Comparative Efficacy and Tolerability of Herbal Versus Pharmaceutical Antidepressants in Adults with Depression: A Scoping Review

1. Introduction

Depression is one of the leading causes of disability worldwide and contributes greatly to the global burden of disease across all age groups and income settings (WHO, 2025; GBD 2019 Collaborators, 2020). Recent global health estimates confirm that depressive disorders affect approximately 332 million people worldwide [1,2]. It is characterised by persistent low mood, loss of interest or pleasure, changes in sleep and appetite, fatigue, and difficulty in thinking or concentrating [3,4]. Depression not only affects mental health but also reduces quality of life, work productivity, and social functioning. Despite effective treatments being available, many people especially in low- and middle-income countries do not receive adequate care due to limited access to mental health services [5,6,7].

Pharmaceutical antidepressants remain a key treatment for moderate to severe depression and are recommended in most clinical guidelines [8,9]. These include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and others. Research shows that antidepressants are generally more effective than placebo, but their effectiveness varies between drugs [9]. However, they can take time to work and may not fully relieve symptoms in all patients. Side effects such as nausea, sleep problems, weight gain, and sexual dysfunction can also reduce adherence and lead some patients to stop treatment [10,11]. Because of these limitations, there is growing interest in alternative and complementary treatments.

In recent years, the use of herbal and complementary medicines for mental health has increased [12]. Many people prefer herbal treatments because they are seen as more natural and potentially safer. The most studied herbal treatment for depression is Hypericum perforatum also known as St John’s wort, which has shown antidepressant effects in clinical studies [13,14]. It is thought to work by affecting serotonin, dopamine, and glutamate systems, as well as reducing inflammation [12]. Other herbs such as Withania somnifera, Crocus sativus, and Rhodiola rosea have also shown possible benefits for mood and anxiety in early research [15,16,17].

Some studies suggest that certain herbal treatments, especially Hypericum perforatum, may be as effective as standard antidepressants for mild to moderate depression and may cause fewer side effects [13,14]. However, there are concerns about the quality and consistency of herbal products. Differences in plant sources, preparation methods, and dosages can lead to inconsistent results across studies [18,19]. In addition, herbal medicines can interact with prescription drugs. For example, Hypericum perforatum can reduce the effectiveness of many medications by affecting liver enzymes involved in drug metabolism [19,20].

Recent studies continue to explore herbal treatments either alone or alongside standard antidepressants [21,22]. Some trials report improvements in depressive symptoms and stress levels, but the evidence is still inconsistent. Differences in study design, patient populations, and outcome measures make it difficult to compare results across studies. Although many reviews have focused on individual herbal treatments [23,24], there is still limited work that directly compares herbal and pharmaceutical antidepressants across effectiveness, safety, and tolerability. Because interest in complementary treatments is increasing, it is important to summarise the existing evidence and identify gaps in research. The scoping review is suitable because it examines available evidence and highlights areas where more research is needed [25,26]. Therefore, this scoping review aimed to examine and synthesise the available evidence on the comparative efficacy, safety, and tolerability of herbal versus pharmaceutical antidepressants in adults with depression.

2. Results

2.1. Study Selection

The study selection process is presented in Figure 1 using the PRISMA 2020 flow diagram. A total of 3182 records were identified through database searching, with 19 additional records identified from grey literature sources. After removal of 1013 duplicates, 2188 records were screened by title and abstract. Following screening, 2045 records were excluded due to non-eligible participant groups, non-comparative study designs, and lack of depression-specific outcomes. A total of 143 full-text articles were assessed for eligibility. Of these, 122 studies were excluded for the following reasons: lack of comparator group (n = 45), ineligible interventions (n = 29), insufficient outcome data (n = 21), non-human studies (n = 12), and methodological limitations (n = 15). Finally, 21 primary comparative studies met the inclusion criteria and were included in the review.

The characteristics of the included studies, including study design, interventions, comparators, and study type, are summarised in Table 1.

2.2. Characteristics of Included Studies

The included studies varied in design and were conducted across multiple countries. A range of herbal and pharmaceutical antidepressants were evaluated. Herbal interventions included Hypericum perforatum (St John’s wort), Crocus sativus (saffron), Withania somnifera, and other plant-based preparations. Pharmaceutical comparators included selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs). Treatment duration varied across studies, and depression severity was assessed using validated scales such as the Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI), and Montgomery Asberg Depression Rating Scale (MADRS). Detailed study characteristics are presented in Table 2.

2.3. Comparative Synthesis of Outcomes

Across the included studies, both herbal and pharmaceutical antidepressants were associated with improvements in depressive symptoms. Findings were broadly consistent across studies but varied in strength depending on depression severity and study design. Hypericum perforatum showed comparable efficacy to SSRIs in patients with mild to moderate depression in several trials, with no major differences reported between groups. However, pharmaceutical antidepressants, particularly SNRIs and TCAs, demonstrated more consistent and stronger effects in moderate to severe depression. In terms of safety, herbal antidepressants were generally associated with fewer and milder adverse effects. Reported side effects of herbal treatments included mild gastrointestinal symptoms, dizziness, and photosensitivity. In contrast, pharmaceutical antidepressants were more frequently associated with sexual dysfunction, weight gain, sleep disturbances, and gastrointestinal effects. A key safety concern for herbal treatments, particularly Hypericum perforatum, was the risk of drug interactions due to cytochrome P450 enzyme induction. Discontinuation rates were generally lower in herbal treatment groups in several studies, likely due to better tolerability. However, reporting of adherence and discontinuation outcomes was inconsistent across studies. A summary of comparative outcomes is presented in Table 3.

3. Discussion

3.1. Principal Findings

This scoping review examined comparative evidence on herbal and pharmaceutical antidepressants in adults with depression. The evidence shows a consistent pattern. Standardised Hypericum perforatum appears to have similar efficacy to selective serotonin reuptake inhibitors (SSRIs) in mild to moderate depression, with generally better tolerability. In contrast, pharmaceutical antidepressants show more consistent and stronger effects in moderate to severe depression but are associated with more frequent adverse effects. These findings are consistent with previous evidence suggesting that antidepressant effects vary according to baseline severity and that Hypericum perforatum may be effective in mild to moderate depressive episodes [9,13,14,23].

3.2. Severity-Dependent Efficacy

A clear pattern of severity-dependent efficacy was observed across the included studies. In mild to moderate depression, Hypericum perforatum showed similar reductions in depressive symptoms compared with SSRIs, suggesting it may be a potential alternative in less severe cases. In contrast, SSRIs, serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) showed more consistent and stronger effects in moderate to severe depression. This aligns with evidence from large network meta-analyses showing that antidepressant effects are generally more pronounced in more severe depression [9,11].

3.3. Safety, Tolerability, and Discontinuation

Herbal antidepressants were generally associated with fewer and milder adverse effects compared with pharmaceutical antidepressants. However, the overall certainty of evidence is limited due to heterogeneity in study design and reporting. Reported side effects for herbal treatments included mild gastrointestinal discomfort, dizziness, and photosensitivity. In contrast, pharmaceutical antidepressants were more frequently associated with sexual dysfunction, weight gain, sleep disturbance, and gastrointestinal effects, which are well-known contributors to reduced adherence [11,21]. Lower discontinuation rates were more commonly reported in herbal treatment groups, likely due to improved tolerability. However, differences in how adherence and discontinuation were measured across studies limit direct comparison. Overall, herbal interventions may be better tolerated in some populations, which may also reflect patient preference for natural or plant-based treatments [12,24].

3.4. Safety Considerations: Herb–Drug Interactions

Despite generally favourable tolerability, herbal antidepressants are not without important safety risks. The most clinically significant concern is the potential for herb–drug interactions, particularly with Hypericum perforatum. It is known to induce cytochrome P450 enzymes, especially CYP3A4, which can reduce the effectiveness of several co-administered medications [19,20]. This interaction risk is particularly important in patients receiving multiple medications and limits the safe use of Hypericum perforatum in routine clinical practice without careful monitoring.

3.5. Clinical Implications

The findings suggest that standardised Hypericum perforatum may be considered as a treatment option for mild to moderate depression in selected patients, particularly those who prefer herbal treatments or experience poor tolerability with SSRIs. This is broadly consistent with guideline discussions that acknowledge its potential use under specific conditions [8,14].

However, pharmaceutical antidepressants remain the first-line treatment for moderate to severe depression due to their more consistent and robust evidence base. Treatment decisions should therefore be individualised, taking into account symptom severity, tolerability, safety considerations, and patient preference. Herbal antidepressants should not be used as first-line treatment without clinical supervision due to potential interaction risks.

3.6. Evidence Limitations

The evidence base is limited by substantial heterogeneity in herbal formulations, antidepressant comparators, dosing regimens, and outcome measures. Most studies were short term (≤12 weeks), limiting conclusions about long-term effectiveness and safety. In addition, variability in the standardisation of herbal products, particularly differences in active compound concentrations in Hypericum perforatum, reduces comparability across studies. Inconsistent reporting of adverse events and discontinuation outcomes further limits synthesis and interpretation of findings [20].

4. Materials and Methods

4.1. Study Design and Framework

This scoping review was conducted to examine the available evidence on the comparative efficacy, safety, and tolerability of herbal versus pharmaceutical antidepressants in adults with depression. The review followed Joanna Briggs Institute (JBI) guidance for scoping reviews and was reported in accordance with the PRISMA-ScR checklist [26,27]. The methodological approach was guided by the Arksey and O’Malley (2005) framework.

4.2. Information Sources and Search Strategy

A comprehensive literature search was conducted in MEDLINE (PubMed), EMBASE, PsycINFO, the Allied and Complementary Medicine Database (AMED), and the Cochrane Central Register of Controlled Trials (CENTRAL). These databases were selected to capture biomedical, psychiatric, and complementary medicine literature relevant to this review topic. Additional sources included grey literature searches, and reference list screening of included studies to improve comprehensiveness and reduce publication bias. The search strategy combined controlled vocabulary (MeSH and Emtree terms) with free-text keywords related to depression, herbal medicines, and antidepressants, consistent with recommendations for systematic and scoping review searches (Tricco et al., 2018; Peters et al., 2020; DeMars and Perruso, 2022).

4.3. Eligibility Criteria

Eligibility criteria were defined using the Population, Concept and Context (PCC) framework [26,28]. The population included adults aged 18 years and older with a diagnosis of depression or clinically significant depressive symptoms, based on Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) diagnostic criteria [1], or validated rating scales such as the Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI), or Montgomery-Asberg Depression Rating Scale (MADRS). The concept of interest was the comparative evaluation of herbal and pharmaceutical antidepressants in terms of efficacy, safety, tolerability, and treatment discontinuation. The context included studies conducted in clinical, outpatient, primary care, psychiatric, and community settings.

Eligible herbal interventions included oral, standardised plant-based medicines, while pharmaceutical comparators included standard antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs). Only primary comparative clinical studies were included, such as randomised controlled trials, crossover trials, quasi-experimental studies, and controlled clinical trials. Case reports, animal studies, and non-comparative designs were excluded. Only English-language publications were considered.

Both primary and secondary evidence sources were included to examine the available literature.

4.4. Study Selection, Data Extraction, and Synthesis

All identified records were imported into Zotero, and duplicates were removed prior to screening. A total of 3182 records were retrieved from database searches and 19 from grey literature sources. After removal of 1013 duplicates, the remaining records were screened for eligibility in two stages: title and abstract screening followed by full-text review. Screening was performed independently. Following full-text assessment, 21 studies met the inclusion criteria and were included in the final analysis.

Findings were synthesised using a narrative approach due to heterogeneity in study designs, interventions, and outcome measures. Results were organised according to efficacy, safety, tolerability, and treatment discontinuation outcomes. In line with scoping review methodology, formal risk-of-bias assessment was not performed, but methodological limitations of included studies were considered when interpreting findings.

5. Conclusions

This scoping review mapped comparative evidence on herbal and pharmaceutical antidepressants in adults with depression. Overall, the findings show a consistent pattern of severity-dependent treatment effects. Standardised Hypericum perforatum appears to have comparable efficacy to SSRIs in mild to moderate depression and is generally better tolerated. In contrast, pharmaceutical antidepressants demonstrate stronger and more consistent effects in moderate to severe depression but are associated with more frequent adverse effects. Herbal treatments were generally better tolerated and associated with lower discontinuation rates; however, important safety concerns remain, particularly herb–drug interactions involving cytochrome P450 enzyme induction with Hypericum perforatum. These risks limit its use in patients receiving multiple medications.

The evidence base is limited by heterogeneity in study design, herbal standardisation, comparators, outcome measures, and short follow-up durations. These limitations reduce comparability across studies. Herbal antidepressants may be considered as a potential option for mild to moderate depression in selected populations but should not replace conventional antidepressant therapy in moderate to severe depression. Future research should focus on well-standardised, long-term comparative trials with consistent outcome measures to strengthen the evidence base.