Depression

Psilocybin with psychological support produced rapid, sustained reductions in depression scores in an open-label treatment-resistant depression study ^{35Reference 35Grob et al. · 2011RCTPilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer — randomised controlled trialView study →}, with fMRI work suggesting the effect tracks a temporary loosening of default-mode-network activity ^{36Reference 36Raison et al. · 2023RCTSingle-Dose Psilocybin Treatment for Major Depressive Disorder — randomised controlled trialView study →} and mediation by acute psychological flexibility ^{37Reference 37Davis et al. · 2021RCTEffects of Psilocybin-Assisted Therapy on Major Depressive Disorder — randomised controlled trialView study →}. Mechanism is 5-HT2A agonism via the active metabolite psilocin ^{38,39Reference 38Ross et al. · 2016RCTRapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer — randomised controlled trialView study →Reference 39Griffiths et al. · 2016RCTPsilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer — randomised, double-blind trialView study →}. Early open-label/mechanistic data on screened, therapist-supported participants — not casual self-treatment.

A 2021 meta-analysis found a small but significant reduction in depression scores versus placebo (SMD −0.47) ^{40Reference 40Ghazizadeh J et al. · 2021Meta-analysisThe effects of lemon balm (Melissa officinalis L.) on depression and anxiety in clinical trials — a systematic review and meta-analysisView study →}, supported by two dedicated RCTs — 700 mg/day hydroalcoholic extract cut Beck Depression/Anxiety scores in type 2 diabetics with depressive symptoms ^{41Reference 41Safari M et al. · 2023RCTThe effects of Melissa officinalis on depression and anxiety in type 2 diabetes patients with depression — randomised double-blind placebo-controlled trialView study →} and 3 g/day powdered leaf lowered DASS-21 depression scores in chronic stable angina patients ^{42Reference 42Haybar H et al. · 2018RCTThe effects of Melissa officinalis supplementation on depression, anxiety, stress and sleep disorder in patients with chronic stable angina — randomised placebo-controlled trialView study →}. Effect sizes are modest, samples small, and both dedicated RCTs studied medically ill populations rather than primary depression.

Saffron’s flagship, best-evidenced use. Dozens of RCTs and multiple meta-analyses find dried stigma / standardised extract (~28–30 mg/day) superior to placebo and non-inferior to SSRIs (fluoxetine, imipramine, citalopram) in mild-to-moderate depression ^{59,60,61,62,63Reference 59Hausenblas et al. · 2013Meta-analysisSaffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trialsView study →Reference 60Tóth et al. · 2019Meta-analysisThe efficacy of saffron in the treatment of mild to moderate depression: a meta-analysisView study →Reference 61Dai et al. · 2020Meta-analysisSafety and efficacy of saffron (Crocus sativus L.) for treating mild to moderate depression: a systematic review and meta-analysisView study →Reference 62Akhondzadeh et al. · 2004RCTComparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomised trialView study →Reference 63Noorbala et al. · 2005RCTHydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomised pilot trialView study →}, with a 2026 GRADE-assessed review of 34 RCTs (1,769 participants) confirming a significant reduction ^{64Reference 64Mahmoudi R et al. · 2026Meta-analysisEffect of saffron on depression, anxiety and mood disorder: a GRADE-assessed systematic review and meta-analysis of 34 randomised controlled trialsView study →}.

Limiter: trials short (6–8 wk), modest-sized, heavily single-region (Iran); severe depression, relapse and long-term data untested; a 2022 umbrella review warns against standalone use ^{65Reference 65Musazadeh et al. · 2022Meta-analysisSaffron, as an adjunct therapy, contributes to relieve depression symptoms: an umbrella meta-analysisView study →}.

Depression is St. John’s wort’s anchor indication. A 2008 Cochrane review of 29 double-blind RCTs (n=5,489) found standardised hypericum extracts superior to placebo and comparable to standard antidepressants with fewer dropouts ^{68Reference 68Linde et al. · 2008Meta-analysisSt John’s wort for major depression — systematic review, meta-analysisView study →}, replicated by later meta-analyses against SSRIs ^{69,70Reference 69Ng et al. · 2017Meta-analysisClinical use of Hypericum perforatum (St John’s wort) in depression: A meta-analysisView study →Reference 70Zhao et al. · 2023Meta-analysisThe efficacy and safety of StView study →} and confirmed for milder depression against fluoxetine ^{54Reference 54Urata et al. · 2025Meta-analysisEfficacy of pharmacological interventions in milder depression — systematic review and meta-analysisView study →}.

Efficacy is tied to specific standardised hydroalcoholic extracts (WS 5570, LI 160, ZE 117) via hyperforin-driven monoamine reuptake inhibition ^{71,72Reference 71Lecrubier et al. · 2002RCTEfficacy of StView study →Reference 72Müller · 2001Hyperforin — antidepressant activity by a novel mechanism of actionView study →} — it does not transfer to teas or generic powders, and two large US trials in severe major depression were null ^{73,74Reference 73Hypericum Depression Trial Study Group · 2002RCTEffect of Hypericum perforatum (St John’s wort) in major depressive disorder: a randomised controlled trialView study →Reference 74Shelton et al. · 2001RCTEffectiveness of St John’s wort in major depression: a randomised controlled trialView study →}.

Griffonia is a botanical delivery vehicle for 5-HTP, which bypasses rate-limiting tryptophan hydroxylase to raise serotonin synthesis; a Cochrane review pooled two adequate trials (n=64) favouring the precursor over placebo (OR ≈ 4.1) but judged the evidence insufficient, while later small RCTs matched fluoxetine and fluvoxamine ^{17,18,19,20Reference 17Shaw K et al. · 2001Systematic reviewTryptophan and 5-hydroxytryptophan for depression — systematic reviewView study →Reference 18Shaw K et al. · 2002Meta-analysisAre tryptophan and 5-hydroxytryptophan effective treatments for depression? A meta-analysisView study →Reference 19Jangid P et al. · 2013RCTComparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in first depressive episode — randomised double-blind trialView study →Reference 20Pöldinger W et al. · 1991RCTA functional-dimensional approach to depression: 5-hydroxytryptophan versus fluvoxamine — randomised multicentre trialView study →}. Every trial used purified 5-HTP, not whole seed extract, and there is no modern adequately-powered placebo-controlled trial.

No trial studies hops in diagnosed depression; this use rests on a small DASS-21 crossover pilot, in which self-reported depression subscale scores fell alongside anxiety and stress in healthy young adults ^{21Reference 21Kyrou I et al. · 2017RCTEffects of a hops (Humulus lupulus L.) dry extract supplement on self-reported depression, anxiety and stress levels in apparently healthy young adults: a randomized, placebo-controlled, double-blind, crossover pilot study — [randomized]View study →}.

Two small human trials: a 2010 placebo-controlled trial in 30 menopausal women (fruiting-body cookies, 4 weeks) lowered CES-D depression scores ^{29Reference 29Nagano et al. · 2010RCTReduction of depression and anxiety by 4 weeks Hericium erinaceus intake — randomised, placebo-controlled trialView study →}, and a 2019 controlled trial in 77 overweight/obese volunteers reduced depression, anxiety and sleep disturbance over 8 weeks alongside raised pro-BDNF ^{30Reference 30Vigna et al. · 2019Clinical trialHericium erinaceus improves mood and sleep disorders in patients affected by overweight or obesity — controlled trialView study →}; a 2018 mouse study links this to hippocampal neurogenesis ^{31Reference 31Ryu et al. · 2018AnimalHericium erinaceus extract reduces anxiety and depressive behaviors by promoting hippocampal neurogenesis in the adult mouse brain — animal modelView study →}. Both trials small, short, single-population, none in diagnosed major depression.

Human antidepressant signal is confined to postmenopausal women in small samples: a 14-woman crossover RCT reduced Greene-scale anxiety/depression symptoms ^{32Reference 32Brooks et al. · 2008RCTBeneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to oestrogen or androgen content — randomised controlled trialView study →}, and a 29-woman pilot RCT (3.3 g/day) lowered depression scores alongside blood pressure ^{33Reference 33Stojanovska et al. · 2015RCTMaca reduces blood pressure and depression in a pilot study in postmenopausal women — randomised controlled trialView study →}. Ovariectomised-mice work found all three maca colours produced a similar antidepressant-like effect ^{34Reference 34Rubio et al. · 2006AnimalEffect of three different cultivars of Lepidium meyenii (Maca) on learning and depression in ovariectomised mice — animal modelView study →}. Caveat: no trials in clinically depressed or general adult populations, and mood endpoints are secondary in the existing RCTs.

A phase III RCT in 89 adults with mild-to-moderate depression found standardised SHR-5 (340 or 680 mg/day, 6 weeks) significantly improved overall depression, insomnia and emotional instability versus placebo ^{52Reference 52Darbinyan et al. · 2007RCTClinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression — randomised controlled trialView study →}, and a US head-to-head vs sertraline (n=57) showed a smaller, non-significant antidepressant effect but far fewer adverse events ^{53Reference 53Mao et al. · 2015RCTRhodiola rosea versus sertraline for major depressive disorder — randomised placebo-controlled trialView study →}; a 2025 meta-analysis of milder depression found benefit versus placebo ^{54Reference 54Urata et al. · 2025Meta-analysisEfficacy of pharmacological interventions in milder depression — systematic review and meta-analysisView study →}, with a proposed MAO-A/B-inhibition mechanism shown ex vivo ^{55Reference 55Van Diermen et al. · 2009In vitroMonoamine oxidase inhibition by Rhodiola rosea L. roots — in vitroView study →}.

Only two placebo-controlled RCTs exist — one underpowered and null on its primary comparison — and there is no evidence in moderate-to-severe depression.

A randomised trial in university students (500 mg twice daily, 1 month) reported reduced depression and anxiety scores alongside memory gains ^{56Reference 56Nematolahi et al. · 2018RCTEffects of Rosmarinus officinalis L. on memory performance, anxiety, depression, and sleep quality in university students: a randomized clinical trialView study →}, and continuous rosemary-extract intake improved mood-disturbance and vigour in working-age Japanese men, most in those with poorer baseline mental health (post-hoc) ^{57Reference 57Araki et al. · 2020RCTEffects of Continuous Intake of Rosemary Extracts on Mental Health in Working Generation Healthy Japanese Men — randomized controlled trial (post-hoc)View study →}. Directly conflicting, though: an inhaled-scent study found rosemary aroma raised tension-anxiety and confusion versus lavender/control ^{58Reference 58Burnett et al. · 2004Clinical trialScent and mood state following an anxiety-provoking task — clinical trialView study →}.

Constituent-level and preclinical only: isolated saponins (bacopaside I/II, bacopasaponin C) reduced immobility in mouse forced-swim and tail-suspension screens ^{1Reference 1Zhou et al. · 2007AnimalTriterpene saponins from Bacopa monnieri and their antidepressant effects in two mice models — animal modelView study →}, and a reserpine rat model restored monoamines/BDNF with an effect the authors called comparable to citalopram ^{2Reference 2Zaazaa et al. · 2022AnimalNeuroprotective role of Bacopa monnieri extract in modulating depression in an experimental rat model — animal modelView study →}. No human antidepressant trial of Bacopa alone exists; the only human depression-scale movement was a secondary outcome in Calabrese’s elderly trial ^{3Reference 3Calabrese et al. · 2008RCTEffects of a standardized Bacopa monnieri extract on cognitive performance, anxiety, and depression in the elderly — randomised, double-blind, placebo-controlled trialView study →}. The “comparable to citalopram” line is a rodent behavioural comparison, not a clinical one.

Small trials of cocoa flavanols on mood are limited and largely acute — one RCT in young adults found acute but little sub-chronic benefit ^{4Reference 4Massee LA et al. · 2015RCTThe acute and sub-chronic effects of cocoa flavanols on mood, cognitive and cardiovascular health in young healthy adults — randomised controlled trialView study →}, and a 2023 RCT in middle-aged Japanese women reported profile-of-mood-state improvement ^{5Reference 5Murakami R et al. · 2023RCTEffect of flavanol-rich cacao extract on the profile of mood state in healthy middle-aged Japanese women: a randomised controlled trialView study →}. The popular trace-phenethylamine mechanism is not pharmacologically supported at dietary doses (extensive MAO degradation after oral intake); this is a mood signal in healthy adults, not a depression trial — very thin support for a clinical depression indication.

Preclinical work on cannabichromene (CBC) points to anti-inflammatory and mild antidepressant effects, with human evidence still thin. There is no dedicated depression research on cannabis, no human trial, and no whole-plant data.

Effects are strongly dose- and chemotype-dependent, and cannabis can worsen mood, particularly at THC-dominant doses and with regular use.

Trichilia catigua produces a robust, replicated antidepressant-like phenotype in rodents via an unusually dopaminergic mechanism: a hydroalcoholic extract cut forced-swim immobility in mice and rats and inhibited monoamine (chiefly dopamine) reuptake in synaptosomes ^{6Reference 6Campos et al. · 2005AnimalAntidepressant-like effects of Trichilia catigua (Catuaba) extract: evidence for dopaminergic-mediated mechanisms — animal modelView study →}, a subchronic ethyl-acetate fraction sustained the effect and raised hippocampal cell proliferation ^{7Reference 7Bonassoli et al. · 2012AnimalSubchronic administration of Trichilia catigua ethyl-acetate fraction promotes antidepressant-like effects and increases hippocampal cell proliferation in mice — animal modelView study →}, and a broader screen confirmed the antidepressant-like action without locomotor stimulation ^{8Reference 8Chassot et al. · 2011AnimalPreclinical evaluation of Trichilia catigua extracts on the central nervous system of mice — animal modelView study →}.

The one human trial (Phase III vs escitalopram, NCT02532660) was terminated for recruitment reasons without reporting, so there is no completed human efficacy data — the dopaminergic story is compelling but entirely animal, on standardised extracts/fractions rather than the whole bark.

Antidepressant-like signal is a by-product of the anxiolytic work: the same aqueous extract that produced anxiolytic effects in mice also produced antidepressant-like effects without locomotor impairment ^{9Reference 9Ana María et al. · 2019AnimalNeurobehavioral and toxicological effects of an aqueous extract of Turnera diffusa in mice — animal studyView study →}.

No depression trial and no dedicated evidence. A pharmacological review collates activity across depression, Parkinson and ischaemia models ^{11Reference 11Li XT et al. · 2022ReviewPharmacological effects of Eleutherococcus senticosus on the neurological disorders — reviewView study →}, and the broader neuroprotective animal set ^{12,13,14Reference 12Bu Y et al. · 2005AnimalSiberian ginseng reduces infarct volume in transient focal cerebral ischaemia in Sprague-Dawley rats — animal modelView study →Reference 13Lu et al. · 2019Eleutheroside E attenuates isoflurane-induced cognitive dysfunction by regulating the α7-nAChR-NMDAR pathway — animal studyView study →Reference 14Zhang Z et al. · 2024Acanthopanax senticosus improves cognitive impairment in Alzheimer’s disease by promoting the phosphorylation of the MAPK signaling pathway — animal studyView study →} provides a mechanistic rationale — but every study is in animals and several lean on network-pharmacology target prediction. Adaptogen/antidepressant interaction cautions exist ^{15Reference 15Siwek M et al. · 2023ReviewAdverse events of interactions between adaptogens and antidepressant drugs — retrospective chart reviewView study →}.

Mesembrine-type alkaloids act as serotonin-reuptake inhibitors, raising synaptic serotonin much as SSRIs do, with the lift reported to bring low mood back toward baseline rather than elevating normal mood ^{22Reference 22Harvey et al. · 2011In vitroPharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids — in vitro receptor/enzyme studyView study →}. Support is the herb’s SRI pharmacology plus traditional mood-lifting use. There is no depression RCT; the evidence is pharmacological ^{22Reference 22Harvey et al. · 2011In vitroPharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids — in vitro receptor/enzyme studyView study →}, a strong mechanistic rationale rather than a proven indication.

In diabetic rats, a kratom extract reduced depression-like behaviour in the forced-swim test alongside lower pro-inflammatory cytokines ^{24Reference 24Chen et al. · 2022AnimalAnxiolytic and Antidepressant-like Effects of Mitragyna speciosa Extract in Diabetic Rats — rat animal modelView study →}, with a plausible serotonergic/opioid/dopaminergic mechanism and self-reported mood lift in surveys ^{25,26Reference 25Grundmann · 2017ObservationalPatterns of Kratom use and health impact in the US — Results from an online survey — observationalView study →Reference 26Hiranita et al. · 2022In vitroIn vitro and in vivo pharmacology of kratom — reviewView study →}. No human trial; forced-swim assays are of debated predictive value and the model is confounded by diabetes.

Licorice has a traditional place in mood formulas, and a plausible but purely preclinical mechanism behind it: SSRI-like and MAO-B-like activity demonstrated in a dish. There is no clinical antidepressant trial, and the evidence suggests the activity may not be potent enough for licorice to be used on its own. The glycyrrhizin blood-pressure and potassium risk applies to any dose large enough to matter.

POEE cut immobility in the tail-suspension and forced-swim tests via D1-dopamine and β-noradrenergic receptors, and in the chronic-mild-stress model it restored coat state and grooming while blocking stress-induced corticosterone rises — an HPA-axis mechanism shared with clinical antidepressants ^{43,44Reference 43Piato et al. · 2009AnimalAntidepressant profile of Ptychopetalum olacoides Bentham (Marapuama) in mice — animal studyView study →Reference 44Piato et al. · 2008Effects of Marapuama in the chronic mild stress model: further indication of antidepressant properties — animal studyView study →}. All rodent; no human mood data, and a dose-dependent anxiogenic signal complicates the picture ^{45Reference 45da Silva et al. · 2002Anxiogenic properties of Ptychopetalum olacoides Benth. (Marapuama) — animal studyView study →}.

Constituent-level, not whole herb: isolated chrysin reversed behavioural despair, normalised corticosterone, and upregulated BDNF/NGF in a chronic-mild-stress mouse model, comparable to fluoxetine ^{46Reference 46Filho et al. · 2015AnimalChronic unpredictable mild stress decreases BDNF and NGF levels and Na⁺,K⁺-ATPase activity in the hippocampus and prefrontal cortex of mice: antidepressant effect of chrysin — animal modelView study →}. No study of P. incarnata itself for depression, and the chrysin doses far exceed what the herb delivers — chrysin is also abundant in propolis and honey.

An ethanolic bark extract produced antidepressant-like effects in the mouse forced-swim and tail-suspension tests, dependent on the monoaminergic system, with a follow-up implicating the NMDA–NO–cGMP pathway; the bark phenolic caffeic acid is proposed as the active constituent ^{47,48Reference 47Freitas et al. · 2010AnimalAntidepressant-like action of the ethanolic extract from Tabebuia avellanedae in mice: evidence for involvement of the monoaminergic system — animal modelView study →Reference 48Freitas et al. · 2013AnimalNMDA receptors and the L-arginine-nitric oxide-cyclic GMP pathway are implicated in the antidepressant-like action of the ethanolic extract from Tabebuia avellanedae in mice — animal modelView study →}. Single-laboratory rodent behavioural models only — no clinical data and no marker-standardised dose.

No trial targets diagnosed depression, but the mood-disturbance reduction in the crossover RCT ^{66Reference 66Brock et al. · 2014RCTAmerican Skullcap (Scutellaria lateriflora): a randomised, double-blind placebo-controlled crossover study of its effects on mood in healthy volunteersView study →} and the 5-HT7 receptor binding ^{67Reference 67Gafner et al. · 2003In vitroInhibition of [3H]-LSD binding to 5-HT7 receptors by flavonoids from Scutellaria lateriflora — in vitroView study →} give the traditional “depression associated with exhaustion” use a partial anchor. The use is mood and nervous-exhaustion support, not an antidepressant one.

The only human depression/anxiety data come from a double-blind RCT of fennel in postmenopausal women, which was essentially null for depression and where the anxiety benefit appeared only in the subgroup that actually had a disorder ^{16Reference 16Ghazanfarpour et al. · 2018RCTEffect of fennel on depression and anxiety in postmenopausal women — double-blind RCTView study →}.

Kava’s clinical evidence is for anxiety, not depression. Its studied activities are anxiolytic, sleep, analgesic, anticonvulsant, neuroprotective and anticancer, with no depression indication among them. The depression use rests on traditional Pacific use of the beverage to lift mood alongside easing anxiety and stress.

The one trial whose name invokes depression, the Kava Anxiety Depression Spectrum Study, enrolled a mixed anxiety-and-depression population but reported anxiety reduction as its outcome ^{23Reference 23Sarris et al. · 2009RCTThe Kava Anxiety Depression Spectrum Study (KADSS) — a randomised, placebo-controlled crossover trialView study →}. It is not a depression efficacy trial.

Kava’s defining caveat is rare idiosyncratic hepatotoxicity. Aqueous extracts of peeled noble-cultivar root are favoured, never combined with alcohol.

No depression trial. This use rests on the shen-tonic tradition (calming the nerves, easing the “knotted, tight chest”) and reishi’s general adaptogen/wellbeing framing ^{49,50Reference 49Rogers · 2011The fungal pharmacy: The complete guide to medicinal mushrooms and lichens of North America [Adobe Digital Editions version]Reference 50Hempen et al. · 2009A Materia Medica for Chinese Medicine: Plants, Minerals, and Animal Products. (Pg}. The closest research signal is improved wellbeing in the neurasthenia RCT ^{51Reference 51Tang W et al. · 2005RCTA randomised, double-blind and placebo-controlled study of a Ganoderma lucidum polysaccharide extract in neurasthenia — randomised controlled trialView study →} — a fatigue/wellbeing, not mood, endpoint.

No depression-specific trial. This use rests on TCM tradition — green tea “has been used to treat… depression, low energy” ^{75Reference 75Barceloux · 2012Medical toxicology of drug abuse: synthesized chemicals and psychoactive plants} — plus adjacent constituent data: L-theanine (± caffeine) improves mood and reduces self-rated stress/anxiety in healthy adults ^{76,77Reference 76Payne et al. · 2025Meta-analysisEffects of tea (Camellia sinensis) or its bioactive compounds L-theanine or L-theanine plus caffeine on cognition, sleep, and mood in healthy participants: a systematic review and meta-analysis of randomised controlled trialsView study →Reference 77Hidese et al. · 2019RCTEffects of L-theanine administration on stress-related symptoms and cognitive functions in healthy adults: a randomised controlled trialView study →}, though the one rigorous clinical-anxiety RCT (adjunctive L-theanine in GAD) was null ^{78Reference 78Sarris et al. · 2019RCTL-theanine in the adjunctive treatment of generalised anxiety disorder: a double-blind, randomised, placebo-controlled trialView study →}.

Traditional South American use — in Brazil the herb is taken for energy, fatigue and depression — resting on its caffeine-bearing stimulant character rather than on any antidepressant trial. The one mood-adjacent human study measured mood state at rest and during prolonged exercise in a metabolic/satiety trial ^{79Reference 79Alkhatib et al. · 2017RCTYerba Maté (Ilex paraguariensis) metabolic, satiety, and mood state effects at rest and during prolonged exercise — randomized trialView study →}; that is transient affect in exercising volunteers, not depression, and it does not support a clinical indication.

A caffeine-bearing herb can aggravate the anxiety and disturbed sleep that so often accompany depression.