Serotonin: Where Psychedelics and Cannabinoids Meet for Depression and PTSD

Although cannabis is known for interacting with the endocannabinoid system (ECS) and psilocybin with the serotonin system, these psychoactives and vital signaling systems also interact extensively. The well-known ability of cannabis to boost the psychedelic experience of psilocybin mushrooms hints at their complex interplay. Now, the modalities of cannabis and psilocybin are areas of intense research for mental health disorders such as depression and post-traumatic stress disorder (PTSD). Decades of research have led to the knowledge about how these substances can be helpful—or harmful—to patients.

However, as pointed out by Peter Grinspoon, MD, author of Seeing Through the Smoke: A Cannabis Specialist Untangles the Truth About Marijuana, “On cannabis, there’s a big chasm between what the psychiatrists believe and what the millions of users believe on whether it’s helpful for depression or PTSD. It’s been confused by the War on Drugs and the US only funding studies on harms, not benefits. That work just wasn’t done. Many people are using cannabis for depression and PTSD. It’s hard to find a veteran who doesn’t say it helps them. So, it’s the conundrum of listening to patients and taking a leap of faith without full evidence.”

The situation is also complicated on the psychedelic side. Julie Holland, MD, author of Good Chemistry: The Science of Connection, From Soul to Psychedelics, says, “When considering risks with psychedelics, interpersonal harms and boundary violations need to be discussed frankly. Psychedelics often engender massive shifts in self-perception and cognitive flexibility. These effects can be both therapeutic or dangerous, fully depending on context.”

The Serotonin Connection

The systems influenced by these complex natural medicines intertwine. The ECS consists of endogenous cannabinoids (primarily anandamide and arachidonoyl glycerol [2-AG]), cannabinoid receptors (eg, CB₁, CB₂), and enzymes that synthesize and degrade endocannabinoids.¹ The serotonin system uses serotonin and serotonin receptors 5-HT1 through 5-HT7 and enzymes that synthesize and degrade serotonin.² Both systems are widely distributed throughout the brain and influence neuronal activity, synaptic plasticity, receptor co-localization, crosstalk, and modulation of neurotransmitter release.

For instance, a recent clinical genetic study found that the low levels of serotonin and endocannabinoids linked to depression may be influenced by a particular genetic variant of the CB₁ receptor.³ And remarkably, the CB₁ receptor forms heteromeric complexes with the serotonin 5-HT2A receptor, joining these 2 systems at their most psychoactive points.⁴ How do these systems work together in depression and PTSD and what is the existing evidence for psilocybin and cannabinoid-based therapy?

The 5-HT2A receptor is implicated in the modulation of cortical activity, perception, cognition, and emotion. As such, it—and the serotonin system in general—is the target of many pharmaceutical approaches to treating depression and PTSD, including selective serotonin reuptake inhibitors (SSRIs).⁵

The ECS interacts with the serotonin system, and they share control over many of the same physiologic functions.⁶ Activating the CB₁ receptors inhibits serotonin release in brain areas, such as the prefrontal cortex and hippocampus, while antagonizing them lowers release in the medial prefrontal cortex.^7-9 CB₁ receptors also regulate the levels of serotonin receptors and the firing rate of serotoninergic neurons, whereas CB₂ receptors form heteromeric complexes with 5-HT1A receptors, creating a joined signaling unit.^10,11 Even the newly discovered endocannabinoid pentadecanoylcarnitine binds to 2 of the serotonin receptors.¹²

The 2 most-studied endocannabinoid neurotransmitters are 2-AG and anandamide (the latter is sometimes called the “neurotransmitter of balance”). Anandamide’s ability to activate CB₁ and CB₂ receptors gives it modulatory power over serotonin via the mechanisms above. But the crosstalk goes both ways. Activating the 5-HT2A receptor causes the release of 2-AG, and serotonin receptors can suppress synaptic firing via the release of endocannabinoids.^13,14

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most well-known cannabinoids from the cannabis plant. THC, a partial agonist at both the CB₁ and CB₂ receptors, is responsible for the psychoactive effects of cannabis, whereas CBD is a weak antagonist or inverse agonist at the cannabinoid receptors. Both these major cannabinoids work closely with serotonin:

• THC binds to the heteromer complex of CB1 and 5-HT2A⁴
• CBD binds to the 5-HT1A, 5-HT2A, and 5-HT3A receptors^15-17
• CBD inhibits fatty acid amide hydrolase (FAAH), an enzyme that breaks down anandamide, thereby increasing anandamide levels¹⁸
• Cannabinoid receptor agonists upregulate levels of 5-HT2A receptors and change their activity, whereas long-term cannabinoid activation downregulates the levels of 5-HT1A receptors^16,19,20

The Mushroom

Psilocybin is a naturally occurring psychedelic compound found in some species of mushrooms. It is metabolized to psilocin, which is a partial agonist at several serotonin receptors, especially the 5-HT2A subtype. This receptor is responsible for mediating the psychedelic effect.

Psilocybin, with a notable clinical safety record, raises levels of the brain growth factor BDNF (brain-derived neurotrophic factor), encourages growth of new dendritic spines, induces neuroplasticity, and increases synaptogenesis in the hippocampus and prefrontal cortex.^21-24 These brain regions are involved in learning, memory, and emotional regulation and are often impaired in depression and PTSD. The ability of classic psychedelics to influence the microbiome and the gut–brain axis, a central source of serotonin, may also underlie their help for these disorders.²⁵

Several clinical trials have demonstrated that psilocybin-assisted psychotherapy can produce rapid and sustained reductions in depressive symptoms in patients with treatment-resistant depression (TRD), major depressive disorder (MDD), or cancer-related depression.^26,27 For example:

• An open-label trial with 12 patients with TRD found that a single dose of psilocybin combined with psychological support significantly reduced depressive symptoms at 1 week and 3 months post-treatment²⁸
• A randomized controlled trial (RCT) with 29 patients with cancer-related distress found that a single dose of psilocybin combined with psychotherapy significantly reduced anxiety and depression at 6 months post-treatment²⁹
• An RCT with 52 patients with MDD found that a single dose of psilocybin helped with symptoms of major depression for 2 weeks³⁰
• An RCT with 24 patients with MDD found that 2 doses of psilocybin combined with supportive therapy significantly reduced depressive symptoms at 4 weeks post-treatment³¹
• An open-label trial reported that psilocybin improved psycho-social-spiritual healing in 30 patients experiencing cancer and depression³²

Additionally, a case study described a man who treated his TRD by microdosing psilocybin.²¹ The effects presented in these publications seem linked to increased brain network integration, changes in the amygdala, and the growth of new brain connections.^22-24

On the pharmaceutical side, a head-to-head study of psilocybin vs the antidepressant escitalopram found that they had similar efficacy scores after 6 weeks.³³ Although psilocybin and escitalopram helped decrease rumination in another trial, only psilocybin helped with thought suppression.³⁴ In October 2022, Compass Pathways announced the results of a phase 2B study finding that 25 mg of psilocybin improved TRD in one treatment group (79 of 233 participants).³⁵ The company has now begun the first-ever phase 3 trial of psilocybin.³⁶

Less work has been done on psilocybin for PTSD and trauma-related disorders.³⁷ In traumatized survivors of AIDS, an open-label study with psilocybin-assisted psychotherapy reduced PTSD symptoms, anxiety, and demoralization.³⁸ Other trials show positive preliminary results for confronting traumatic memories; decreasing emotional avoidance, pessimism, and disconnection from others; and increased self-compassion, forgiveness of abusers, and self-acceptance.³⁷

The Weed

The Theory Behind the Therapy

Cannabinoid-based therapy refers to the use of substances that act on the cannabinoid receptors CB₁ and CB₂, which are widely distributed throughout the brain and body. As described above, these receptors are integrally involved in the modulation of serotonin levels, making cannabinoid-based therapy of potential interest in treating depression and PTSD. For depression specifically, the cannabinoids also target several related molecules, including the N-methyl-d-aspartate, g-aminobutyric acid, and cholecystokinin receptors, as well as monoamine oxidase.³⁹ It is even thought that the mood-boosting effects of exercise (“the runner’s high”) and the benefits of shock therapy and transcranial magnetic stimulation may be mediated by the ECS.^40-42

Although THC may have antidepressant effects in low doses, it can also cause anxiety and paranoia in high doses.^43,44 CBD’s antidepressant effects may be mediated by its anti-inflammatory effects in the brain and its ability to interact with serotonin and glutamate, as well as increase BDNF and neurogenesis.^44-46 In mice, the antidepressant effects of CBD are dependent on brain serotonin levels, and in rats, CBD blocks the formation of fearful memories via a circuit in the mesolimbic system.^47,48 Similar to SSRIs, CBD modulates sensitivity to serotonin, and the activation of the CB₂ receptor enhances the efficacy of antidepressants.^49,50 In a PTSD-like effect, CBD uses the 5-HT1A receptor to calm mice placed next to snakes.⁵¹ Blocking the 5-HT1A serotonin receptor suppresses the antidepressant effects of CBD.^15,52,53

When recommending cannabinoid-based therapy, some clinicians prefer full-plant extracts that draw on the dozens of minor cannabinoids, terpenes, and fatty acids in the plant. The ability of these cannabinoids and terpenes to enhance the power of THC or CBD is called “the entourage effect.”⁵⁴ Ethan Russo, MD, has suggested that an “endocannabinoid deficiency syndrome” may underlie several pathologies; this may be true for endocannabinoid levels and depression.^55,56 In the future, endocannabinoid levels may even be a useful diagnostic tool for depression.^57,58 Additionally, for the 5-HT1A receptor, cannabigerol acts as an antagonist, tetrahydrocannabidivarin and cannabidiolic acid are agonists (the latter also enhances receptor activation), and the terpene linalool inhibits serotonin receptor transmission.^59-62

The Literature

Cannabinoid-based therapy has shown promise for treating depression and PTSD, although the evidence is less consistent and conclusive than psilocybin.^63,64 Many studies on cannabinoid-based treatment for depression and PTSD have used synthetic cannabinoids, such as nabilone and dronabinol, rather than cannabis, THC, or CBD. Moreover, the studies have been limited by small sample sizes, short duration, lack of placebo or active comparators, and heterogeneous outcome measures. Therefore, more rigorous and larger trials are needed to establish the efficacy and safety of cannabinoid-based therapy for these disorders.

As Dr. Grinspoon shared, “I’ve had tremendous success using cannabis for PTSD with patients, but for depression, people say it alleviates symptoms. But the question of the psychiatrist is whether it changes the disease course of the depression. And it seems like cannabis doesn’t change the course of the disease, just the symptoms. But that’s the same case for the SSRIs. Why is there a different standard being used?”

Other positive evidence for cannabinoid-based therapy for depression includes:

• A review of data from the UK Medical Cannabis Registry that found cannabis treatment to be associated with depression severity reduction for up to 6 months⁶⁵
• Data from a cannabis app in which people reported immediate relief from depression symptoms⁶⁶
• A rare survey of users of cannabigerol-rich full-spectrum cannabis, who reported it helpful for depression⁶⁷
• A case study of a teen with depression and problematic drug use who was able to stop his depression medication with high levels of CBD⁶⁸

However, not all the literature supports the use of cannabis in treating depression. Examples include:

• A review of Canadian public health data that found medical cannabis use was associated with an increased risk for depressive disorders⁶⁹
• A Canadian review of clinical studies with bipolar disorder and MDD that found cannabis use was associated with worsening symptoms and course of the disease as well as increased suicidality and decreased functioning⁷⁰
• A study of patients with MDD that found abstinence from cannabis for 1 month improved their performance in some cognitive domains⁷¹
• In a survey of college students, a greater severity of cannabis use disorder symptoms was associated with more severe PTSD symptoms and an increased risk for non-suicidal self-injury⁷²
• A literature review that found “considerable evidence of a strong relationship between cannabis use and depression in adolescents”, but compounding factors limit the ability to draw an “indistinct correlation between cannabis use and depression in adolescents”⁷³

The benefits are more clearly marked with cannabinoid-based therapy for PTSD. For example:

• A review of data from the UK Medical Cannabis Registry found that those with PTSD using cannabinoids saw significant improvements in PTSD symptoms, sleep, and anxiety⁷⁴
• A study of adults with PTSD found that 10 mg of THC helped with problems in the limbic system while 5 mg decreased activation of the amygdala⁷⁵
• A double-blind, placebo-controlled trial found CBD significantly lowered stress levels in people with PTSD while recalling traumatic events⁷⁶
• A survey and a double-blind study in Canadian soldiers with PTSD found that nabilone (synthetic THC) was helpful for nightmares^77,78
• A pilot study in humans showed that THC helped to extinguish fear conditioning induced by visual stimuli and electric shocks⁷⁹
• An RCT of individuals with PTSD found that a low dose of THC helped with emotional processing during an emotional regulation task⁸⁰
• In a case series of 11 patients, CBD improved the PTSD scores for 10 of them⁸¹
• A case report on a woman with complex dissociative PTSD reported very positive effects from cannabis-assisted psychotherapy⁸²

On the pharmaceutical side, Jazz Pharmaceuticals recently started enrolling patients in its PTSD clinical trial for JZP150, an inhibitor of FAAH (a mechanism shared by CBD).⁸³

Conclusions

Both psilocybin and cannabinoid-based therapy have potential advantages over conventional pharmacotherapy for depression and PTSD. They may have faster onset of action, longer duration of effect, fewer side effects, lower risk for dependence or tolerance, and more holistic effects on cognition, emotion, and spirituality. However, they also have potential disadvantages, such as unpredictable effects, unpleasant reactions, potential interactions with other drugs or medications, legal risks, and social stigma. Moreover, both psilocybin and cannabinoid-based therapy require careful screening, preparation, monitoring, and integration of the drug-induced experiences, which may limit their accessibility and acceptability for some patients.

Psilocybin and cannabinoid-based therapy are 2 promising modalities for the treatment of depression and PTSD, but they are not magic bullets or panaceas. Both substances have been shown to modulate the ECS and serotonin systems, which are involved in mood regulation and stress response. However, the evidence for their efficacy and safety remains limited and inconsistent, and more research is needed to establish their optimal doses, formulations, modes of administration, and long-term effects.

For more on psychedelic-assisted therapy for depression and PTSD, be sure to watch AJEM Live with Yale-trained psychiatrist Jordan Sloshower, MD, MSc.