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Herbal Cannabis and Depression: A Review of Findings Published over the Last Three Years

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24 April 2024

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25 April 2024

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Abstract
Public perception contrasts scientific findings on the depression-related effects of cannabis. However, earlier studies were performed when cannabis was predominantly illegal, its production was mostly uncontrolled, and the idea of medical cannabis was incipient only. We hypothesized that recent changes in attitudes and legislations may have favorably affected research. In addition, publication bias against cannabis may have also decreased. To investigate this hypothesis, we conducted a systematic review of research studies published over the last three years. We found 156 relevant studies. In most cross-sectional studies, depression was higher in those who consumed cannabis than in those who did not. An increase in cannabis consumption was typically followed by an increase in depression, whereas withdrawal from cannabis ameliorated depression in most cases. Albeit medical cannabis reduced depression in most studies, none of these were placebo controlled. In clinical studies published in the same period, placebo also ameliorated depression and in addition, the average effect size of placebo was larger than the average effect size of medical cannabis. We also investigated the plausibility of the antidepressant effects of cannabis by reviewing molecular and pharmacological studies. Taken together, the reviewed findings do not support the antidepressant effects of herbal cannabis.
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Subject: Medicine and Pharmacology  -   Psychiatry and Mental Health

1. Brief Historical Overview and the Presentation of the Problem

Medical uses of cannabis are ancient; the first Chinese and Indian accounts of its hypnotic, pain relieving and anxiolytic properties date back to the first century BC [1]. In Europe and North America, the plant was used mainly to produce fibers till the 19th century, when its psychoactive properties were rediscovered [2]. Beyond becoming a widespread recreational drug, cannabis was also used to treat insomnia, pain, and asthma, but in addition to these primary indications, it was also used to treat several other conditions and diseases, including depression. Among the patients we find notable persons like the Austro-Hungarian empress Elizabeth (Sissi) and Queen Victoria of England [3]. This first golden age of medicinal cannabis use, however, came to an end at the beginning of the 20th century, when new legislations made its use more and more difficult. The first trial to limit cannabis was the Marihuana Tax Act in 1937 [4]. This was primarily motivated by societal worries, but medical and criminological concerns were also considered. The process culminated in the 1961 United Nations Single Convention on Narcotic Drugs that placed cannabis under strict control, with the aim of protecting the physical and psychological health of the population [5]. Concerns related to the addictive properties of herbal cannabis were reiterated in this convention as well.
The discovery of the active constituents of herbal cannabis, and their mechanisms of action in late 20th–early 21st century (see section Mechanistic considerations for details) gave a great impetus to cannabinoid research. It was soon suggested that the endocannabinoid system may become an important target of drug development for a series of medical conditions, among others for the development of a novel class of antidepressants [6]. In parallel with scientific development, a second golden age of medical cannabis use emerged, gradually leading to its widespread liberalization. The basic idea of this movement was that natural cannabis is per se appropriate to treat a variety of diseases, and patients should be allowed to self-medicate themselves by lifting the bans on cannabis.
In general terms, the main motives of cannabis consumption are the enhancement of positive emotions, the improvement of social events or relationships, the promotion of coping with anxiety and depression, and the enhancement of experience and creativity [7]. As such, two of the main motives are related to the improvement of mental health, which potentially makes the argumentation of the UN Single Convention on Narcotic Drugs obsolete. Depression – the focus of this review – is a major public health concern, which constitutes a high economic burden to the society, dramatically increases the risk of suicide, and markedly impairs the quality of life [8]. Despite great advancements in the treatment of depression, antidepressant medications still suffer from shortcomings [9]. They are not always effective, have severe side effects in many patients, and may interact with other medications administered for comorbid diseases. As such, any novel treatment opportunity for depression is highly valuable from the point of view of public health.
There is an abundance of material on the Internet that claim that cannabis effectively treats depression, from professionally conducted exploratory research [10], through blogs and Internet archives summarizing the personal experiences of clinicians and general practitioners [11,12,13], to the dedicated writings of activists fighting for cannabis legalization [14]. Their point of view was most succinctly formulated as follows: “The power of cannabis to fight depression is perhaps its most important property” ([15], p. 58).
Despite this enthusiasm, however, the antidepressant effects of cannabis are controversial at best. Reviews covering findings obtained over the last two-three decades conclude in a reasonably consistent fashion that herbal cannabis aggravates rather than ameliorates mood disorders and depression in particular [16,17,18,19,20,21]. In addition, early cannabis use may lower the age of onset of mood disorders and increase suicidality [22,23,24,25].
We hypothesized, however, that recent debates over cannabis increased public awareness, the legalization of cannabis promoted the use of licensed products and decreased publication bias against cannabis, and in addition, the medically supervised use of cannabis improved consumption habits. All these developments may have favorably affected the use of cannabis to ameliorate depression. To investigate this hypothesis, we reviewed research studies published over the last three years.

2. The Selection of Studies for Review

We searched the PubMed database by using the following search term: (marihuana [title/abstract] OR marijuana [title/abstract] OR cannabis [title/abstract]) AND (depression [title/abstract] OR depressive [title/abstract] OR bipolar [title/abstract] OR mood [title/abstract]). The search returned 1143 hits for the last three years, e.g., for the period between February 2021 – February 2024. We selected for the review those studies, which were published in English; the research was done in humans; reported research findings together with clearly described methodologies; depression was studied by a validated methodology, e.g., by a psychometric instrument or by DSM- or ICD-based diagnostic criteria; study participants consumed herbal cannabis; the relationship between depression symptoms and cannabis consumption was studied. We excluded studies if the consequences of cannabis consumption could not be differentiated from those of other drugs (e.g., due to polysubstance use); cannabis consumption was confusingly described (e.g., cannabis-based treatments were indicated without specifying the actual nature of treatment); the symptoms of depression could not be differentiated from those of other disorders (e.g., anxiety and depression were studied by a common score); the study contained only data on general mood, wellbeing, internalizing symptoms, etc.; changes in depression were judged by participants only (e.g., by answering simple questions like “Did your depression improve?”). Importantly, we selected only those studies that investigated herbal cannabis, e.g., natural preparations that are commercially available to consumers, and for which the claims described in the first section were made. Studies employing purified or synthesized Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) or their mixture were excluded similar to those on synthetic cannabinoids or on natural cannabis enriched by any means. We found 156 studies that were eligible in terms of the criteria presented above.

3. Research Findings

More than half (81) of the studies investigated the interaction between cannabis consumption and depression cross-sectionally; 44 studies investigated the longitudinal associations of enhanced cannabis consumption, 9 investigated the impact of cannabis withdrawal, whereas 22 studied the longitudinal effects of medical cannabis treatment on the evolution of depressive symptoms. Almost all studies were purely observational, which made the establishment of consumption characteristics and sample sizes difficult. As it regards the former, we used the terms employed by the authors (e.g., “heavy use”) even if the term was not quantified in the study. Where consumption characteristics were not specified, or where these differed widely across participants, we used the term “unclear” (see below). Regarding sample sizes, these were quite often variable across longitudinal studies, and sometimes it was difficult to establish the actual sample size that substantiated a particular finding. Therefore, we indicated sample size ranges instead of precise sample sizes.

3.1. Cross-Sectional Studies

In theory, cannabis consumption should be negatively correlated with depression, as the latter is widely believed to be ameliorated by the former. At the same time, positive associations could not be excluded either, as cannabis consumption is frequently initiated by those with depressive mood. It occurs that 79.0% of cross-sectional studies found a positive correlation between cannabis consumption and depression: those consuming cannabis showed higher levels of depression than those who did not consume cannabis (Table 1). The positive correlation was found in community samples as well as in participants who had a variety of social and health conditions, and in all ages and genders. This finding is theoretically consistent with the self-medication hypothesis, if we assume that the reason for consumption – depression – was still present in the users, because not enough time had passed for the antidepressant effect of cannabis to take effect.
The impact of the amount of cannabis consumed is difficult to establish because most studies did not address this issue, or their participants were highly different in this respect, without consumption habits being differentially investigated (59% of all cross-sectional studies). In other studies, consumption was characterized by terms that were seldom explained, e.g., “habitual”, “harmful”, “heavy”, “non-disordered”, “occasional”, “positive drug testing” (without separating participants based on the results of the tests), “problematic”, or “regular”. The vague description of consumption characteristics is likely explained by the heterogeneity of the large samples (up to over a million), temporal fluctuations in the consumption habits of consumers, and the lack of consumption records which is understandable in such naturalistic studies. More precise figures were given in 12% of all cross-sectional studies. For instance, cannabis consumption was described as “daily”, “weekly”, or “3 days a week”, or “daily for more than 30 days”, etc. Yet in other studies, consumers were characterized as having cannabis use disorder (13%), which may not directly specify the dose taken, but is indicative of the cannabis-related state of participants. Cannabis was positively associated with depression in all these cases, suggesting that consumption habits and the amounts of cannabis ingested had little extra impact on depression symptoms.
Cannabis consumption was not related to depression in 14.8% of the studies and was associated with low depression in 6.2%. The particulars of participants in these studies were not different from those seen in the studies where the association was positive (Table 1). This holds true for the particulars of consumption.
Although it was not always clearly stated, it transpires from most studies that cannabis consumption was enduring for most participants by the time of data sampling. This suggests that if participants used cannabis to relieve their depression, this goal was achieved only according to 6.2% of the studies. The opposite happened in 79.0% of studies, even though in three such studies the participants consumed medical cannabis (Table 1).

3.2. Longitudinal Studies

Longitudinal associations were studied in three contexts. One group of studies explored the impact of emerging depression symptoms on cannabis consumption; the second group studied the impact of increased cannabis consumption on depression, whereas the third studied the consequences of cannabis withdrawal.
An increase in depression symptomatology was invariably followed by an increase in cannabis consumption (Table 2A). No conflicting results were reported. These findings are in line with the self-medication hypothesis, i.e., they suggest that once faced with depressive symptoms, participants turned to cannabis, likely to alleviate such symptoms. Again, the association did not depend on the particulars of participants, e.g., on their age, gender, or social/health background. The increase in cannabis consumption was detected month or years after the emergence of depressive symptoms.
The initiation of cannabis consumption or its increase were associated with the aggravation of depression symptoms in 81.1% of studies (Table 2B). It would be interesting to see separately the impacts of initiation and increased consumption, but most studies did not differentiate the two. Depression symptoms were aggravated on a timescale of weeks to decades, most studies being performed 1-2 years after the change in cannabis consumption. Changes in consumption were usually evaluated by self-reports, but psychometric instruments were also employed. In a subgroup of studies (18.9%) changes in cannabis consumption did not show long-term associations with changes in depression, but importantly, no study showed a negative association. In other terms, no study reported that depression was alleviated after the initiation of cannabis use or after an increase in its consumption.
Withdrawal from cannabis consumption was followed by an amelioration of depression in 55.6% of studies (Table 3). The opposite (aggravation of depression after withdrawal) was reported by just 1 study (4.5%), whereas depression did not change in the remaining studies. The particulars of participants did not explain the variation of findings. Importantly, the efficacy of withdrawal was checked by drug screening in more than half of the studies.
Taken together, these findings suggest that cannabis is a depressogenic rather than an antidepressant agent, as an increase in cannabis consumption increased, whereas withdrawal from cannabis decreased depression in most studies.

3.3. Treatment with Medical Cannabis

We found 22 studies where cannabis was used to treat various conditions and where depressive symptoms were also evaluated (Table 4A–C). In such studies, the agents administered were called “medical cannabis”. It is important to note, however, that the term refers to the purpose of use rather than to a particular composition of herbal cannabis [152]. Cannabis preparations termed “medical” contain widely different amounts of the main constituents. For instance, the THC content of medical cannabis preparations of licensed Canadian producers varied from 0.14% to over 25% [153], and the CBD content of medical cannabis was similarly variable [154]. In addition, the term may refer to any product (dried flower, resin, tincture, capsule, etc.) or delivery system (inhalation, oral, sublingual, topical, etc.) [155]. The same was true for the preparations used in the studies reviewed here. The THC and CBD doses of medical cannabis intakes varied between 1-50 mg and 0-20 mg, respectively, whereas the THC:CBD ratio varied from overwhelmingly THC-dominant to overwhelmingly CBD-dominant within the same study [156,157]. The only exception was the study by Gambino et al. [158] where the dose varied by a factor of 4 only (10-40 drops of oil), and each participant received a preparation that contained 63 mg THC and 80 mg CBD per 10 ml oil. In most studies, however, participants consumed preparations of their own choice and consequently, these were of varying composition. Dosage, and the route of administration was also decided by the participants. Moreover, treatment details were not even given in many studies. In addition to herbal cannabis, participants received other treatments, which were explained by their medical condition. These included antidepressants in 7 studies where herbal cannabis was effective. Noteworthy, the efficacy of medical cannabis vs. the combined treatment was not investigated. Treatments other than medical cannabis were not reported in 8 of the studies where cannabis was effective.
The studies presented here therefore did not meet the classical requirements of clinical studies. Despite this deficiency, it is still remarkable that there was only one study where medical cannabis increased depression, there were only four where it did not affect it, while depression was ameliorated by the treatment in 77.3% of studies (Table 4A–C). This beneficial effect was reported in patients having a variety of conditions, including major depression. Importantly, we also calculated effects sizes where the published data made this possible, and these were rather large in some studies. Note that we used Hedges’ g for evaluating effect sizes because sample sizes were small in some studies, and this measure is preferable over Cohen’s d in such cases [158].
Findings obtained with medical cannabis were in sharp contrast with the findings obtained with cannabis in general. In contrast to the depressogenic effects of cannabis as shown by cross-sectional and longitudinal studies, medical cannabis appeared to alleviate depression in most studies, on a timescale of weeks to month.
A closer inspection of the reports suggests, however, that this conclusion is largely unfunded. The first – less important – reason is that concurrent antidepressant medications were allowed in 7 studies (see above). The most important reason for questioning the conclusions is that out of the 17 studies where medical cannabis was effective, 14 did not use controls at all, whereas the remaining 3 used no-treatment controls only. This raises the possibility that the results were partly or entirely due to placebo effect.
To investigate this possibility, we reviewed placebo controlled clinical studies published in the same period, which used similar psychometric instruments (Table 5). The search terms and eligibility criteria employed for selected studies were like those used for the cannabis-depression interaction, with three differences. The search term “cannabis [title/abstract]” was replaced with “placebo [title/abstract]”, we added a search term that referred to the psychometric instrument (e.g., BDI [title/abstract]) and we inspected only those reports, which were freely available at our institute. We looked for those psychometric instruments, which were used at least twice in medical cannabis studies, i.e., where an average was calculable. We searched the studies backwards beginning with the most recent ones and continued the search till we found twice as many studies than those studying medical cannabis (separately for each instrument). As expected, placebo also ameliorated depression over time; its effect sizes were large, moreover, larger than the effect sizes of medical cannabis.

3.4. Overall Assessment

In cross-sectional studies, a cannabis consumption history was typically associated with high depression. In most longitudinal studies, increased cannabis consumption was followed by an increase in depression symptoms, whereas withdrawal from cannabis ameliorated depression (Figure 1). These findings suggests that cannabis increases rather than treats depression. Albeit medical cannabis administration ameliorated depression over time, none of the studies performed over the last three years was placebo controlled. In clinical studies published in the same period, placebo also ameliorated depression and in addition, the average effect size of placebo was larger than the average effect size of medical cannabis. Naturally, findings cannot be statistically compared across studies. Taken together, however, the larger efficacy of placebo questions the validity of the antidepressant effects suggested by studies employing medical cannabis.

4. Mechanistic Considerations

Neither previous reviews nor the current one found reliable evidence for the claim that cannabis relieves depression. Are there any theoretical considerations that would make the antidepressant effect of cannabis plausible? Despite the abundance of research on the relationship between cannabis and depression, this question was rarely if ever asked. This is probably because cannabis contains many psychoactive compounds, each of which affects multiple mechanisms. Although we are still far from understanding this complexity, the possibilities can perhaps be assessed, even if roughly only.

4.1. Neurochemistry

It is widely believed that THC, the most important psychotropic component of cannabis mimics the effects of neural signaling molecules called endocannabinoids, particularly anandamide, and 2-arachidonoylglycerol (2-AG) as well as of other lipid messengers called N-acylethanolamines [196,197,198]. We recently described endocannabinoid mechanisms in detail, together with a brief overview of the history of discoveries [199]. Briefly, the effects of cannabinoids are exerted through two G-protein coupled receptors, the CB1 and the CB2 [200,201], both being present in the central nervous system [202,203]. The receptors are located presynaptically and inhibit neuronal signaling according to the retrograde inhibition concept [204,205,206]. The essence of this concept is that neurotransmission elicits the postsynaptic release of endocannabinoids, which bind to the presynaptic cannabinoid receptor, and inhibit the release of the neurotransmitter that elicited the process. As such, the cannabinoid receptors work as molecular brakes that limit neurotransmission when this exceeds certain limits.
These “molecular brakes” are expressed on the presynaptic membranes of a variety of neurons, including GABAergic, glutamatergic, serotonergic, cholinergic, dopaminergic, opioidergic, noradrenergic, and cholecystokinin neurons [207,208,209,210,211]. As such, endocannabinoids can limit the release of 8 different neurotransmitters.
In addition to CB1 and CB2, endocannabinoids postsynaptically activate the vanilloid receptor type 1 (TRPV1) and other transient receptor potential channels (TRPV1-4; TRPA1, TRPM8) [212,213]. They are also active at the G-protein coupled receptors GPR55 and GPR18 [214,215,216], as well at a series of intracellular pathways that control basal neurotransmitter release, and the interaction between neurons and glia cells [217,218,219].
Importantly for this review, the affinity of THC to these binding sites is similar to, and sometimes higher than that of endocannabinoids [220,221,222,223]. Hence the assumption that these mechanisms mediate the effects of THC.
We are currently unable to directly link any molecular effects of THC to its potential antidepressant actions. However, the effects of THC are indirect, i.e., it acts by influencing other mechanisms. Therefore, it is possible to examine how the individual sub-mechanisms relate to the effects of known antidepressants or to the depression-related effects of specific ligands (Figure 2).
It occurs that there are no neurochemical effects of THC, which would be consistent with an antidepressant effect. For instance, the retrograde inhibition of glutamate release may be detrimental in depression as deficits in glutamatergic neurotransmission are considered to be the primary mediators of this psychiatric pathology [224]. Similarly, GABAergic deficits were associated with major depression; therefore, the retrograde inhibition of GABA release is more compatible with depressogenic rather than with antidepressant effects [225]. According to the serotonergic hypothesis of depression, diminished serotonergic neurotransmission should aggravate depression [226]. The role of noradrenergic neurotransmission is somewhat controversial as some effective antidepressants decrease brain norepinephrine levels [226]. Yet the selective noradrenaline reuptake inhibitor reboxetine, which promotes noradrenergic neurotransmission, is an effective antidepressant [227]. Diminished dopaminergic neurotransmission is believed to play a role in the development of major depression, whereas cholinergic dysfunctions may be responsible for the cognitive symptoms of depression [228,229]. Therefore, the reduction of dopamine or cholinergic neurotransmission may not be considered favorable in depressive states. Finally, TRPV1 antagonists were shown to have antidepressant properties, whereas cannabinoids act as agonists at these receptors [230].
The brief analysis provided above is naturally rudimentary for two reasons. Firstly, information on the neurochemical effects of THC and their interaction, dose dependence, brain distribution etc. are poorly understood at present. Secondly, a more thorough discussion of the issue would stretch the scope of this review. Nevertheless, it is perhaps telling that the effects of THC on the neurochemical phenomena that play a major role in depression are the opposite of what we would expect from an antidepressant.
The effects of CBD are more favorable in terms of an antidepressant effect. For example, this active ingredient has positive effects on serotonergic signaling [231]. Yet, the herbal cannabis administered to the participants of the studies reviewed above contained THC in large amounts; moreover, the products used were often THC-dominant. In addition, it should be noted that herbal cannabis has many active ingredients, not just THC and CBD. The terpene composition, for example, shows large differences between individual chemovars, and even with the same THC:CBD ratio, a differential terpene composition can lead to opposite effects on depression [232]. Unfortunately, however, very little is known about the depression-related effects of various terpenes.
One cannot rule out that the multitude of mechanisms result in an antidepressant effect by interaction, but the succinct presentation of the main neurochemical effects do not provide a theoretical framework that would make the antidepressant effects of herbal cannabis plausible.

4.2. Pharmacology

One can hypothesize that preclinical pharmacological findings have influenced therapeutic expectations for cannabis. For example, it was shown relatively early that knocking out the CB1 receptor results in depression-like behavior [233], while inhibition of the FAAH enzyme reduces depression [234]. Since the former inhibits whereas the latter enhances endocannabinoid signaling, it can be assumed in principle that depression can be ameliorated with exogenous cannabinoids. These and similar findings are often referred to when there is a need to substantiate the antidepressant effects of herbal cannabis with preclinical arguments. However, there are significant differences in how gene disruption, FAAH enzyme inhibition, and receptor ligands affect cannabinoid signaling.
The main components of the endocannabinoid system are not only the ligands and receptors, but also the synthesizing and degrading enzymes. The reason is that these signaling molecules are synthesized on demand, and after completing their role are transported back into the cytoplasm where they are degraded [235]. The rate-limiting synthesizing enzymes are NAPE-PLD and DAGL for anandamide and 2-AG, respectively [236,237]. After accomplishing their role, endocannabinoids are taken up by a carrier-mediated transport. Within the cytoplasm, anandamide is degraded via fatty-acid amide hydrolase (FAAH), whereas 2-AG is degraded via monoacylglycerol lipase (MAGL) [238]. These processes are of great pharmacological importance.
Receptor ligands (e.g., THC) affect all those mechanisms that were listed above, and perhaps several others that were not mentioned above due to uncertainties regarding their nature. On its turn, CB1 gene disruption disrupts the flow of information through the CB1 receptor but does not affect mechanisms that are independent of these receptors. Such mechanisms appear to constitute about half of the mechanisms affected by receptor ligands (see Figure 2), which means that gene disruption is considerably more selective than receptor ligands. The most selective interventions, however, are those that target synthesizing or degrading enzymes. As endocannabinoids are synthesized on demand and are rapidly degraded after their release [235,239], they are present in the synapse for short periods only. The enzymes have no substrates between bouts of activation; therefore, their inhibition is inconsequential when the endocannabinoid system is inactive. This implies that enzyme, e.g., FAAH inhibitors augment physiological responses rather than induce non-physiological responses. The question that may be asked by the application of FAAH inhibition can be formulated as follows: “What happens if the natural endocannabinoid signaling was prolonged”? By contrast, receptor ligands answer a broader question: “What happens if all cannabinoid binding sites are affected at the level of the whole brain?”, whereas gene disruption allows answering the question “What happens if part of the mechanisms are eliminated?” [199].
Not surprisingly, there often are major differences in the effects of manipulations that belong to different classes. For instance, the disruption of the CB1 gene increased, whereas the pharmacologic blockade of the very same receptor by the antagonist SR141716A decreased anxiety; the blockade of the FAAH enzyme did not affect anxiety directly but altered the way in which challenges (e.g., stressors) were responded [240,241].
As such, not all the findings of pharmacological studies are supportive of, or are explanatory regarding the effects of herbal cannabis, not even those employing pure THC or CBD, because cannabis contains both and a series of other psychoactive agents in addition, that also influence the herb’s effect. Only those preclinical pharmacologic studies make the antidepressant effects of cannabis plausible, which use herbal cannabis per se.

5. Concluding Remarks

The hypothesis formulated in the first section proved false. The review of findings published over the last three years led to conclusions very similar to those, which were based on studies performed in more unfortunate conditions, i.e., when cannabis was predominantly illegal, its production was mostly uncontrolled, and the idea of medical cannabis was very incipient only.
Conclusions so unfavorable from the point of view of expectations were explained in various ways. Degenhardt et al. [242] for instance suggested that the unfavorable association of cannabis consumption and depression may be due to common social, family, and contextual factors that increase risks of both heavy cannabis use and depression. The same authors also found relief in stating that even “If the relationship is causal, then on current patterns of cannabis use in the most developed societies cannabis use makes, at most, a modest contribution to the population prevalence of depression” (Degenhardt et al., 2003, last sentence of abstract). One may argue against these and similar claims. For instance, the enhancement of depression after the increase in cannabis consumption and the amelioration of depression after withdrawal are not supporting the “common cause theory”. One can also argue that the contribution of cannabis to the prevalence of depression in the “most developed societies” may depend on the prevalence of cannabis consumption. If the latter increased, its relative contribution to depression also increased. These, however, are only details. The essence of such defensive approaches is that their adherents contrast speculations with experimental results, enthusiasm with factual information, which is scientifically counterproductive. Explanations to unfavorable findings do not help treating depression.
However, it is worth emphasizing that cannabis contains a wide variety of compounds, some of which have molecular effects compatible with antidepressant effects. It cannot be ruled out that products containing components in right proportions can indeed alleviate depression. Unfortunately, however, the authors paid little attention to the composition of the products, so the work to decipher the interaction between particular compositions and antidepressant effects has not even begun. It is also important to note that hopes regarding pharmacological agents that influence the endocannabinoid system are definitely not compromised by the inefficacy of herbal cannabis, e.g., by the disappointing effects of a very complex mixture of active agents, which in addition has a highly variable composition, and is currently administered in unestablished dose regimens and routes of administration. The endocannabinoid system is still a major drug research target, including its involvement in depression. Yet herbal cannabis, as it regards the alleviation of depression, does not seem to live up to the expectations.

Funding

This research received no external funding.

Conflicts of Interest

The author declares no conflicts of interest.

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Preprints 104732 g001
Figure 1. The main findings of the study.
Figure 1. The main findings of the study.
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Preprints 104732 g002
Figure 2. Neurochemical effects of THC and their relation to mechanisms underlying depression. ↓, decrease in function; red, neurochemical effects of THC consistent with antidepressant action; Gray, unknown or too complex to be discussed here. For details see text.
Figure 2. Neurochemical effects of THC and their relation to mechanisms underlying depression. ↓, decrease in function; red, neurochemical effects of THC consistent with antidepressant action; Gray, unknown or too complex to be discussed here. For details see text.
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Table 1. Cross-sectional associations between cannabis consumption and depression.
Table 1. Cross-sectional associations between cannabis consumption and depression.
CANNABIS CONSUMPTION WAS ASSOCIATED WITH HIGH DEPRESSION
Consumption
specifics 		Sample
specifics 		Gender
at birth 		Age class Sample
size 		Ref
unclear community
sample		 both Adolescent
/young adult		 100+ [26]
unclear community
sample		 both young adult 10,000+ [27]
unclear community
sample		 both adolescent 2,000+ [28]
unclear community
sample		 both young adult 1,000+ [29]
unclear community
sample		 both adolescent 1,000+ [30]
unclear community
sample		 both 18+ <100 [31]
unclear community
sample		 both adolescent 500+ [32]
unclear community
sample		 men adolescent
/young adult		 500+ [33]
unclear community
sample		 both adolescent 5,000+ [34]
unclear community
sample		 both adolescent
/young adult		 2,000+ [35]
unclear community
sample		 both 18+ 2,000+ [36]
unclear community
sample		 both young adult
/middle-aged		 100+ [37]
unclear community
sample		 both young adult 500+ [38]
unclear community
sample		 both 18+ 10,000+ [39]
unclear community
sample		 female adolescent
/young adult		 2,000+ [40]
unclear community
sample		 both 16+ 10,000+ [41]
lifetime use community
sample		 both adolescent 10,000+ [42]
lifetime use community
sample		 both adolescent 2,000+ [43]
Non-disord-
ered use		 community
sample		 both adolescent 10,000+ [44]
harmful community
sample		 both young adult 500+ [45]
> 1/ month
for a year		 community
sample		 both adolescent
/young adult		 100+ [46]
>weakly community
sample		 both young adult 1,000+ [47]
>weekly community
sample		 both adolescent
/young adult		 100+ [48]
daily for
>30 days		 community
sample		 both 18+ 100,000+ [49]
Cannabis use
disorder		 community
sample		 both adolescent 10,000+ [44]
unclear Alzheimer
disease		 both elderly 2,000+ [50]
unclear Army
veterans		 both young adult 100+ [51]
unclear Army
veterans		 both young adult 1,000+ [52]
unclear
medical		 Army
veterans		 both 21+ 2,000+ [53]
> 3 days
/week		 Army
veterans		 both young adult 100+ [54]
cannabis use
disorder		 Army
veterans		 both 21+ 2,000+ [55]
unclear Athletes female young
adult		 <100 [56]
cannabis use
disorder		 Bipolar
disorder		 both 18+ 100,000+ [57]
unclear Cancer both 18+ 10,000+ [58]
daily Cancer
survivors		 both middle aged 1,000+ [59]
daily Cancer
survivors		 both 18+ 10,000+ [60]
cannabis use
disorder		 Cannabis
use disorder		 both 18+ 1,000,000+ [61]
cannabis use
disorder		 Cannabis
use disorder		 both young adult 1,000+ [62]
heavy Childhood
adversity		 both 18+ 10,000+ [63]
unclear Concussion both adolescent 10,000+ [64]
unclear COVID19 both adolescent 2,000+ [65]
unclear COVID19 both 18+ 10,000+ [66]
unclear COVID19,
army veterans		 both young adult
/middle-aged		 1,000+ [67]
lifetime use COVID19 both 18+ 2,000+ [68]
abuse COVID19 both adults 100+ [69]
daily COVID19 both young adult 2,000+ [70]
cannabis use
disorder		 Homelessness both adolescent
/young adult		 100+ [71]
unclear
medical		 Hospitalized
(cannabis clinic)		 both 18+ 100+ [72]
unclear Hospitalized
(integrated care)		 both elderly 500+ [73]
unclear Hospitalized (stress
cardiomyopathy)		 both 18+ 10,000+ [74]
problematic
use		 Hospitalized
(chronic disease)		 both 18+ 100+ [75]
Cannabis use
disorder*		 Hospitalized both adolescent 100,000+ [76]
unclear Infertility female 18+ 100+ [77]
unclear Inflammatory
Bowel Disease		 both 18+ 1,000+ [78]
unclear Insomnia both adolescent 100+ [79]
unclear Pregnancy female young adult
/middle-aged		 1,000+ [80]
positive drug
testing		 Pregnancy female young adult
/middle-aged		 500+ [81]
cannabis use
disorder		 Pregnancy female young adult
/middle-aged		 1,000,000+ [82]
unclear
medical		 Primary care
Patients		 both 18+ 1,000,000+ [83]
cannabis use
disorder		 Primary care
patients		 both 18+ 1,000,000+ [83]
unclear PTSD
COVID19		 both 18+ 100+ [84]
heavy PTSD both 18+ 2,000+ [85]
cannabis use
disorder		 PTSD both 18+ 10,000+ [86]
unclear Various (mostly
chronic pain)		 both 18+ 1,000+ [87]
CANNABIS CONSUMPTION AND DEPRESSION DID NOT ASSOCIATE
Consumption
specifics 		Sample
specifics 		Gender
at birth 		Age class Sample size Ref.
unclear community
sample		 both adolescent 2,000+ [88]
unclear community
sample		 both young adult 500+ [89]
regular community
sample		 both 15+ 100,000+ [90]
daily community
sample		 both 18+ 10,000+ [91]
unclear Binge eating both 18+ 100+ [92]
unclear Cancer
survivors		 both elderly 2,000+ [93]
unclear Hospitalized
(bariatric surg.)		 both 18+ 500+ [94]
unclear Juvenile
offenders		 males adolescent
/young adult		 100+ [95]
unclear Late chronotype both young adult 100+ [96]
daily
medical		 PTSD
army veterans		 both middle-age 100+ [97]
Cannabis use
disorder*		 Schizophrenia
spectrum dis.		 both 18+ 2,000+ [98]
unclear Substance use
disorder		 both middle-age 100+ [99]
CANNABIS CONSUMPTION WAS ASSOCIATED WITH LOW DEPRESSION
Consumption
specifics 		Sample
specifics 		Gender
at birth 		Age class Sample
size 		Ref.
unclear community
sample		 both middle-age 500+ [100]
occasional community
sample		 both 18+ 2,000+ [36]
habitual community
sample		 both 18+ 2,000+ [36]
unclear IBD
COVID19		 both middle-age 500+ [101]
unclear Psychosis
first episode		 both child
/adolescent		 100+ [102]
Legend. *, alternatively, participants used cannabis more than twice a week; age classes, children (< 11 years); adolescents (12-18); young adults (19-30); middle-aged (31-50); elderly (51 +); No.+, age classes covered above the age shown by the number; COVID19, study performed during the Covid-19 pandemic; IBD, Inflammatory bowel disease; PTSD, posttraumatic stress disorder; sample size classes, n+, larger than n; <100, smaller than n; unclear, participants used and administered cannabis in various doses and routes, respectively, or consumption specifics were not detailed.
Table 2. Longitudinal relationships between cannabis use and depression.
Table 2. Longitudinal relationships between cannabis use and depression.
A. CANNABIS USE EMERGES OR INCREASES AFTER DEPRESSION
Periodcovered Consumption
change 		Sample
specifics 		Age class Sample size Ref.
1 year Self
-reported		 community
sample		 adolescents
/young adults		 500+ [103]
2 years Self
-reported		 community
sample		 adolescents 1,000+ [104]
Month* Self
-reported		 COVID19 18+ 100+ [105]
1 year Self
-reported		 COVID19 adolescents
/young adults		 2,000+ [106]
2 years Self
-reported		 COVID19 midle-aged
/elderly		 2,000+ [107]
1 year Self
-reported		 Depression,
major		 elderly 10,000+ [108]
4 years Diagnostic# Army
veterans		 18+ 1,000,000+ [109]
B. DEPRESSION EMERGES OR WORSENS AFTER INCREASED CANNABIS USE
Period
covered		 Consumption
change		 Sample
specifics		 Age class Sample size Ref.
30 days Self
-reported		 community
sample		 adolescents 1,000+ [110]
1 year Self
-reported		 community
sample		 adolescents
/young adults		 500+ [103]
1 year Self
-reported		 community
sample		 adolescents 2,000+ [111]
1 year CDDUR community
sample		 adolescents
/young adults		 <100 [112]
1 year Self
-reported		 community
sample		 adolescents
/young adults		 2,000+ [113]
2 years Self
-reported		 community
sample		 adolescents
/young adults		 1,000+ [114]
years-decades Self
-reported		 community
sample		 adolescents 100,000+ [115]
4 years ASSIST ‡community
sample		 children 500+ [116]
4,5 years Self
-reported		 community
sample		 young adults 2,000+ [117]
~5 years Self
-reported		 community
sample		 adolescents
/young adults		 100+ [118]
5 years ASSIST †community
sample		 young adults 1,000+ [119]
5 years CUDITr ♂community
sample		 young adults 5,000+ [120]
6 years Self
-reported		 community
sample		 young adults 2,000+ [121]
6 years Self
-reported		 †community
sample		 young adults 2,000+ [122]
12 years Self
-reported		 ♂community
sample		 adolescents 1,000+ [123]
~17 years Self
-reported		 community
sample		 adolescents 5,000+ [124]
20 years Self
-reported		 community
sample		 adolescents 1,000+ [125]
< 1 year Self
-reported		 †Bipolar
disorder		 midle-aged 1,000+ [126]
5 years Diagnostic# †Bipolar
disorder		 midle-aged 100+ [127]
1 year Diagnostic# Cannabis
use disorder		 18+ 10,000+ [128]
1 year Self
-reported		 COVID19 young adults 2,000+ [129]
1 year Self
-reported		 COVID19 elderly 10,000+ [130]
3 & 6
month		 Self
-reported		 Hospitalized,
surgery		 middle-aged
/elderly		 1,000+ [131]
30 days
& 1 year		 Self
-reported		 Hospitalized,
bariatric surg.		 middle-aged 5,000+ [132]
2 years Self
-reported		 Hospitalized,
orthopaedic surg.		 18+ 1,000+ [133]
Month* Medical
records		 ♀Pregnant 18+ 500+ [134]
Month* Diagnostic# ♀Pregnant young adults
/middle-aged		 100+ [135]
≥1 years Self
-reported		 ♀Pregnant young adults
/middle-aged		 500+ [136]
≥5 years Self
-reported		 ♀Pregnant young adults 100+ [137]
12 weeks PXTSU PTSD young adults 1,000+ [138]
C. NO TEMPORAL RELATIONSHIPS BETWEEN DEPRESSION AND CANNABIS USE
Period
covered 		Consumption
change 		Sample specifics Age class Sample size Ref.
~5 years Self
-reported		 ♂community
sample		 young adults 500+ [139]
<16 years* Self
-reported		 †community
sample		 adolescents 2,000+ [140]
2 years Self
-reported		 community
sample		 young adults 2,000+ [141]
longterm use Self
-reported		 community
sample		 elderly <100 [142]
20 years Self
-reported		 community
sample		 adolescents 1,000+ [125]
month* Self
-reported		 COVID19 18+ 100+ [105]
≤ 24 month* Self
reported		 psychosis,
first episode		 young adults 100+ [143]
Legend. #, changes in the prevalence of cannabis use disorder; *, temporal distance between study points varied; †, interaction between cannabis use and bipolar disorder; ‡, interaction between cannabis use and subclinical hypomania; age classes, children (< 11 years); adolescents (12-18); young adults (19-30); middle-aged (31-50); elderly (51 +); No.+, age classes covered above the age shown by the number; ASSIST, Alcohol, Smoking and Substance Involvement Screening test; CDDUR, Customary Drinking and Drug Use Record; COVID19, study performed during the Covid-19 pandemic; CUDITr, Cannabis Use Disorders Identification Test-Revised; gender at birth, ♂, males; ♀, females, no label, both; PTSD, posttraumatic stress disorder; PXTSU, Phenotype and eXposures Toolkit Substance Use; sample size classes, n+, larger than n; <100, smaller than n; Self-reported, answers to questions like ““During the past 12 months, have you used hashish or marihuana?”.
Table 3. Withdrawal effects.
Table 3. Withdrawal effects.
CANNABIS WITHDAWAL DECREASED DEPRESSION
Withdrawal
length 		Withdrawal
check 		Sample
specifics 		Age class Sample size Comparison
group 		Ref.
28
days		 Drug
screen		 Multiple
sclerosis		 middle-aged <100 no
withdr.		 [144]
few
month		 Drug
screen		 Pregnancy young a.
/middle-a.		 500+ no
withdr.		 [81]
1
year		 Self
report		 Community
sample		 adolescents
/young a.		 10,000+ no
withdr.		 [145]
1
month		 Self
report		 Cannabis
use disorder		 18+ <100 none [146]
~5,5
years*		 Self
report		 Cannabis
use disorder		 14+ 100+ none [147]
CANNABIS WITHDAWAL HAD NO EFFECT ON DEPRESSION
Withdr.
length 		Withdr.
check 		Sample
specifics 		Age class N Comparison
group 		Ref.
3
weeks		 Drug
screen		 Community
sample		 young a. <100 non
-users		 [148]
4
weeks		 Drug
screen		 Community
sample		 adolescents
/young a.		 100+ none [149]
7
years		 Diagno-
stic#		 Substance
abuse		 adolescents 1,000+ none [150]
CANNABIS WITHDAWAL INCREASED DEPRESSION
Withdr.
length 		Withdr.
check 		Sample
specifics 		Age class N Comparison
groups 		Ref.
14 weeks Drug
screen		 Cannabis
use disorder		 adolescents
/young a.		 <100 none [151]
Legend. #, changes in the prevalence of cannabis use disorder; *, temporal distance between study points varied; age classes, adolescents (12-18 years); young a. (19-30); middle-a. (31-50); age classes: No.+, covered above the age shown by the number; sample size classes, n+, larger than n; <100, smaller than n; Self-reported, answers to simple questions.
Table 4. Treatment with medical cannabis.
Table 4. Treatment with medical cannabis.
A. MEDICAL MARIJUANA AGGRAVATED DEPRESSION
Followup Instrument Change Condition Effect
size 		Age
class 		N Comparison
group 		Ref.
5-6
years		 Pharm. diagnostic Chronic
pain		 - 18+ 100+ no
disorder		 [160]
B. MEDICAL MARIJUANA DID NOT AFFECT DEPRESSION
Followup Instrument Change Condition Effect
size 		Age
class 		N Comparison
group 		Ref.
6
month		 ESAS nil Various
**		 - Ma.
/Eld		 100+ none [161]
12
weeks		 HADS-D nil Various
***		 - 18+ 100+ no
treatment		 [162]
12
weeks		 HADS-D nil Various
***		 - 18+ 100+ no
treatment		 [163]
vari-
able		 PHQ4 nil Chronic
pain		 - 25+ 100+ none† [164]
C. MEDICAL MARIJUANA ALLEVIATED DEPRESSION
Followup Instrument In→fin
(dif.) 		Condition Effect
size 		Age
class 		N Comparison
group 		Ref.
18
weeks		 custom 6.9→3.8
(3.1)		 Major
depression		 n.c Ya
/Ma.		 <100 none [165]
12
month		 BDI 3.2→2.2
(1.0)		 Chronic
pain		 0,59 19+ 500+ none [166]
various BDI 18.0→11.0
(7.0)		 Chronic
pain		 n.c Ma. 500+ none [167]
1
year		 BDI 11.3→5.8
(5.5)		 Community
sample		 0,79 Ma. < 100 none [168]
6
month		 BDI 12.6→5.5
(6.9)		 Chronic
pain		 0,87 18+ < 100 none [169]
3
month		 DASS-21 15.2→10.7
(4.5)		 Various
***		 0,45 18+ 2,000+ none [156]
3
month		 ESAS 3.2→2.3
(0.9)		 Various
**		 n.c Ma.
/Eld		 100+ none [161]
6
month		 GDS 6.4→5.0
(1.4)		 Various** 0,35 Eld 100+ none [170]
4
weeks		 GDS 9.0→3.0
(6.0)		 BMS n.c Eld <100 none [158]
variable HADS-D 11.7→8.6
(3.1)		 Anxiety
/depre.		 n.c Ma. 500+ no
treatment		 [100]
9
month		 HADS-D 4.3→3.8
(0.5)		 Various*** 0,13 18+ 100+ no
treatment		 [171]
various HADS-D not
reported*		 Various
**		 n.c Adol
/Ma.		 100+ no
treatment 		[101]
3
month		 PHQ-8 8.5→5.7
(2.8)		 Chronic
pain		 0,52 Ma.
/Eld		 <100 none [157]
6
month		 PHQ-9 12.0→7.0
(5)		 Depres. n.c Ya
/Ma.		 100+ none [172]
2
years		 PHQ-9 13.7→7.2
(6.5)		 Various
***		 1,03 Ma.
/Eld		 5,000+ none [173]
~3
month		 diagnostic diagnostic Multiple
Sclerosis		 n.c Ma. 100+ none [174]
various PROMIS-29 61.6→57.5
(4.1)		 Anxiety
/PTSD		 0,41 Ma. 100+ none [175]
Legend. * only beta coefficients given; ** mostly chronic non-cancer pain; *** pain, insomnia, anxiety, depression; †, some participants reported no use at followup (“cannabis naïve”), but their number was insignificant compared to the treated group (~5% of the sample); ‡, incuding antidepressants; Adol, adolescent; BDI, Beck Depression Inventory; BediolR, THC:CBD 63:80 mg/10 g oil; 10-40 drops/day; BMS, Burning Mouth Syndrome; COPD, chronic obstructive pulmonary disease; custom, single-item, 10-point rating scale (validated); DASS-21, Depression, Anxiety, Stress Scale -21; diagnostic, change in the prevalence of mood disorders; Effect size, Hedges’ g; Eld, elderly; ESAS, Edmonton Symptom Assessment System; GDS, Geriatric Depression Scale; HADS-D, Hospital Anxiety and Depression Scale, depression subscale; IBD, Inflammatory Bowel Disease; IBS, Irritable Bowel Syndrome; In→fin, initial and final scores; Ma, Middle-aged; n.c, not calculable from the data provided; no treatment, usually also cannabis consumers; where checked, cannabis use was smaller than in the treated group Pharm, depression identified by medications received; PHQ, Patient Health Questionnaire; the number indicates the question number variant of the test; PROMIS-29, Patient-Reported Outcomes Measurement Information System-29; Ya, young adult.
Table 5. Placebo effects in similar studies, which were reviewed because those on medical cannabis were not placebo controlled.
Table 5. Placebo effects in similar studies, which were reviewed because those on medical cannabis were not placebo controlled.
D. PLACEBO ALLEVIATED DEPRESSION IN CONTROLLED STUDIES
Followup Instrument Initial→final
score (dif.) 		Condition Effect
size 		Age
class 		N Ref.
4
weeks		 BDI 37.3→29.8
(7.5)		 Major
depression		 0,71 children
/adolescents		 227 [176]
63
days		 BDI 14.0→7.4
(6.6)		 Constipation
depression		 1,00 middle-aged 60 [177]
5
weeks		 BDI 16.6→8.4
(8.2)		 Bariatric
surgery		 1,19 middle-aged 38 [178]
3
month		 BDI 6.0→2.0
(4.0)		 Lung cancer
surgery		 n.c middle-aged
/elderly		 156 [179]
8
weeks		 BDI 13.5→5.5
(8.0)		 Unexplained
fatigue		 n.c middle-aged 80 [180]
1
year		 BDI 17.7→8.1
(9.6)		 Coronary heart
disease		 n.c elderly 128 [181]
9
weeks		 BDI 24.5→22.3
(2.2)		 Community
sample		 n.c young adults
/middle-aged		 70 [182]
6
weeks		 BDI 27.0→14.9
(12.1)		 Depressive
symptoms		 n.c adolescent
/young adults		 62 [183]
12
weeks		 GDS 7.0→5.8
(1.2)		 Parkinson 0,37 middle-aged
/elderly		 171 [184]
1
month		 GDS 8.0→3.0
(5.0)		 Cardiac
surgery		 0,47 elderly 83 [185]
6
weeks		 GDS 4.4→3.7
(0.7)		 COPD 0,55 elderly 60 [186]
8
weeks		 GDS 10.5→8.4
(2.1)		 Major
depression		 0,76 elderly 117 [187]
3
month		 GDS 10.5→8.4
(2.1)		 Community
sample		 3,47 elderly 80 [188]
12
month		 HADS-D 3.2→2.3
(0.9)		 Prostate
cancer		 0,32 middle-aged
/elderly		 130 [189]
8
weeks		 HADS-D 11.0→7.2
(3.8)		 Functional
dyspepsia		 0,79 not
specified		 30 [190]
30
days		 HADS-D 14.6→10.5
(4.1)		 Irritable Bowel
Syndrome		 1,33 middle-aged 42 [191]
1
year		 HADS-D 7.0→4.2
(2.8)		 Coronary he-
art disease		 n.c elderly 128 [181]
6
month		 PHQ-9 3.9→1.9
(2.0)		 Migraine 0,39 middle-aged 807 [192]
6
weeks		 PHQ-9 12.2→8.8
(3.4)		 Depression 0,59 18+ 653 [193]
7
days		 PHQ-9 15.2→13.0
(2.2)		 Bowel
Resection		 0,73 young adults
/middle-aged		 120 [194]
8
weeks		 PHQ-9 11.2→6.3
(4.9)		 Atypical
depression		 1,11 middle-aged 200 [195]
Legend. age classes, children (< 11 years); adolescents (12-18); young adults (19-30); middle-aged (31-50); elderly (51 +); No.+, age classes covered above the age shown by the number; COPD, chronic obstructive pulmonary disease; n.c., sample size not calculable based on the data provided.
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