food motivation, and alterations within neurotransmitter systems of serotonin and glutamate production.

Open Field Tests Examine Agitation, Anxiety, and Hyperactivity

Open Field Tests Examine Agitation, Anxiety, and Hyperactivity

This study examined both behavioral and neurochemical tests. Behavioral tests included open field and sucrose preference tests, and the neurochemcial tests included microdialysis and autoradiography of serotonin receptor (5-HT1A) functionality.

Traditional Depression Medications and How Neurotransmitters Treat Depression

Traditional western medicine employs a variety of medications to treat depression. Different chemicals are used in antidepressant medication, each one targeting a specific neurotransmitter, or group of neurotransmitters. A particularly well known type of antidepressants are called SSRIs (selective serotonin reuptake inhibitors).

“SSRIs block the reabsorption (reuptake) of the neurotransmitter serotonin in the brain. Changing the balance of serotonin seems to help brain cells send and receive chemical messages, which in turn boosts mood.”

Mayo Clinic on SSRIs

There are many SSRIs with brand names that are regularly advertised on television and radio: Prozac, Lexapro, Zoloft, and more.

This study focuses on the cannabis compound CBD (cannabidiol) as a novel treatment for depression symptoms.  Activity of serotonin, glutamate, and the 5-HT1A  receptor are of particular interest for these researchers as they monitor the OBX and sham-operation mice. The results of the study indicate that CBD can provide both rapid and long-term antidepressant-like effects.

Graphical Findings from the CBD Study

All graphs are from the study: “Cannabidiol Induces Rapid-Acting Antidepressant-Like Effects and Enhances Cortical 5-HT/Glutamate Neurotransmission: Role of 5-HT1A Receptors,” with image credit going to  R. Linge et al. in Journal of Neuropharmacology: 103 (2016) 16-26 (DOI: 10.1016/j.neuropharm.2015.12.017).

Figure 1:


Fig. 1. Acute effects of CBD in the open field test. Acute CBD (50 mg/k; i.p.) significantly reversed both OBX-induced hyperactivity (A) and decreased central ambulation (B) 30 min post-injection and it was devoid of any behavioral effect in sham counterparts. Data represented as mean ± SEM, n 1⁄4 6e7 mice per experimental group (*p < 0.05 and ***p < 0.001 vs. SHAM VEH; #p < 0.05 and ##p < 0.01 vs. OBX VEH).

Figure 2

Figure 2. Time-course effects of CBD administration in the open field and sucrose preference tests. The effect of CBD upon the OBX-induced hyperactivity (A) and decreased central activity (B) was evidenced throughout the treatment assessed 24 h post 1, 3, 7 and 14 days of drug administration. Additionally, chronic CBD reversed OBX-induced anhedonia following 7 days of administration (C). Data represented as mean ± SEM of n 1⁄4 7e9 mice per experimental group (*p < 0.05, **p < 0.01 and ***p < 0.001 vs. SHAM VEH; ##p < 0.01 and ###p < 0.001 vs. OBX VEH).

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Figure 3. Differential effects of acute and chronic CBD upon 5-HT and glutamate levels in ventro-medial prefrontal cortex of OBX and sham mice. Acute CBD (50 mg/kg; i.p.) increased extracellular 5-HT in the vmPFCx of OBX-mice but not in sham animals (A), and increased glutamate levels in both groups (B). Following chronic administration, a challenge dose of CBD increased extracellular 5-HT in sham and OBX mice (C), whereas it induced an increase of glutamate efflux only in OBX mice (D). Chronic CBD did not produce any significant change in 5-HT absolute basal levels (E) though it did increase glutamate absolute basal levels in both sham- and OBX-treated mice (F). Data represented as mean ± SEM, n 1⁄4 5e7 animals per experimental group (**p < 0.01 vs. SHAM VEH; #p < 0.05 and ##p < 0.01 vs. OBX VEH).

Figure 4. Box and whiskers plot of 5-HT1A receptors functionality in different brain areas after chronic administration of CBD. A decreased (±)8-(OH)-DPAT stimulated [35S]GTPgS binding was measured in DRN, CA1-CA2, and AMY in OBX mice compared with sham animals. This impaired 5-HT1A receptor functionality in OBX-mice was restored after chronic administration of CBD. A higher (±)8-(OH)-DPAT stimulated [35S] GTPgS binding was detected in the mPFCx in all CBD-treated mice. Results are expressed as percentage of [35S]GTPgS binding stimulation over basal values, as mean ± minimum/maximum of n 1⁄4 6e9 mice per experimental group (*p < 0.05 and **p < 0.01 vs. SHAM VEH; #p < 0.05 and ##p < 0.01 vs. OBX VEH).

Figure 4. Box and whiskers plot of 5-HT1A receptors functionality in different brain areas after chronic administration of CBD. A decreased (±)8-(OH)-DPAT stimulated [35S]GTPgS binding was measured in DRN, CA1-CA2, and AMY in OBX mice compared with sham animals. This impaired 5-HT1A receptor functionality in OBX-mice was restored after chronic administration of CBD. A higher (±)8-(OH)-DPAT stimulated [35S] GTPgS binding was detected in the mPFCx in all CBD-treated mice. Results are expressed as percentage of [35S]GTPgS binding stimulation over basal values, as mean ± minimum/maximum of n 1⁄4 6e9 mice per experimental group (*p < 0.05 and **p < 0.01 vs. SHAM VEH; #p < 0.05 and ##p < 0.01 vs. OBX VEH).

Figure 5. Behavioral effects of acute CBD in OBX mice were prevented by 5-HT1A receptor blockade. In the open field test, WAY100635 (0.3 mg/kg; i.p) prevented both the reversal of OBX-hyperactivity (A) and the increase of central activity (B) induced by CBD (50 mg/kg). By contrast the selective CB1 receptor antagonist AM251 (0.3 mg/kg; i.p.) did not counteract any of these effects. Data represented as mean ± SEM of n 1⁄4 5e7 animals per experimental group (*p < 0.05 vs. vehicle-treated group; #p < 0.05 and ##p < 0.01 vs. CBD- treated group).

Figure 5. Behavioral effects of acute CBD in OBX mice were prevented by 5-HT1A receptor blockade. In the open field test, WAY100635 (0.3 mg/kg; i.p) prevented both the reversal of OBX-hyperactivity (A) and the increase of central activity (B) induced by CBD (50 mg/kg). By contrast the selective CB1 receptor antagonist AM251 (0.3 mg/kg; i.p.) did not counteract any of these effects. Data represented as mean ± SEM of n 1⁄4 5e7 animals per experimental group (*p < 0.05 vs. vehicle-treated group; #p < 0.05 and ##p < 0.01 vs. CBD- treated group).

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Figure 6. Neurochemical effects of acute CBD were prevented by 5-HT1A receptor blockade. In microdialysis studies, cortical 5-HT outflow induced by CBD in OBX animals was prevented by WAY100635 co-administration (A). In sham mice, the co-administration of WAY100635 and CBD resulted in increased 5-HT levels in vmPFCx (B). Increased cortical glutamate levels induced by CBD were also abolished by WAY100635 in both OBX (C) and sham mice (D). Data represented as mean ± SEM of n 1⁄4 5e7 animals per experimental group (*p < 0.05 and **p < 0.01 vs. respective vehicle-treated group; #p < 0.05 and ##p < 0.01 vs. respective CBD-treated group).

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Figure 7. Proposed neurochemical mechanism of action of CBD to induce fast antidepressant effects. In prefrontal cortex, CBD would potentiate the inhibitory function of 5-HT1A receptors upon GABA-ergic interneurons, favoring glutamate signaling in postsynaptic areas, the stimulation of pyramidal descending projections to DRN, and therefore the neuronal firing of serotonergic neurons, and the 5-HT increase in mPFCx. In DRN, CBD would increase the firing of serotonergic neurons by reducing the inhibitory effect of GABAergic interneurons, without the detrimental effect of somatodendritic 5-HT1A receptors which are desensitized in OBX mice, therefore leading to an increase in 5-HT levels in PFCx.

Results and Discussion: CBD as a Novel Treatment for Depression

As shown in the graphs above, the symptoms of depression were mitigated by CBD in mice that had undergone OBX and sham operations. CBD exhibited positive effects for both acute and chronic depression models. The conclusion section of the study explains the overall findings very succinctly:

“In all, CBD is a multi-target drug that can modulate a variety of systems implicated in mood control and therefore, result in a great value from a clinical point of view.

This work evidences that CBD could represent a novel drug for treating depressive disorders in a very fast manner, acting via the enhancement of serotonergic and glutamatergic transmission through the modulation of 5-HT1A receptors.

The fast onset of antidepressant action of CBD and the simultaneous anxiolytic effect would solve some of the main limitations of the current antidepressant therapies.

Furthermore, the broad range for therapeutic dosage and the lack of psychotomimetic effects confers a fundamental advantage for its use in clinical practice compared to other fast-acting antidepressant alternatives.

Finally, this novel strategy consisting in the dual potentiation of serotonergic and glutamatergic transmission could bring new light to the discovery of new fast and effective antidepressant therapies.”

Cannabidiol clearly has a role in neurotransmitter activity. Science is beginning to understand more about interactions between CBD and the many receptors involved in mood regulation, which will hopefully result in new medical approaches for treating symptoms of depression.

Cannabis Reports supports all cannabis studies because clinical data will help us all better understand our relationship with cannabis. Check out our science feed for future examinations of cannabis research. For the most up to date info on Cannabis Reports, follow us on Twitter, and like us on our Facebook page.