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Above the Sea of Fog: Dietary and Lifestyle Interventions for the Treatment of Depression

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Submitted:

18 February 2024

Posted:

23 February 2024

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Abstract
Antidepressants are among the most used medications in the US, with significant deleterious effects on people’s well-being. At any given time, depression impacts approximately 1 in 10 Americans, causing wide and broad societal costs. Interest is developing for non-pharmacological treatments and preventative measures. We summarize the literature on non-invasive dietary and lifestyle approaches for treating depression, including recent work with the psychedelic treatment of depression. This review aims to inform future research and treatment programs for depression. This review provides an evidentiary summary of integrative therapeutic approaches for depression.
Keywords: 
Major Depression
;  
Lifestyle Medicine
;  
Dietary approaches
;  
Antidepressants
Subject: 
Medicine and Pharmacology  -   Psychiatry and Mental Health

1. Introduction

Some 17% of the US population experiences clinical depression at some point in their life. It can be a debilitating disease, where many with depression feel a complete lack of joy. It should be noted that depression increases suicide risk, and many suicides can be attributed to depression that way. The population average belies the astronomical rate among some risk cohorts, and the magnitude of the impact of depression is difficult to quantify. Hitting close to home, during the Covid-19 pandemic 1 in 5 doctors experienced depression(1), and doctors experience higher rates of depression than the normal population(2, 3).
Beyond the immediate effects of depression, those with depression are at higher risks for many other conditions, including heart attacks, diabetes, and suicide. The debilitating nature of the condition makes it difficult for one to enjoy a fulfilling life with social connection. Depression has very many multifarious impacts on one’s career prospects and one’s ability to experience joy from goal pursuit or enacting a hobby.
People with depression often feel alone. Overall, depression while not manifesting as physical symptoms, is a debilitating condition, and one which causes a significant degree of suffering, especially considering its extent. It must also not be underestimated the indirect impact of depression on others, whether through the withdrawal of depressed persons from social life, or from regular interactions with depressed people, which can also depress mood in the phenomenon of mental contagion(4, 5).
In the Netherlands, about 1 of every 13 adults is currently using an antidepressant (6). In recent years, the trend has been towards the increasing duration of antidepressant use (7), and in the US, 2/3 of patients continue antidepressants for at least two years (8, 9).

2. Epidemiology

While depression is seen as a condition affecting solely the mind, still, epidemiological factors underly depression on the population level. Authentic spirituality reduces the risk of developing depression by half(10).
Characteristics of one’s family of origin can predispose one to depression. While it is unclear the mechanism of causation, the children of parents with major depressive disorder (MDD) are 3 times more likely to develop MDD than the children of parents without MDD(11). A history of childhood abuse is associated with a greater risk of depression(12, 13), as well as lack of parental affection(14).
Other factors associated with depression were low education, recent negative life events, loneliness, alcohol consumption, low physical activity(15, 16) and smoking(17). The personality traits of low agreeableness, low extraversion, low openness, low mastery, low conscientiousness and high neuroticism are also associated with depression(17). Internet addiction is also associated with a greater depression risk (18). Significant life disruptions can also precipitate the onset of depression, including heart attacks(19), even childbirth(20). Due to the mental nature of depression, a discussion about its causes traverses many questions about how one is living their life, including work(21, 22), relationships and self-care.
Nutritional associations have also been investigated. Coffee consumption was associated with a lower risk of depression in women(23). Vegetable and fruit consumption is also associated with lower risk of depression(24), and dietary magnesium and calcium significantly lower depression risk(25). A recent umbrella review of the dietary associations with depression prevention and treatment demonstrated a significant protective benefit from healthy diet patterns(26). Unhealthy beverage consumption habits, as parametrized by the Healthy Beverage Index (HBI) score(27), were also associated with an increased depression risk(28).
Specific factors showing strong evidence for decreased depression risk included fish consumption, coffee or tea consumption, dietary zinc, light to moderate alcohol (<40g/day)(26). Consumption of sugar sweetened beverages also raised the risk of depression(26). Moderate quality evidence exists for the association of consumption of probiotics, omega-3 polyunsaturated fatty acid and acetyl-L-carnitine with decreased depression risk(26).
Other dietary factors studied for their anti-depression, revealing equivocal evidence for efficacy include cocoa-rich foods(29), red or processed meat(30), vitamin D(31), folic acid(32) and B-vitamins(33).
Genetic factors can contribute to or protect against the depression phenotype(34-37), and heritability of depression is estimated at 37% from twin studies(38).
Nature exposure is associated with better affective states and lower risk of depression (39-42), an affect which can be mediated by the quality of the urban built environment(43, 44). Sociality can also protect against depression, as evidenced by an interventional study, where women with chronic depression in London made new friends, and observed a significant improvement in their present state examination (PSE) scores(45), an assessment of affect(46). Additionally, having hobbies is associated with a lower risk of depression(47, 48).
High stress environments and jobs can also contribute to depression, though this relationship is mediated by other factors(49), including (perceived) level of support(50) and psychosocial safety in the workplace(51).

3. Aims and Methods

This narrative review aims to include non-pharmacological, evidence-based treatments for the treatment of depression. We divide these into the broad categories of interventions: dietary/nutraceutical, lifestyle and experiential therapies. The difference between lifestyle interventions and experiential interventions is the primacy of a singular session, as opposed to a lifestyle change which is continually performed. Experiential interventions are time-bound, though they may be multiple in number, they continue to exert their impact after they are completed.
We perform a manual search for 1) dietary factors impacting depression, including specific supplements and herbal treatments, 2) lifestyle factors influencing depression and 3) psychedelic-based experiential treatments for depression. Our search strategy searches for reviews summarizing the interventions in each category. When reviews are found, the interventions summarized in the review are included in Supplementary Tables S1, S3 and S4 for dietary, lifestyle and psychedelic interventions respectively. These interventions are included in Table 1, Table 2 and Table 3 respectively in the main text. Some interventions are worthy of note, but are not mentioned in reviews on the topic (Supplementary Tables S1, S3 and S4). These may be included in the main text Table 1, Table 2 and Table 3.
In section 5, we include in Table 1 and Supplementary Table S1 any dietary/nutraceutical and herbal factors which have shown evidence for efficacy in meta-analyses of human clinical trials or individual clinical trials for depression. We follow Table 1 by discussing qualitatively the mechanisms behind diet-mediated impacts on depression.
Supplementary Table S2 includes dietary/nutraceutical and herbal factors from our search which have shown efficacy for depression in pre-clinical models.
In section 6, we include in Table 2 and Supplementary Table S3 any lifestyle factors which have shown evidence for efficacy in meta-analyses of human clinical trials or individual clinical trials for depression. After Table 2, we include a qualitative discussion of different promising lifestyle intervention therapeutics.
We include in Table 3 and Supplementary Table S4 any psychedelic interventions which have shown evidence for efficacy in meta-analyses of human clinical trials or individual clinical trials for depression. In this section, we also include a qualitative review of psychedelic use for the treatment of depression.

4. Nutritional Support for Depression treatment

As mentioned, the nutritional factors behind depression have been elucidated in meta-analyses. Vegetarian dets are associated with a higher rate of depression in people(52), whereas Mediterranean diets are associated with a lower risk of depression(53, 54). Other specific nutrient deficiencies and their impact on depression are outlined in Table 1.
Nutraceuticals in the context have been reviewed in (32, 55-63). Several nutritional deficiencies may exist in the depressed patient(64), which, if addressed, may positively influence the prognosis of depression.
We searched for reviews on nutritional supplements in depression, and found several reviews providing an evidentiary overview of different nutraceutical and nutritional supplementary protocols for depression (Supplementary Table S1) (55, 65-77). The specific interventions are included in Table 1.
Table 1. A summary of dietary agents and their impacts on depression.
Table 1. A summary of dietary agents and their impacts on depression.
Factor Impact Sources
Zinc Depression associated with zinc deficiency (78) Meat, shellfish, dairy, legumes, nuts
Magnesium Consumption associated with lower risk of depression RR=0.81 [0.70,0.92] (25) Leafy greens, nuts and seeds, legumes
Calcium Consumption associated with lower risk of depression RR=0.66 [0.42,1.02] (25) Leafy greens, fish with bones, almonds, dairy
Caffeine Associated with reduced depression risk RR=0.72 [0.52,1.00] highest vs lowest consumption (79) Coffee, tea
Coffee Associated with reduced depression risk RR=0.76 [0.62,0.92] highest vs lowest consumption (79) Coffee
Tea Lowers depression risk RR=0.69 [0.63,0.75] highest vs lowest consumption (80) Tea
Cocoa Decrease in depressive symptoms g=-0.42 [-0.67,-0.17] Cocoa
Fish Lowers depression risk RR=0.89 [0.80,0.99] highest vs lowest consumption (81)

RR=0.83 [0.74,0.93] highest vs lowest consumption (82)		 Fish
Omega 3 polyunsaturated fatty acids EPA+DHA consumption associated with lower depression risk (83)

Lowered depression risk RR=0.87 [0.74,1.04] highest vs lowest consumption (81)		 Fatty Fish
Selenium Intake associated with lower risk of postpartum depression OR=0.97 [0.95,0.99] and reduction in depressive symptoms WMD=-0.37 [-0.56,-0.18] (84) Wheat products, meat (85)
B-vitamins Lower risk of remission (86) Liver, fish, leafy greens, eggs, seeds
Biotin Associated with lower odds of depression (OR=0.71 [0.55,0.91]) (87) Organ meat, egg yolk, some vegetables, milk (88)
Folic acid Associated with lower odds of depression OR=0.78 [0.61,0.99] (87) Legumes, leafy greens, citrus, vegetables, liver, dairy products(89)
Vitamin D In cases of deficiency, vitamin D supplementation may help depressive symptoms (90)

Inverse correlation between serum vitamin D levels and depression (91)		 Sunlight(92), oily fish, fortified foods (93)
Probiotics Small but significant effects for trials lasting at least one month (SMD=-0.28, [-0.44,-0.13] ) (94)

Significant difference in depression score (SMD=-0.47 [-0.67,-0.27]) (95)

Other meta-analyses reveal no significant difference, though very close to statistical threshold of p=0.05 (SMD=-0.128, [-0.261,0.005]) (96)		 Yogurts, kefir (97), kombucha (98), fermented meat and fish products, sauerkraut, kimchi, natto, miso, sourdough bread (99, 100)
Acetyl-L-Carnitine Significant reduction in depressive symptoms (SMD=-1.10) [-1.65,-0.56] (101) Meat (102)
Creatine Reduction in depression associated with level of dietary creatine consumption.
AOR=0.68 [0.52,0.88] (103)		 Meat (104)
Amino acids Positive (105) Protein rich foods, supplements
Niacin Lower risk with increased consumption up to a point, after which risk increase(106) Meat products, fish, peanuts, whole grains (107)
Methylfolate Impro
vement SMD=-0.38 [-0.59,-0.17] (108)

SMD=-0.61 [-0.97, -0.24](109)		 Leafy greens,
Legumes,
Fortified cereals, Liver
5-HTP Significant improvements (g=1.11 [0.53,1.69] (110) Turkey, Chicken, Fish, Dairy products, supplements
St. John’s Wort Similar response to SSRI treatment (111) Hypericum perforatum
Saffron Significantly better than placebo g = 0.891 [0.369,–1.412] (112) Saffron spice derived from the Crocus sativus flower
Curcumin Significant clinical efficacy in depression (113)

Effective as adjunctive therapy (114)		 Turmeric spice, commonly used in curry dishes and various recipes
Methylene Blue Reduction in manic depressive attacks (115)

Marked improvement in depressive symptoms (116)		 Supplements
Chinese Herbal Medicine Positive effect (117, 118) Depends on formulation
Nigella Sativa Decreased depression score (-5.5±2.5, DASS-21 survey) (119) Black cumin seed
S-adenosyl methionine Low quality evidence for efficacy(120) Supplements
Cannabionoids Limited evidence (121)

Long term users more likely to develop depression (122)		 Cannabis
psilocybin(microdose) Lower depression scores in retrospective survey (123) certain species of psychedelic mushrooms.
Ayahuasca Significant Improvement (124) Banisteriopsis caapi and a DMT containing platn, typically Psychotria viridis
LSD Improvement (125) Synthesized
Psilocybin Improvement (124) certain species of psychedelic mushrooms.
Bacopa Monnieri Improved Depressive symptoms (126) Bacopa Monnieri
SHR-5 Improves depressive symptoms (127) Rhodiola rosea L.
Kava kava Improvement in symptoms in human subjects(128) Piper methysticum
Inositol Equivocal evidence(58) Fruits, beans, grains, and nuts (129)
Chromium RCT shows effectiveness compared to placebo (130) Meats, grain products, fruits, vegetables, nuts, spices, brewer’s yeast, beer, and wine (131)
Alpha Lipoic Acid Equivocal evidence (58) Muscle meats, heart, kidney, and liver(132)
N-acetyl Cysteine (NAC) Positive evidence from trials (133, 134) Supplements
Ginseng Improvements in QOL in patients complaining of stressor fatigue (135) Ginseng
Co-enzyme Q10 (59)
SMD=0.97 [0.01,1.93] p<0.00001		 Meat, fish, nuts, and some oils (136)
Crocin (59)
MD=6.04 [3.43, 8.65] p=0.01		 Saffron
Antioxidant supplements Significant improvement (SMD = 0.40, 95 % CI = 0.28–0.51, p < 0.00001) (59) Supplements
Tryptophan Not significant (32) Meat and dairy
Ethyl-EPA Positive impact (32) Fish oils
DL-Tryptophan Positive impact (32) Supplements
Vitamin C Mixed impact (32) Citrus fruits, colorful vegetables
Catechins Positive impact (55) Tea
Hydroxytyrosol Positive impact (56) Extra virgin olive oil
Valerian Positive impact (137) Valeriana officinalis
Rhodiola Positive impact (138) Rhodiola rosea
Lavender Positive impact (138) Lavandula angustifolia
Borage Mixed (138) Borago officinalis or Echium
Chamomile Not significant (139) Matricaria chamomilla or Chamaemelum nobile
Dan zhi xiao yao Positive impact (77) Mixture of Bupleurum chinense, Scutellaria baicalensis, Paeonia lactiflora, Glycyrrhiza uralensis, Mentha haplocalyx, Zingiber officinale, and Ziziphus jujuba
Other agents with preclinical data are shown in Supplementary Table S2 (140-201).

4.1. The Gut Microbiome and Depression: Exploring the Gut-Brain Axis

Depression is a complex mental health disorder that affects millions worldwide. While the exact causes of depression are not fully understood, emerging research suggests that the gut microbiome may play a significant role in its development and progression. The gut-brain axis, a bidirectional communication system between the enteric microbiota and the central nervous system, is thought to be a key mediator in this relationship and seems to have significant implications for depression.

4.1.1. The Gut-Brain Axis

The gut-brain axis refers to the intricate interactions between the enteric microbiota, the central nervous system (CNS), and the enteric nervous system (ENS)(202), creating a paradigm change in neuroscience(203). The enteric microbiota, consisting of trillions of microorganisms residing in the gastrointestinal tract, influence various physiological processes, including immune function, metabolism, and neurotransmitter production (204). These microorganisms produce neurotransmitters, such as serotonin and gamma-aminobutyric acid (GABA), which are known to regulate mood and emotions (205) and even modify epigenetic processes of the gut-brain axis (206).

4.1.2. The Role of the Gut Microbiome in Depression

Studies have found alterations in the composition and diversity of the gut microbiome in individuals with depression (207). Researchers (208) highlighted the bidirectional communication between the gut microbiota and the CNS, emphasizing the gut microbiome's influence on neurological and psychiatric disorders(209). Additionally, others (210) discussed the impact of the gut-brain axis on mental health, emphasizing the potential therapeutic benefits of modulating the gut microbiota.

4.1.3. Mechanisms

Several mechanisms have been proposed to explain how the gut microbiome may contribute to depression(205). Short-chain fatty acids (SCFAs) (211), produced by the gut microbiota through the fermentation of dietary fibers, have been shown to modulate brain function and behavior (212). Scientists (213) discussed the role of SCFAs in microbiota-gut-brain communication, highlighting their potential as therapeutic targets. Moreover, a dysregulated microbiota-gut-brain axis has been observed in patients with bipolar depression (214, 215) and associated with depressive-like behaviors in animal models (207, 209). Emerging evidence suggests that alterations in gut permeability (216) and the subsequent inflammatory response may play a crucial role in the relationship between the gut microbiome and depression(217). It was demonstrated (204) how the gut microbiome influences the production and metabolism of neurotransmitters such as serotonin (218), dopamine(219), and gamma-aminobutyric acid (GABA) (220), and how alterations in these neurotransmitter systems may contribute to depressive symptoms.

4.1.4. Clinical Implications and Treatment Approaches

Understanding the gut-brain axis and its association with depression opens up possibilities for novel therapeutic interventions. In studies, a predominance of some potentially harmful bacterial groups or a reduction in beneficial bacteria in depressive patients(215) has been found in depressive patients. Dietary interventions have been the subject of research and studies examining their potential impact on symptoms of depression. There is emerging evidence that suggests a link between diet and mental well-being, indicating that dietary improvements may positively affect symptoms of depression (61, 221). Probiotics, which are live microorganisms that confer health benefits when consumed, have shown promise in modulating the gut microbiota and improving depressive symptoms. Research (222) reviewed the mechanisms of action of probiotics as potential therapeutic targets for depression and anxiety disorders. For example, Lactobacillus rhamnosus directly regulates the GABAergic system via a vagus nerve-dependent way and mitigates depression- and anxiety-like behaviors in mice (223). Bifidobacterium breve, proven to have an antidepressant-like effect, could stimulate the production of intestinal 5-hydroxytryptophan in mice and then regulate the host's serotonin metabolism (224, 225). Pediococcus acidilactici could mitigate anxiety symptoms in mice by producing lactic acid and inhibiting the over-proliferated gut pathogenic bacteria under stress(226). Fecal Microbiota Transplantation (FMT) is a procedure in which a healthy donor's fecal matter is transplanted into a recipient's gastrointestinal tract to restore a healthy balance of gut bacteria. There is growing interest in the potential therapeutic effects of FMT on various conditions, including depression (227, 228).
Overall, The gut microbiome and the gut-brain axis are emerging areas of research in the field of depression. The bidirectional communication between the gut microbiota and the CNS highlights the potential for microbiome-based interventions in treating depression. While promising, more research is required to elucidate the underlying mechanisms and develop targeted therapies to modulate the gut-brain axis to alleviate depressive symptoms effectively.

4.2. The Link Between Depression and Inflammation

Depression, a prevalent mental health disorder, has long been associated with alterations in the immune system and chronic inflammation. The findings highlight potential therapeutic targets and the importance of a holistic approach to managing depression. The etiology of depression remains multifactorial and complex; emerging evidence suggests a strong connection between depression and inflammation (229). Inflammation, traditionally associated with the immune response to infection or injury, has been implicated in the pathophysiology of various psychiatric disorders. Numerous studies have demonstrated elevated levels of pro-inflammatory cytokines (230), such as interleukin-6 (IL-6) (231, 232) and tumor necrosis factor-alpha (TNF-α) (233), in individuals with depression. Conversely, chronic inflammation, often triggered by external factors such as stress, trauma, or medical conditions, has been shown to contribute to developing or exacerbating depressive symptoms. The dysregulation of the immune system, particularly the imbalance in pro-inflammatory and anti-inflammatory cytokines, plays a crucial role in altering neurotransmitter metabolism, neuroplasticity, and neuroendocrine function, ultimately affecting mood regulation (234).
The bidirectional relationship between depression and inflammation suggests a complex interplay between the immune and central nervous systems. Inflammation-induced activation of the kynurenine pathway (235), dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (236), and disruption of the blood-brain barrier(237) are among the proposed mechanisms linking inflammation to depressive symptoms. Moreover, chronic inflammation may impair the efficacy of conventional antidepressant treatments, emphasizing the need for personalized approaches that target both the neurochemical imbalances and the underlying inflammatory processes. It is worth noting that studies indicate that EMF exposure can increase the secretion of pro-inflammatory cytokines (238), including IL-6, TNF-alpha, and IL-1. The increasing intensity of EMF via mobile phones, Wi-Fi, etc, should initiate more research into the potential association between depression and EMF devices. This proinflammatory effect has been shown to be inhibited by curcumin (239).
Curcumin, a compound found in turmeric, has been the subject of scientific research exploring its potential use in depression (240-243). Curcumin has been found to possess anti-inflammatory properties, which, as we can see, may be relevant to depression. Inflammation has been implicated in the development and progression of depression, and curcumin's anti-inflammatory effects may help alleviate depressive symptoms (244). Curcumin has also shown neuroprotective properties in preclinical studies, including antioxidant and anti-apoptotic effects. These effects may help protect against neuronal damage and promote neuroplasticity, essential factors in depression (245). It has been found to modulate various neurotransmitters, including serotonin, dopamine, and glutamate, which are involved in mood regulation. By influencing these neurotransmitter systems, curcumin may impact depressive symptoms (244). BDNF is a protein that plays a crucial role in the growth and maintenance of neurons. Reduced levels of BDNF have been associated with depression. Curcumin has been shown to increase BDNF levels, possibly contributing to its potential antidepressant effects (246). Some studies have explored the combination of curcumin with other antidepressant medications, suggesting possible synergistic effects. Combining curcumin with standard antidepressant treatment may enhance the therapeutic response (242, 243).

4.3. The Complex Relationship Between Thyroid Dysfunction and Depression

Thyroid dysfunction refers to the abnormal functioning of the thyroid gland, which can result in either hyperthyroidism (overactive thyroid) or hypothyroidism (underactive thyroid). Depression, on the other hand, is a mood disorder characterized by persistent feelings of sadness, loss of interest, and a lack of motivation. While the connection between thyroid dysfunction and depression has been the subject of scientific inquiry (247-249) the relationship between these two conditions remains complex and multifaceted (250). Research has shown a bidirectional relationship between thyroid dysfunction and depression, with each condition potentially influencing the other (251) . Several studies have found that individuals with thyroid dysfunction are at a higher risk of developing depression. For instance, a meta-analysis found a significant association between hypothyroidism and depression(252), suggesting that individuals with an underactive thyroid may be more prone to depressive symptoms. Moreover, thyroid hormones play a crucial role in regulating neurotransmitters(253) such as serotonin (251), dopamine (254), and norepinephrine (255), which are involved in mood regulation. Imbalances in these neurotransmitters have been linked to the development of depression. Therefore, disruptions in thyroid hormone levels can impact the functioning of these neurotransmitters, potentially contributing to the development of depressive symptoms (256). Conversely, depression may also affect thyroid function. Chronic stress, a common contributor to depression, can lead to dysregulation of the hypothalamic-pituitary-thyroid (HPT) axis (257) which controls thyroid hormone production. This dysregulation can result in alterations in thyroid hormone levels (258, 259), potentially leading to thyroid dysfunction. Autoimmune thyroiditis is also associated with an increased risk of depression (260). Elevated thyroid-stimulating hormone (TSH), antithyroglobulin (TgAb), and thyroid peroxidase antibodies (TPOAb) levels have all been linked to depression and an increased risk of suicide (251). Moreover, hypothyroidism is known to be one of the leading causes of treatment-resistant depression. Furthermore, chronic inflammation, often observed in individuals with depression, can also impact thyroid function. The complex relationship between thyroid dysfunction and depression necessitates comprehensive treatment approaches that address both conditions. For individuals with thyroid dysfunction, appropriate thyroid hormone replacement therapy can help restore hormonal balance and alleviate depressive symptoms. It is crucial to closely monitor thyroid hormone levels and micronutrients like Iodine, Zinc (261), Iron (262) and Selenium (263) and adjust medication dosages as necessary. If an individual with depression also exhibits symptoms of thyroid dysfunction, it is important to assess thyroid function and consider appropriate interventions to optimize treatment outcomes (264). Thyroid dysfunction and depression share a complex and bidirectional relationship. While individuals with thyroid dysfunction may be at a higher risk of developing depression (265) depression can also impact thyroid function (258). Addressing both conditions simultaneously is crucial for effective treatment outcomes. Further research is needed to unravel the precise mechanisms underlying this relationship and develop targeted interventions that can improve the lives of individuals affected by both thyroid dysfunction and depression.

5. Psychedelic assisted treatment of depression

Evidence for the treatment efficacy of psychedelics in depression is shown in Supplementary Table S4 (124, 266-278), summaries are shown in Table 2.
Table 2. A summary of psychedelic agents and their impacts on depression.
Table 2. A summary of psychedelic agents and their impacts on depression.
Substance Evidence
Ketamine Significant but temporary (1 week) effect (279)
MDMA Hedge’s g = -0.71; 95% CI, -1.39 to -0.03 (280)
Psilocybin Hedges' g was 1.289 (95%CI=[1.020, 1.558], heterogeneity I2=50.995%, p<0.001) (272)
Ayahuasca Improvements in depressive symptoms in large cross sectional study (281)
LSD Non significant decrease in depressive symptoms (282)
The use of psychedelics to treat depression is different from the use of most pharmacological agents and is differentiated. An important factor to consider with psychedelic use is the primacy of the experience. Psychedelics can be thought of as tools which allow one to assume a different frame of mind for the duration of the effects. It can be very helpful for the treatment of various states of dis-ease to see it form an alternative perspective. Even non-pharmacologically, exposing one’s self to new ways of thinking, either through hobbies(47, 283), learning(284), engaging with people(285) or traveling(286).
Psychedelics are legally restricted in many jurisdictions, though legalization is increasingly being considered by policymakers(287). A typical psychedelic assisted therapy session involves a facilitator and the person taking the psychedelic. The person taking the psychedelic will typically journal or otherwise clarify their intentions for the session through a conversation or a set of journal prompts(288).
During the session, it is vital to create a safe environment where the recipient is able to fully relax. Psychedelics combined with the introspection encouraged by the facilitator aids the recipient to examine their life from a depatterned frame of mind(289). Many people rate psychedelic experiences as among the most meaningful in their life, and usually overwhelmingly positive (290, 291). Adverse reactions can be minimized through proper set and setting, though psychedelics can be used responsibly with a skilled practitioner and in accordance with local regulations (292).

5.1. Ketamine

Ketamine, derived from phencyclidine (PCP), functions as an N-methyl-D-aspartate (NMDA) receptor antagonist and has been utilized as an anesthetic for over half a century (293). Notably, ketamine demonstrates a rapid and pronounced improvement in mood symptoms and suicidal ideation by directly targeting the glutamate system (293). The pivotal study by Zarate et al. highlighted its potential in patients who do not respond to standard antidepressants, where a single 40-minute ketamine infusion resulted in a very rapid and robust antidepressant effect, with over 50% of patients experiencing a positive response within 24 hours (294). A subsequent collaborative study by Murrough et al. in 2013 further supported these findings, revealing a response rate of approximately 67% for participants with treatment-resistant depression (TRD) receiving ketamine, compared to a 28% response rate in the midazolam control group at 24 hours (295). However, the antidepressant effects of ketamine diminished by 7 days. This renewed awareness of the limitations of monoamine-based mechanisms for treating depression has fueled increased interest in ketamine as an alternative (296).
In a 2015 meta-analysis by Newport et al., seven trials involving 147 participants with treatment-resistant depression who underwent a single ketamine infusion demonstrated a rapid and transient antidepressant effect, with odds ratios approaching 10 for treatment response and 14.47 for symptom remission at 24 hours (279). However, the benefits tended to dissipate by 7 days, as indicated in an additional meta-analysis (297). Moreover, ketamine was found effective in reducing suicide ideation for up to 7 days (298). Most ketamine studies have utilized an intravenous dose of 0.5 mg/kg infused over approximately 40 minutes, with a dose-finding study recommending doses within the range of 0.5 mg/kg to 1 mg/kg (299). While single-dose protocols have been prominent in research settings, multi-dose regimens are gaining attention, such as twice-weekly treatments for 2 to 4 weeks or thrice-weekly for 3 weeks. A recent study by Phillips et al. highlighted the potential of maintenance ketamine, indicating lasting antidepressant effects when administered 3 times per week for 6 doses, followed by a weekly dose for 4 additional weeks (300).
Ketamine's use for depression treatment is, however, constrained by the need for administration in a medical facility under strict monitoring, rendering it an expensive and resource-limited option (293). Additionally, treatment-emergent hypertension has been observed in approximately 44% of ketamine infusion cases, with blood pressure increases exceeding 165/100 mmHg, necessitating pharmacological intervention in 12% of patients (301). Despite these limitations, ketamine is increasingly considered as adjunctive therapy for patients with treatment-resistant depression and may also be a valuable option for those with suicidal ideation or severe depression admitted to the hospital.

5.2. Psilocybin

Psilocybin, the active component of psychedelic mushrooms, has been used in human cultures for millennia. While controversy exists over the extent and impact of states induced by psychedelics, they undoubtedly played an important role in the human cultures in which they were adopted as part of ritual, appearing in artworks and sacred locations(302). Species of psilocybin producing mushroom are found in varied geographies, and on all continents (with the exception of Antarctica) (303).
Indigenous relationships with psychedelic plants often regarded them as teachers(304), and their consumption would be performed within a ceremonial setting for such purposes.
Psilocybin has been studied for the treatment of depression, and placebo controlled trials revealed statistically significant reductions in depression and anxiety symptoms, with Hedge’s g=0.83 compared to placebo (273).

5.3. Ayahuasca

Ayahuasca is a brew made from the mixture of a DMT containing plant substance, typically the leaves of Psychotria viridis (or chakropanga species) and a Monoamine oxidase inhibitor (MAOI), typically Banisteriopsis caapi (281). The brew is made over multiple days of heating the components together, and the final product is a dark and thick brewed tea, which traditionally, is taken only in the context of ceremony.
The effects of Ayahuasca last for approximately 6 hours (305),wherein the journeyer experiences psychedelic and physical impacts from the psychedelic. Physical experiences can include purging, which is regarded as part of the medicinal action of Ayahuasca(306).
Several trials have explored the therapeutic use of Ayahuasca for depression. Given the salience of the effects, placebo controlled trials are difficult. A survey of 11,912 people who had previously participated in an Ayahuasca ceremony revealed that of the 1571 people reporting depression at the time of the ceremony, 46% reported ‘very much’ improvement and 32% reported that their depression was ‘completely resolved’ (281). While this study has the limitation of not comparing results to a non-treatment control, still, the results are highly promising.

5.4. LSD and MDMA

Lysergic acid Diethylamide (LSD) has recently been used in the context of psychedelic assisted psychotherapy after a hiatus in research due to regulatory reasons (307). A recent trial demonstrated clinically significant reductions after two LSD assisted psychotherapy sessions compared to placebo(308).
3,4-methylenedioxymethamphetamine (MDMA) is a common party drug which is being adopted in the context of psychotherapy. A recent meta-analysis revealed statistically significant reductions in depressive symptoms with MDMA-assisted psychotherapy (Hegde’s g = -0.71; 95% CI, −1.39 to −0.03) (280).

6. Lifestyle changes for treatment of depression

There are several changes that one can make in their life to recover from depression. These useful strategies have an evidence base documenting their efficacy. We performed a literature search on lifestyle treatment for depression and found several reviews (Supplementary Table S3) (309-317). These findings are summarized below in Table 3.
Table 3. A summary of lifestyle interventions and their impacts on depression.
Table 3. A summary of lifestyle interventions and their impacts on depression.
Intervention Effect
Hobbies Dance: effect similar to antidepressants (318)
Lower risk (47, 48).
Mindfulness Decreases in depressive symptoms (319)
Sleep Improved sleep quality decreased depressive symptoms (320)
Natural environments increases in positive mood, and lowered feelings of depression(321, 322).
Time with animals reducing depression(323).
Socialization significant improvement in their present state examination (PSE) scores after making a new friend (45)
Journaling Positive impact (324)
Gratitude associated with positive mental health, including alleviating depression (325-329)
Deep brain stimulation small but significant effect(326, 327).
Sauna/ whole body hyperthermia Positive effect (330)
Goal setting Some limited evidence for efficacy (331)

6.1. Exercise

There is growing recognition that lifestyle behaviors, such as physical activity and exercise can be useful strategies for treating depression, reducing depressive symptoms, improving quality of life, and improving physical health outcomes. Cross-sectional studies have shown that people with higher levels of physical activity present decreased depressive symptoms, and these results are consistent across different countries and cultures. For example, recent evidence using data from the Brazilian National Health Survey, accounting for 59,399 individuals, demonstrated that a lack of physical activity for leisure was associated with depression in young males, middle age, and older adults.(332) A study across 36 countries demonstrated that lower levels of physical activity (defined as less than 150 min of moderate-vigorous physical activity per week) were consistently associated with elevated depression (OR, 1.42; 95%CI, 1.24–1.63). (333) However, mental health benefits have been noted from being physically active, even at levels below the public health recommendations.(334) In The Irish Longitudinal Study on Ageing participants performing 400 to less than 600 MET-min/wk had a 16% lower rate of depressive symptoms (adjusted incidence rate ratio [AIRR], 0.84; 95%CI, 0.81-0.86) and 43% lower odds of depression compared with 0 MET-min/wk.(335) These findings are consistent with recent meta-analytic data suggesting that salutary mental health benefits among adults can be achieved with physical activity below public health recommendations; specifically, an activity volume equivalent to 2.5 hours per week of brisk walking was associated with a 25% lower risk of depression, and half that activity volume was associated with an 18% lower risk compared with no activity.(334) The findings of The Irish Longitudinal Study on Ageing suggest that accumulating as little as 100 minutes per week or 20 minutes per day for 5 days per week of moderate-intensity activity (eg, brisk walking; 4 METs) may be sufficient to significantly lower the risk of depressive symptoms and odds of major depression over time among older adults
A large body of trials has been performed over the last 40 years evaluating the role of exercise as a therapy for depression. These results have been summarized in several metaanalyses. A Cochrane analysis of 35 trials (1356 participants) comparing exercise with no treatment or a control intervention, the pooled outcome for the primary outcome of depression at the end of treatment was standardized mean difference (SMD) -0.62; 95% CI-0.81 to -0.42, indicating a moderate clinical effect. Schuch et al performed a meta-analysis which included 25 RCTs comparing exercise versus control comparison groups. (336) Overall, exercise had a large and significant effect on depression. Similarly, Krogh et al performed a meta-analysis which included 35 trials enrolling 2498 participants.(337) The effect of exercise versus control on depression severity was −0.66 SMD (95% CI −0.86 to −0.46; p<0.001).
Exercise can improve depressive symptoms in people with depression. However, like other treatments, exercise is not a panacea and may not work equally for all. A seminal study by Dunn et al., the Depression Outcomes Study of Exercise, found a response rate of about 40% in depressed people free from other treatments.(338) However, it is likely that when combined with other interventions (i.e vitamin D, L-methyl-folate, etc) the response rate and degree of response will be much greater. In essence, exercise has multiple benefits to several domains of physical and mental health and should be promoted to everyone. To ensure compliance, adapting exercise prescription for people with depression should account for personal preferences and previous experiences in terms of making it the most enjoyable experience possible. Acute exercise should be used as a symptom management tool to improve mood in depression, with even light exercise an effective recommendation.(339) These data suggest that physical activity is beneficial for the depressed patient regardless of the intensity of the exercise.
The neurobiological mechanisms underpinning the antidepressant effects of exercise are largely unclear. However, some hypotheses involving inflammation, oxidative stress, and neuronal regeneration are speculated. Exercise training can promote increases in anti-inflammatory and antioxidant enzymes, referred to as a hormesis response and subsequently decrease IL-6 levels. This effect was demonstrated in the REGASSA trial, where decreases in IL-6 serum levels were associated with reductions in depressive symptoms. (340)

6.2. Time in nature

Time in nature is associated with increases in positive mood, and lowered feelings of depression(321, 322).

6.2.1. Animal-Assisted Therapy

Time spent with animals can be an effective way of reducing depression(323).

6.3. Mindfulness

Several mindfulness based therapies can potently treat depression. The most studied treatments are cognitive behavioral therapy (CBT), mindfulness based stress reduction (MBSR) and mindfulness based cognitive therapy (MBCT), which have important distinctions. Mindfulness based therapies demonstrate significant reductions in depression(319).

6.4. Connection with others

In the middle of depression, one of the things which falls by the wayside are plans and social interactions. Existing in large cities, one lives a largely anonymized existence, where they do not experience connection with others, including seeing others and being seen by others.

6.4.1. Purpose and goals

Positive, goal directed activity is associated with a decrease in depressive symptoms and has the added benefit of providing structure and a reason to positively interact and create with others. Progress in any aspect increases positive self-regard, confidence, and sense of self-efficacy, as well as one’s social status. These factors are associated with a decrease in depressive symptoms(341, 342).
Another benefit is that learning positively uses neural pathways and grows new neurons and is also associated with a sense of optimism. Furthermore, a challenging task necessarily takes much of the mental bandwidth, leaving less space for ruminations characteristic of depression. During periods of intense stress including the London Blitz during World War II, there was a paradoxical decrease in psychiatric presentation to hospitals, owing to the dire need of hospital beds(343). The efforts of every man and woman were needed, and this sense of purpose is protective against depression.
Depression is often a reason for introspection into the aspects of one’s life that are not working. Often a major life area, such as one’s career, or one’s close relationships or lack thereof are brought into focus. In these cases where dissatisfaction with one’s current life is the proximal cause of one’s depression, working with a life coach or otherwise reflecting on one’s ideal life (and how to achieve it), is a powerful practice for inspiring hope and action which follows that. A significant proportion of depression is a lack of meaning and purpose.
Interestingly, regular Argentinian tango was comparable to mindfulness meditation in terms of the impact on depression (318), suggesting value in novel pursuits and hobbies.
Indigenous communities living traditional existences do not suffer from psychiatric issues. The differences in the sense of purpose between modern and tribal cultures can be attributed to the tight-knit tribal communities where everybody feels a sense of importance in the eyes of the community. Furthermore, practices such as initiation into manhood and womanhood, most notably the vision quest, provide the individual with a clear role to play in the community.
Over millennia, these practices have corrected wayward youth and to integrate at risk youth into constructive roles within the community. While this review mostly focuses on the individual treatment of depression, it should be noted that initiatives like upward bound, which provide a similar experience for youth on the cusp of adulthood, increase the likelihood of post-secondary education(344).
These programs, involve people getting out in nature, which in itself has positive benefits for mood disorders(345), and additionally provides the benefits of physical activity(346). The program positively impacts self-concept(347).

6.5. Gratitude

An outlook of gratitude has been valued by all the major monotheistic religions(348). Furthermore, in modernity, when gratitude is operationalized as an explicit practice, it is associated with positive mental health, including alleviating depression (325-329). Gratitude journaling is one of the most accessible ways that one can practice journaling, which simply involves recording 3-5 things that one is grateful for on a daily basis(349, 350).

6.6. Deep Brain Stimulation

Noninvasive brain stimulation methods have been studied for their favorable modulation of a wide variety of neural states. For the treatment of depression, some promising data exists for these therapies, showing a small but significant effect(326, 327).
Non-invasive brain stimulation (NIBS) using transcranial direct current stimulation or transcranial magnetic stimulation has been demonstrated to be highly effective in the treatment of depression (351-355).

6.7. Whole-Body Hyperthermia

Historically, hyperthermia interventions have been utilized to address depressive symptoms, with evidence dating back to ancient times, such as the practices of Galen of Pergamon (129–198 C.E.), who treated melancholia by immersing patients in hot tubs and providing skin massages (330). Contemporary research has highlighted the positive effects of regular sauna bathing, including reductions in all-cause and cardiovascular mortality, increased lifespan, improved exercise performance, and the activation of autophagy through the expression of heat shock proteins (356-359). Heat therapy also enhances cell stress pathways, possesses antioxidant and anti-inflammatory properties, and enhances mitochondrial function. Sauna bathing exhibits physiological similarities to aerobic exercise, increasing heart rate, stroke volume, and cardiac output (360, 361). Furthermore, whole-body hyperthermia (WBH) selectively raises IL-6 levels(362) and shows promise in conditions like chronic fatigue syndrome (363, 364).
Animal studies have indicated that WBH activates portions of the dorsal raphe nucleus associated with mood regulation and produces antidepressant-like responses (365). Clinical studies have shown that a single session of WBH can significantly reduce depressive symptoms when assessed five days post-treatment (366). Additionally, a randomized, double-blind study comparing WBH with a sham condition in depressed patients revealed significant reductions in Depression Rating Scale scores over a six-week post-intervention period in the active WBH group (367). Hanusch et al. conducted a meta-analysis on the effect of WBH on depression indices, encompassing seven studies with a total of 148 subjects. Six out of seven studies reported statistically significant reductions in depressive symptoms between one and six weeks post-intervention. The treatment effect appeared to be independent of the total number of WBH sessions, with target temperatures between 38°C and 39°C and a slower increase in core body temperature during the intervention resulting in larger treatment effects. This suggests potential benefits of near-infrared (NIR) sauna over regular sauna, as NIR sauna sessions can be more controlled, shorter in duration (5-10 mins initially, increasing to 20 mins), and performed two to three times a week for maximal cardiovascular benefit (330).

6.8. Photobiomodulation

Photobiomodulation (PBM) is referred to in the literature as low-level light therapy, red light therapy, and near-infrared (NIR) light therapy. Depression is associated with brain hypometabolism and cerebral as well as systemic mitochondrial dysfunction (368-370). In a rat model of depression, vital steps in the production of adenosine triphosphate (ATP) were inhibited in the cerebral cortex and cerebellum (371).
Peripheral blood mononuclear cells of depressed patients were shown to have significantly impaired mitochondrial function (372, 373), and greater mitochondrial dysfunction correlated with severity of neuro-vegetative symptoms, including fatigue and poor concentration (372). Muscle biopsy samples from depressed patients with physical symptoms had a decreased rate of ATP production and more frequent mitochondrial DNA deletions than controls (370).
The most well-studied mechanism of action of PBM centers around enhancing the activity of cytochrome C oxidase (CCO), which is unit four of the mitochondrial respiratory chain, responsible for the final reduction of oxygen to water (374). The theory is that CCO enzyme activity may be inhibited by nitric oxide (NO). This inhibitory NO can be dissociated by photons of light that are absorbed by CCO. These absorption peaks are mainly in the red (600–700 nm) and near-infrared (760–940 nm) spectral regions. When NO is dissociated, the mitochondrial membrane potential is increased, more oxygen is consumed, more glucose is metabolized and more ATP is produced by the mitochondria (375).
PBM has been found to specifically increase CCO activity and expression (374, 376, 377). Studies have also shown increases in complex II, III, and IV activity, as well as upregulation of gene coding for subunits of complex I, complex IV, and ATP synthase. (374) Low-level laser therapy has been shown to increase levels of ATP, the rate of oxygen consumption, and cerebral oxygenation (374). Though t-PBM with red and NIR light can include wavelengths from 600 to 1070nm, specific wavelengths have been directly linked to mitochondrial activity. Near Infrared activates CCO, increases mitochondrial oxygen consumption, and leads to higher levels of ATP (378-380).
There is some evidence that PBM applied peripherally, not just transcranially, may have an effect in attenuating depressive symptom (374). There is no clear mechanism proposed explaining this effect. In a recent study, 5 outpatients with low-back pain and concurrent self-reported depression were treated over five weeks with physical therapy (PT) (5-sessions) and concurrent PBM (3-sessions) and matched to five control patients treated with PT alone (5-sessions) (381). Participants receiving s-PBM reported a larger decrease in their depression score. Oron and co-workers have shown that delivering NIR light to the mouse tibia resulted in improvement in a transgenic mouse model of Alzheimer's disease (382).

7. Conclusion

More integrative approaches, including diet and lifestyle may improve the quality of life of people with depression and enable them to live a fulfilling life. Currently, practitioner understanding is a barrier, as well as the limited time that primary care physicians spend with patients. Additionally, other systemic issues remain about the cost of therapy, while simultaneously therapists themselves are overburdened and undercompensated. Expectations of one’s self can be a barrier to those experiencing depression even acknowledging it, let alone seeking help (383). Much work remains on the public health understanding of depression, and an integrative approach, combining dietary, lifestyle change with other therapies and embracing a trauma-aware perspective can help greatly. Additionally, the resiliency of the person experiencing depression must be acknowledged, and he or she must be captain of the process. Practitioners can help through educating and coaching the person recovering depression, and by pointing them to resources and therapeutics for their specific case.

Supplementary Materials

The following supporting information can be downloaded at the website of this paper posted on Preprints.org.

Acknowledgements

We thank Mazhar Hussain for assisting with reference formatting.

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