The current study supports and expands upon the recent work by Cuttler et al. (2018) [38] by measuring which types of Cannabis flower characteristics among common product alternatives are associated with relief from depression. Rather than including a wide range of cannabis products (e.g. topical and edibles) and treating THC and CBD potency levels as continuous measures, we focused exclusively on Cannabis flower and allowed the effects of THC and CBD to vary nonlinearly, comparing across ordinal categories (e.g. low, medium, and high) to best represent the restricted range of potency levels in which Cannabis flower “strains” are typically marketed and to reflect recent findings in the literature that suggest that the increasing THC can have opposite effects depending on the baseline level [43] or that the effect may plateau at high levels, at least for pain conditions [44]. Both the current study and Cuttler et al. (2018) [38] showed that common and commercially available Cannabis products used by millions of people every day affect self-reported depression intensity. Also similar, while some user sessions resulted in the manifestation of experiences that contribute to depression and low mood (e.g. feeling unmotivated), both studies showed the vast majority of people reported an overall symptom intensity reduction (over 95% in the current study), with an average reduction of three to four points on a standard 0 to 10 scale. The mobile software technology helps solve the challenge of measuring and informing the patient as to the pharmacodynamic effects of an inherently variable ethnomedicinal product that was once alive and that, even across cloned batches, can show chemotypic differences. Not only does plant heterogeneity limit the value of randomized controlled trials using a specific cannabis formulate, but it also forces patients to constantly experiment with fundamentally new products. By enabling prospective, real-time recording of cannabis administration sessions across the vast range of commonly available and chemotypically distinct products and consumption methods used by the general population, the current study made it possible to measure whether consumption of Cannabis flower products immediately affected changes in depression symptom intensity levels and which types of common product characteristics are associated with the strongest effects. The findings suggest benefits from patient-directed, cannabis therapy as an antidepressant treatment; however, effectiveness and side effect manifestation vary across different types of Cannabis flower with different cannabinoid potency levels.

In addition to the similarity across studies in the apparent general clinical effectiveness of using Cannabis flower for reducing feelings of depression, differences existed in the associations between the product characteristics and the extent of symptom relief. Although Cuttler et al. (2018) [38] reported that cannabis products with high CBD / low THC values statistically predicted the greatest improvements in feelings of depression, it is unclear which types of products (e.g. topicals vs edibles) such values would apply. Instead, we found that Cannabis flower with relatively higher THC potency levels emerged as the strongest independent predictor of symptom relief and experienced side effects, but that the benefit of higher THC appears to plateau to some extent such that products with THC ranges of 10-19% and 20-35% offer greater relief than products with THC less than 10%, but increasing from 10-19% to 20-35% does not convey additional benefits in terms of symptom relief. In contrast, flower with CBD potency levels greater than 1.0% were generally not predictive of changes in depressive symptom levels and may even reduce depression symptom relief reported within short treatment windows, e.g. less than 2 hours to ending effect. Understanding these effects is challenging given the complexity of the etiology of depression which involves much more than a mere neurochemical imbalance. Dysregulation of the hypothalamic-pituitary-arenal (HPA) axis, cancer, pathogens, gut dysbiosis (microbial imbalance), nutritional deficiencies, degenerative neurological conditions, endocannabinoid system disruption, immune system dysregulation, chronic pain, substance abuse, prescription medications, abuse, social isolation, conflict, death, trauma, family history, and chronic stress may all be contributing factors of depression [45,46].

Early antidepressants, primarily monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants, targeted dopamine receptors in the brain, and were effective for reducing depressive symptoms, but only after several weeks to effect and with potentially severe negative side effects, including sedation, substantial weight gain, and deadly food interactions [47]. Selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), which target serotonin and norepinephrine generation rather than dopamine levels, can also carry intolerable side effects (e.g. sedation, agitation, anxiety, suicidal ideation, anorgasmia, and demotivation) and also have times-to-effect of as many as 5 to 6 weeks, making them of little use in the short run to many dangerously ill individuals at risk of harming themselves or others [48]. More recent research has furthermore documented significant withdrawal symptoms associated with cessation of SSRI use [49]. As a result, individuals who are nonresponsive to or who cannot tolerate selective SSRIs and SNRIs are frequently prescribed older or modified versions of the older antidepressants that enhance dopamine neurotransmission (e.g. MAOIs, dopamine receptor agonists) [50]. Newer versions of some products, e.g. EMSAM, a transdermal version of the monoamine oxidase inhibitor selegiline, carry lower risks including reduced food interactions, but still involve significant risks and relatively long times-to-effect, when they are effective, which appear to vary by person and with medication-specific tolerances [51,52]. When comparing these drawbacks to the relatively minor negative side effects and quick acting effects reported by the Cannabis users in the current study, it is understandable why some patients might choose to replace or augment their conventional pharmaceutical antidepressant treatment with medical Cannabis when given the legal opportunity to do so.

Our results indicate that THC in particular is positively correlated with an immediate reduction in the intensity of depressive feelings. Animal studies have shown that, like conventional antidepressants, THC affects dopamine, serotonin, and norepinephrine generation [53,54]. The differences in time-to-effect and relative side effect prevalence across products and users could arise from other antidepressant and synergistic compounds in the plant beyond THC or CBD, and prior research suggests there may be several thousand cannabis chemotypes, each with its own unique symphony of compounds [55]. In addition to the mood-elevating effects of THC, several terpenoids are known to exhibit antidepressant properties independent from cannabinoids. At least 200 terpenoids are reported to be present within Cannabis, and while their yield is usually less than 1% in dried flower, they may constitute as much as 10% of the total trichome content [56]. Only limited research exists on the effects of specific terpenoids. The terpenoid, D-limonene, in particular, appears likely to have antidepressant effects in humans and typically composes more than 50% of commercially available citrus oils [57]. One study found that citrus oil-based fragrance either eliminated the need for or substantially reduced the required dosage of antidepressants [58]. A later study using mice found that, when compared to the SSRI fluoxetine, 400 mg/kg of lemon essential oil was shown to reduce immobility time in mice that were subjected to a tail suspension test (TST). The dose was shown to significantly increase the levels of serotonin, norepinephrine, and dopamine in the mouse prefrontal cortex (PFC), striatum, and hippocampus. The results also indicated no evidence of negative side effects across all dosage levels received by the mice [59].

The relative predominance of specific cannabinoids, flavonoids, and terpenoids can also vary considerably from one plant to another according to combustion method. For example, vaporizing Cannabis flower differs from other forms of combustion by allowing the user to select the precise temperature required to target the desired compounds, while pipe use and joints require full combustion of the plant material. In addition to preserving cannabinoid, flavonoid, and terpenoid contents that evaporate at lower temperatures than THC and CBD, vaporizing rather than combusting the plant material could preserve THC levels as well. Although some research has shown that THC rate of delivery is comparable between vaporization and combustion, the process of combustion may destroy as much as 20-30% of the THC [60,61]. Combustion can also result in the pyrolytic degradation of hundreds of therapeutic terpenoids and phenolic compounds, such as flavonoids [62,63], which are conventionally believed to contribute to the enhanced “entourage” effect of whole flower rather than what is experienced from using THC or CBD isolates. Compounds found in the Cannabis plant have demonstrable anti-microbial, anti-oxidant, analgesic, neuroprotective, anxiolytic, and anti-inflammatory effects [64]. Certain combinations of both cannabinoid and noncannabinoid components, therefore, may increase the therapeutic effects of THC and reduce unwanted side effects, making vaporization a more optimized delivery mechanism as compared to combustion using pipes and joints [55,65]. Likewise, because vaporization permits lower consumption temperatures than is possible with pipes and joints, vaporization also should be a safer method of administration. The normal process of combustion generates substantially more carbon monoxide, ammonia, nitric oxide, hydrogen cyanide, polynuclear aromatic hydrocarbons (PAHs), and carcinogens such that vaporization may be an attractive delivery option in terms of harm reduction [62,63]. The lack of a difference by combustion methods in our results suggests that either users were vaping at temperatures comparable to those required for full combustion, that some terpenoids are still sufficiently present at higher temperatures to elicit antidepressant effects, or that terpenoid effects are not required for cannabis to have an antidepressant effect, controlling for THC and CBD levels. Future research would benefit from tracking vaping temperatures along with overall product heating method, as well as the direct examination of the effects of terpenes found in the Cannabis plant on depression in humans.

The current study does have limitations. Importantly, this study did not include a control placebo group, that is, individuals who did not use Cannabis to treat their depression or any Cannabis consumption sessions not tracked in the app, potentially resulting in selection bias. People who choose to use Cannabis to treat their depression may be those most likely to benefit from it or those for whom conventional treatments are less effective. The direction of the bias for app use is not as clear. Not using the app could be simply a matter of no knowing about the app or a dislike of app-based technologies, which would introduce noise into our analysis, or it could arise from an intolerance or dissatisfaction with Cannabis, making our results an overestimate of expected population effects. Alternatively, not using the app or stopping app use could arise from satisfaction with existing cannabis use and the lack of a need to explore other product options. Although our study extended the literature by incorporating a wider range of product characteristics than had been previously examined, we still were not able to include the full range of characteristics of products available (e.g. terpene profiles, vaping temperatures) and did not include non-flower cannabis products. We also did not account for factors beyond those time-invariant characteristics captured by the user fixed effects, including time-varying user demographics, cannabis experience, whether or not respondents had a diagnosis of depression, or the concomitant use of medications other than Cannabis. The current cannabis industry in the US is also wrought with product mislabeling [66,67], and black market products without labels may result in people guessing the product characteristics rendering the need for further product validation in future studies. Lastly, because we are focused on short-term effects and do not have every single Cannabis use session of the patients documented in our data, we do not know the long-term effects of Cannabis use. For example, Cuttler et al. (2018) [38] found a correlation between repeated use of their data recording system and increased baseline depression levels, however, it is unclear whether this may be a function of the effects of using Cannabis or a sample selection bias among respondents that used the system repeatedly, for example, people using the app to experiment with unfamiliar products, which could be less effective than the treatment approach the patient typically uses.

In conclusion, almost all patients in our sample experienced symptom relief from using Cannabis to treat depression and with minimal evidence of serious side effects in the short run. However, use of Cannabis does have well-established clinical drawbacks, including the potential for dependence and addiction, alterations in judgment, and an increased risk of behavioral accidents [68,69]. In addition, there is a well-established association between adolescent use of Cannabis and increased risk of depression in adulthood [20,70], but directionality of this relationship remains elusive. Likewise, the positive effects found in this paper along with the negative long-term associations documented in the prior literature support the importance of supplementing our analysis of short-term Cannabis symptom relief with causal studies of the longer term benefits and risks from using commercially available Cannabis.

One of the most clinically relevant findings from this study was the widely experienced relief from depression within 2 hours or less. Because traditional antidepressants have times-to-effect in weeks, short-term Cannabis use might be a solution to these delays in treatment or could be used to treat acute episodes associated with suicidal behavior and other forms of violence. Such short-term or acute episode treatment approaches would fill an important gap in existing clinical methods while avoiding the addiction and dependence risks of long-term Cannabis use. Given the significant costs to our society from depression, the research herein offers hope for new avenues of treatment. Future research on Cannabis and depression is needed, directly comparing the short- and long-term treatment effectiveness and side effect severity of Cannabis use with conventional antidepressant treatment, in conjunction with conventional treatment approaches, and in the presence of clinically discouraged behaviors, such as alcohol consumption.