Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology (2015)

Having experienced weight gain side effects from clozapine, it’s nice to see some progress being made towards ameliorating them… I’m particularly impressed by the authors in depth discussion of the potential use of phytochemicals. I’ve included some highlights.

Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology

Second generation antipsychotics (SGAs), such as clozapine, olanzapine, risperidone and quetiapine, are among the most effective therapies to stabilize symptoms schizophrenia (SZ) spectrum disorders. In fact, clozapine, olanzapine and risperidone have improved the quality of life of billions SZ patients worldwide. Based on the broad spectrum of efficacy and low risk of extrapyramidal symptoms displayed by SGAs, some regulatory agencies approved the use of SGAs in non-schizophrenic adults, children and adolescents suffering from a range of neuropsychiatric disorders. However, increasing number of reports have shown that SGAs are strongly associated with accelerated weight gain, insulin resistance, diabetes, dyslipidemia, and increased the cardiovascular risk. These metabolic alterations can develop in as short as six months after the initiation of pharmacotherapy, which is now a controversial fact in public disclosure. Although the percentage of schizophrenic patients, the main target group of SGAs, is estimated in only 1% of the population, during the past ten years there was an exponential increase in the number of SGAs users, including millions of non-SZ patients. The scientific bases of SGAs metabolic side effects are not yet elucidated, but the evidence shows that the activation of transcriptional factor SRBP1c, the D1/D2 dopamine, GABA2 and 5HT neurotransmitions are implicated in the SGAs cardiovascular toxicity. Polypharmacological interventions are either non- or modestly effective in maintaining low cardiovascular risk in SGAs users. In this review we critically discuss the clinical and molecular evidence on metabolic alterations induced by SGAs, the evidence on the efficacy of classical antidiabetic drugs and the emerging concept of antidiabetic polyphenols as potential coadjutants in SGA-induced metabolic disorders.

“…we summarized the results of 20 clinical studies and three preclinical studies, assessing the efficacy of pharmacological interventions (i.e. metformin, nizatadine, orlistat, ranitidine, topiramate, etc.) against SGA-induced metabolic side effects. This summarized evidence shows that one out of five studies with metformin resulted in negative results. The other four positive studies concluded that weight gain, insulin resistance can be efficiently controlled, but lipid profile may even worsen. Metformin reduced body weight in clozapine-treated patients, but its beneficial effects disappeared after discontinuing this medication. Orlistat in overweight/obese clozapine-or olanzapine-treated patients failed to prevent obesity and lipid accumulation, which suggest that the intestinally absorbed lipids may not be relevant for SGAs-induced obesity. Atomoxetine, a selective norepinepherine reuptake inhibitor with appetite suppressant activity, was not effective in preventing obesity in patients treated with olanzapine and clozapine.”

  • With respect to the serotoninergic hypothesis, the interventions with fluoxetine also failed. The use of sertraline in clozpaine-induced weight gain resulted in cardiac death in rodents.
  • Tetradecylthioacetic acid (TTA), a modified fatty acid, recently showed a minor protective effect against hypertriglyceridemia, but failed to prevent weight gain induced by clozapine in rodents.
  • Berberine, a natural alkaloid, inhibited in vitro adipogenesis and SREBP-1 overexpression induced by clozapine and risperidone in 3T3 adipocytes: “Berberine is an example of an antidiabetic phytochemical with potential protective effect against lipid accumulation induced by clozapine.”
  • Resveratrol and green tea, showed some efficacy in decreasing weight gain and fat mass accumulation induced by olanzapine in rodents.

“Our group and others have demonstrated that specific polyphenols from dietary sources ameliorate insulin resistance, inflammation and obesity.”

  • Anthocyanins, a family polyphenols, have shown significant clinical effect in improving insulin sensitivity in obese, nondiabetic, insulin-resistant patients.

“Polyphenols are family of polar compounds found in fruits and vegetables, they have been popular for their potent antioxidant effect, but in the past 5 years increasing evidence has shown that, anthocyanins, a specific category of polyphenols, are effective in ameliorating obesity and insulin resistance.

The mode of action and pharmacokinetic profile of these compounds is not yet fully elucidated and their bioavailability after oral administration is a matter of continuous controversy. However, there is robust evidence on their efficacy in cardiometabolic problems. Kurimoto et al. reported that anthocyanins from black soy bean increased insulin sensitivity via the activation of AMP-activated protein kinase (AMPK) in skeletal muscle and liver of in type 2 diabetic mice. AMPK, a regulator of glucose and lipid metabolism in liver and muscle cells, is inhibited by olanzapine, which may contribute to the olanzapine-induced hepatic lipid accumulation. Anthocyanins also display insulin-like effects even after intestinal biotransformation.

We have previously demonstrated that anthocyanins ameliorate signs of diabetes and metabolic syndrome in obese mice fed with a high fat diet have. Delphinidin 3-sambubioside-5-glucoside (D3S5G), an anthocyanin from Aristotelia chilensis, is as potent as Metformin in decreasing glucose production in liver cells, and it displays insulin-like effect in liver and muscle cells. The anti-diabetic mode of action of anthocyanins have been associated with the transcriptional down-regulation of the enzymes PEPCK and G6P gene in hepatocytes. Prevention of adipogenesis is also another reported mechanmis for some anthocyanins from Aristotelia chilensis. Anthocyanins also induce significant increase in circulating levels of adiponectin in murine models of MetS. This is relevant, since adiponectin is reduced in clozapine-treated patients and weight reduction is associated with higher circulating levels of adiponectin. In a recent study Roopchand et al., demonstrated that blueberry anthocyanins are as potent as metformin in correcting hyperglycemia and obesity in obese hyperglyceminc mice. Dietary anthocyanins have also proven efficacy in decreasing les of the inflammatory mediators PAI-1 and retinol binding protein 4 in obesity and type 2 diabetes . Recent medical and nutritional studies suggest that anthocyanins from diverse dietary sources are potent anti-diabetic, anti-obesity and cardioprotective molecules. Another fact that makes anthocyanins candidates for preventing clozapine-induced lipogenesis is that they are capable of suppressing the inflammatory response through targeting the phospholipase A2, PI3K/Akt and NF-kappaB pathways. These pre-clinical findings were corroborated by clinical evidence showing the dietary anthocyanins from blueberries improve insulin resistance in young obese, non-diabetic adults. The clinical efficacy of polyphenols in SGAs-induced MetS has not yet been established, but a recent pre-clinical demonstrated that, resveratrol, a polyphenol found in grapes, decreases olanzapine-induced weight gain.”

Some  polyphenols showing positive outcomes for diabetes, obesity and metabolic syndrome [see article for more information]:

Purified anthocyanins 160 mg  twice a day
Cinnamon extract 250 mg, twice a day
Whole  blueberries 22.5 g twice a day
Resveratrol 150 mg
Pomegranate juice 1.5 mL/Kg
Raisins (Vitis vinifera) 36 g/day
Green tea extract 375 mg  (270mg catechins) per day

See more:

Attenuating antipsychotic-induced weight gain and metabolic side effects

Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood. (2015)

An interesting research direction for ‘prophylactic psychiatry’:

Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood. (2015)

Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood.

“Neurodevelopment during early adolescence is a key stage during maturation, with various structural, neurochemical, and molecular changes taking place in response to genetic and environmental cues. The formation of new neuronal connections during early adolescence also means a high level of vulnerability to pathologic insults ranging from stress to dietary deficiencies. The nutritional status during early adolescence has a great impact on the onset and severity of psychiatric diseases at adulthood. In the past decade, increasing interest in the potential benefits of early intervention for psychiatric diseases, such as schizophrenia, has been seen. Subjects at a high risk of developing psychosis exhibit cognitive impairments, compared with healthy subjects. Approximately one-third of subjects at a high risk develop psychosis within three years, and most are diagnosed as having schizophrenia. In this study, we found that the dietary intake of SFN-rich food during the juvenile and adolescence was capable of preventing PCP-induced cognitive deficits and oxidative stress at adulthood in mice. Although the precise mechanism underlying the preventive effect of SFN-rich food is currently unclear, the dietary intake of SFN-rich foods may be capable of regulating gene expression through epigenetic mechanisms. Since SFN has potent antioxidant and anti-inflammatory effects, SFN may prevent the onset of psychosis in subjects at a high risk and who exhibit oxidative stress and inflammation. Therefore, a randomized, double-blinded, placebo-controlled study of the dietary intake of SFN-rich foods in subjects at a high risk of psychosis is of great interest.”

“In the present study, we found that SFN exhibited prophylactic and therapeutic effects in a PCP-induced cognitive deficits model. Very recently, we found that supplementation with SFN-rich broccoli sprout extract for 8 weeks was effective for the treatment of cognitive impairment in medicated patients with schizophrenia, although other scores (such as psychotic symptoms) were not altered. Furthermore, a recent randomized, double-blinded, placebo-controlled study demonstrated that treatment with SFN-rich broccoli sprout extract significantly improved social interaction, abnormal behavior, and verbal communication in young men with autism spectrum disorder. Glucoraphanin (GF), a glucosinolate precursor of SFN, is widely consumed in cruciferous plant-rich diets; therefore, SFN is considered to have a low toxicity, and its administration in humans is well tolerated. It is reported that SFN readily crosses the blood-brain barrier of mouse after i.p. administration, suggesting that SFN in the brain can improve PCP-induced cognitive deficits. Together, these results suggest that SFN-rich broccoli sprout extract could have a potential therapeutic effect in patients with a number of psychiatric diseases including schizophrenia and autism spectrum disorder, since patients with these psychiatric diseases exhibit cognitive impairment”

As covered in Natural products for schizophrenia :

A small study found benefits from sulforaphane administration [1]: “Sulforaphane (SFN) is a molecule belonging to the isothiocyanate group of organosulfur compounds found in broccoli sprouts. It is known to have potent anti-oxidant and anti-inflammatory activity. Previously, we reported that SFN attenuated behavioral abnormalities in mice after administration of methamphetamine or phencyclidine, suggestive of a potential therapeutic potency in schizophrenia. Recently, we found that SFN improved cognitive deficits in phencyclidine-treated mice”.


See also:

New Targets for Prevention of Schizophrenia: Is it Time for Interventions in the Premorbid Phase? (2015)

Stage specific and prophylactic treatments?

Natural products for schizophrenia

The natural D2 antagonist/D1 agonist L-stepholidine [1], may offer relief of positive symptoms, negative symptoms and deficits in working memory [2].  In vitro, D1 agonism has been disputed, recent research indicating that it is a pan-dopamine receptor antagonist [3]. (−)-Stepholidine.svg

L-tetrahydropalmatine – a D1/D2 antagonist (with multiple relevant pharmacological targets, including affinity for the sigma-1 receptor [4],  may offer some benefit but research into its use in schizophrenia is lacking. 220px-Tetrahydropalmatine.png “L-tetrahydropalmatine (l-THP), has robust anti-inflammatory properties, particularly TNF-alpha and ICAM inhibition; has antiprotozoal activity; and possesses an antipsychotic-like pharmacological profile of D1, D2 and D3 receptor antagonism. The high affinity of l-THP for D1 versus D2 receptors distinguishes it from first generation antipsychotics and its D1 to D2 ratio resembles that of the superior antipsychotic, clozapine” [link]

Schizophrenia is a devastating and complex illness, with multiple symptom and behavioral manifestations. Antipsychotic medications are the mainstay of treatment; however, many patients only partially respond to treatment. Development of new treatment has not progressed rapidly, in part, because the underlying etiopathophysiology of the illness is not well understood. To date, all pharmacological treatments approved for use in schizophrenia involve primary modulation of the dopamine system. Many agents without dopamine action have failed to demonstrate efficacy. There is growing evidence that schizophrenia may be, in part, due to an inflammatory process and pharmacological treatment approaches that decrease inflammation have shown promise. Thus, treatments that may have anti-inflammatory properties (e.g., TNF-alpha inhibition), but also possess dopamine modulation may prove to be beneficial. This novel medication, l-tetrahydropalmatine (l-THP), has robust anti-inflammatory properties, particularly TNF-alpha and ICAM inhibition; has antiprotozoal activity; and possesses an antipsychotic-like pharmacological profile of D1, D2 and D3 receptor antagonism. The high affinity of l-THP for D1 versus D2 receptors distinguishes it from first generation antipsychotics and its D1 to D2 ratio resembles that of the superior antipsychotic, clozapine. Also, an almost identical compound, l-stepholindine (l-SPD), demonstrates robust antipsychotic activity in humans (both positive and negative symptoms) and is currently used clinically in China.

l-THP has been used for over 40 years clinically in China, has a good safety profile to date, and represents a novel and exciting mechanism for schizophrenia treatment. Initial safety data from our phase I study of l-THP (20 healthy controls) shows excellent tolerability and lack of any substantial side effects. L-THP has been tested in outpatient drug abuse trials for 4 weeks with good safety data, (Hu et al 2006, Yang et al 2003). Yang et al (2003) randomized this medication in over 120 participants for 4 weeks with 4 week observation without any notable side effects. We will test this compound (30 mg BID) as an adjunct treatment in a randomized, double-blind, 4-week trial, in which we will assess treatment efficacy, changes in peripheral cytokine concentrations, and, secondarily, antiprotozoal effects, (antibody titers to Toxoplasma gondii), an infection that is known to occur at higher rates in schizophrenia than healthy controls and may be related in part to the illness.

  • L-tetrahydropalmatine (30mg) vs  Sugar pill

Pharmacology [5]:

  • D1 receptor antagonist with a Ki of 94 ± 9 – 124 nM and an IC50 value of 166 nM [Note: this is contrary to clozapine which behaves as a D1 agonist (and/or has indirect effects leading to D1 receptor agonism), believed to partially account for its ‘superior’ efficacy as an antipsychotic]
  • D2 receptor antagonist with a Ki of 388 nM and an IC50 value of 1.47 μM
  • IC50 values for antagonism of GTPγS binding to dopamine D2S receptor by THP is 1.32 µM (469 ng/mL)
  • Inhibits voltage gated calcium channels in a manner similar to verapamil
  • Shows weak inhibitory activity against the dopamine D3 receptor with IC50 of 3.25 μM
  • In addition to the antagonism of postsynaptic dopamine receptors, inhibition of presynaptic autoreceptors by THP leads to increased dopamine release, which is probably attributed to lower affinity towards D2 receptors.
  • Potently inhibits 5-HT1A with IC50 of 374 nM and Ki of 340 nM
  • Interacts with a number of other receptor types, including α-1 adrenergic receptors, at which it functions as an antagonist, and γ-aminobutyric acid receptors, at which it facilitates γ-aminobutyric acid binding through positive allosteric effects.
  • Attenuates the rewarding effects of drugs of abuse, including stimulants and opioids. It may be an effective anti-addiction therapy.

¤ L-THP may have interactions with other medications [i] [ii] [Pharmacokinetics]

Modified from Jung et al. 2015: Absorption of THP from the GI tract seems almost complete, as GI24 h values were negligible. Most of the administered dose of THP is eliminated via non-renal clearance. A previous pharmacokinetic study of THP also reported negligible recovery of unchanged THP in urine and bile (1.48% and 0.4% of the administered THP dose) following oral administration of 40 mg/kg THP, and identified three O-desmethyl metabolites. THP is reportedly metabolized predominately by CYP3A1/2 and CYP1A2 in rat liver microsomes. The F values of THP are reportedly low: 2.5–17.8% for THP following oral administration of various formulations of Corydalis rhizome extracts at doses containing ca. 12 mg/kg THP.

Brain/Periphery (Br/P) ratios of THP were greater than unity (approximately 2–4) at 30, 120, and 360 min after single and multiple oral administration. The maximum concentrations of THP in brain were observed at 30 min after administration. These results suggest that THP passes through the blood-brain barrier. A previous study examining the distribution of THP following oral administration of a 40 mg/kg dose also demonstrated that Br/P ratios reach a maximum of approximately 5.0 after 5–30 min in all brain regions, except the hippocampus, where the ratio reached a maximum of 3.2 at 2 h, confirming that THP crosses the blood–brain barrier rapidly. Intravenous administration of THP (1–10 mg/kg) caused central nervous dopamine D2 receptor antagonism and induced hypotension and bradycardia.

Multiple oral administrations of an extract for 7 d (equivalent to 0.77 mg/kg/d as THP) did not result in accumulation of THP in plasma or brain. The maximum concentrations of THP in the brain were observed at 30 min after the last oral treatment; 131 ng/g for THP which is much lower than the IC50 values for antagonism of GTPγS binding to dopamine D2S receptor by THP [1.32 µM (469 ng/mL)]

Their research indicates that human doses of 30mg may not be sufficient for central dopamine D2 receptor antagonism

Other alkaloids such as alstonine [6, 7] have demonstrated antipsychotic activity in animal models. Alstonine2DACS3.svgThe MoA of alstonine is unique:

Original mechanisms of antipsychotic action by the indole alkaloid alstonine (Picralima nitida).

Alstonine is the major component of plant based remedies that traditional psychiatrists use in Nigeria. Alstonine is an indole alkaloid that has an antipsychotic experimental profile comparable with that of clozapine and is compatible with the alleged effects in mental patients. Representing a desirable innovation in the pharmacodynamics of antipsychotic medications, the evidence indicates that alstonine does not bind to D2 dopamine receptors (D2R) and differentially regulates dopamine in the cortical and limbic areas. The purpose of this study was to further investigate the effects of alstonine on D2R binding in specific brain regions using quantitative autoradiography (QAR) and its effects on dopamine (DA) uptake in mouse striatal synaptosomes. The effects of alstonine on D2R binding were determined in the nucleus accumbens and caudate-putamen using QAR in mice treated with alstonine doses that have antipsychotic effects. The effects of alstonine [3H]DA uptake were assessed in synaptosomes prepared from striatal tissue obtained from mice treated acutely or for 7 days with alstonine. Alstonine did not change the D2R binding densities in the studied regions. DA uptake was increased after acute (but not after 7 days) treatment with alstonine. Consistent with the alstonine behavioral profile, these results indicate that alstonine indirectly modulates DA receptors, specifically by modulating DA uptake. This unique mechanism for DA transmission modulation contributes to the antipsychotic-like effects of alstonine and is compatible with its behavioral profile in mice and alleged effects in patients. These results may represent an innovation in the antipsychotic development field.


Consumption of Betel nut is associated with decreased positive symptoms in users with schizophrenia [8]. Arecoline, a constituent alkaloid may confer benefits via mAChR agonism. Arekolina.svg Similarly, nicotine use – particularly of tobacco – is extremely common in schizophrenics, offering reductions in negative symptoms and cognitive benefits to the user. nAChR agonists and positive allosteric modulators are promising leads for future therapeutics. Nicotine.svg Galantamine, acting as an AChE inhibitor and nAChR PAM, may offer some benefits, similarly to donepezil [9].Galantamine.svg

  • Adjunctive treatment with galantamine improved memory and attention in patients with schizophrenia who were stabilised on risperidone [a]
  • Patients stabilised on clozapine reported much improved sustained attention, improved psychomotor speed and selective attention. Two patients with low pretreatment memory reported improvements [b]


Despite some limitations – particularly related to bioavailability – supplementation with curcumin may be of benefit. A clinical trial is underway to determine if curcumin nanoparticles will improve behavioral measures and biomarkers of cognition and neuroplasticity in patients with schizophrenia. Skeletal formula

Bacopa monnieri may offer benefits [10, 11, 12] Increased expression of TPH2, alterations to histone acetylation, VGLUTs, GABAergic activity and anti-inflammatory/immunomodulating properties add to bacopa’s broad spectrum of activity

See more: Antipsychotic activity of standardized Bacopa extract against ketamine-induced experimental psychosis in mice: Evidence for the involvement of dopaminergic, serotonergic, and cholinergic systems.

Cannabidiol is also promising: “A compound found in Cannabis sativa can treat schizophrenia as effectively as antipsychotic medications, with far fewer side effects, according to a preliminary clinical trial. Researchers led by Markus Leweke of the University of Cologne in Germany studied 39 people with schizophrenia who were hospitalized for a psychotic episode. Nineteen patients were treated with amisulpride, an antipsychotic medication that is not approved in the U.S. but is comparable to other medications that are antipsychotic. The rest of the patients were given cannabidiol (CBD), a substance found in C. sativa that is thought to be responsible for some of its mellowing or anxiety-reducing effects. Unlike the main ingredient in marijuana, THC, which can produce psychotic reactions and may worsen schizophrenia, CBD has antipsychotic effects, according to previous research in both animals and humans. The use of CBD for schizophrenia is becoming more and more common. Studies from around the world are showing great promise. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD involve the striatum and temporal cortex that have been traditionally associated with psychosis [link].”

See more: Cannabidiol Attenuates Sensorimotor Gating Disruption and Molecular Changes Induced by Chronic Antagonism of NMDA receptors in MiceCannabidiol.svgΔ9 -tetrahydrocannabivarin may also produce 5-HT1a dependent antipsychotic effects

Berberine may offer benefit in the control of psychotic and depressive symptoms, along with metabolic side effects [13]. It has a broad range of CNS relevant pharmacological actions, including sigma-1 agonism. There are some limitations to its use, including bioavailability and difficulties in reaching active levels in the CNS. “The potential use in schizophrenia was suggested when berberine was found to act as a D2-receptor antagonist, although it was also noted that dopamine level was increased in the brain as partly responsible for its antidepressant mechanism. It is unclear if these influences on dopamine level and action may counter each other, diminishing the proposed antipsychotic effect. Future studies may also elucidate whether berberine will exacerbate extrapyramidal motor symptoms due to the blockade of D2 receptors. On the other hand, it was proposed that the anxiolytic effect of berberine resulted from its antagonism at 5-HT2 receptor. This finding may indicate less severe motor side effects, if there are any, when berberine is used as an antipsychotic since atypical antipsychotics also act via 5-HT2 receptor blockade. A possible advantage of berberine over other antipsychotics is its ability to inhibit prolyl oligopeptidases, the activity of which is elevated in psychosis and not targeted by antipsychotics at present.” Berberin.svg

Low doses of lavender oil may be an effective adjunct therapy for anxiety. At 80+ mg/day – a dose used to effectively treat anxiety – orally administered lavender oil non-selectively reduces the calcium influx through several different types of voltage dependent calcium channels such as the N-type, P/Q-type and T-type [14]. This effect is similar to, but lacks the specificity of, pregabalin’s selective binding to P/Q type calcium channels at the α2δ subunit . Pregabalin has potential in treating anxious syndromes in schizophrenia and can be effective and tolerable [15] It may however increase clozapine serum levels [16] making lavender an intriguing alternative for some patients

A multi-center, double-blind, randomised study of the lavender oil preparation silexan in comparison to lorazepam for generalized anxiety disorder.

An orally administered lavandula oil preparation (Silexan) for anxiety disorder and related conditions: an evidence based review. Lavender Oil-Potent Anxiolytic Properties via Modulating Voltage Dependent Calcium Channels

Lavender oil preparation Silexan is effective in generalized anxiety disorder – a randomized, double-blind comparison to placebo and paroxetine

Effects of Silexan on the serotonin-1A receptor and microstructure of the human brain: a randomized, placebo-controlled, double-blind, cross-over study with molecular and structural neuroimaging.

Skeletal formulaLinalyl acetate.svg

Oleanolic acid has recently been proposed as a potential antipsychotic [17]

Oleanolic acid

Whilst CB1 agonism carries an undesirable risk of worsening psychosis, CB2 agonism has recently been studied and may prove beneficial. [18] Modulation of dopaminergic pathways by CB2 agonism has antipsychotic and anti-addictive potential: activation of CB2Rs inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of a CB2 agonist into the VTA inhibited cocaine self-administration [19] CB2 agonists, via skewing towards an anti-inflammatory M2 polarisation of microglia, may provide beneficial therapies for multiple psychiatric disorders [20] An interesting approach is to use β-caryophyllene rich essential oils, administered orally. One patient used ~1500mg of Copaiba oil per day for a month (containing 60%+ β-caryophyllene, Ki 155 ± 4 nM towards CB2) which was well tolerated but lacked efficacy in reducing residual auditory hallucinations Beta-Caryophyllen.svg⇒ See patent: ‘TREATMENT OF SCHIZOPHRENIA USING BETA-CARYOPHYLLENE AND CB2 RECEPTOR AGONISTS

L-theanine may have some benefits, potentially relieving positive, negative and activation/anxiety symptoms [21, 22]

Stereo, skeletal formula of theanine (S)

Ginkgo biloba may also be beneficial [23]

See more at: Psychiatric disorders and polyphenols. Can they be helpful in therapy?

Potentially of relevance to schizophrenia, researchers discovered that “…social contact deficits are reversed by resveratrol administration” emphasising a “prosocial role for this dietary phenol” and evoking “the possibility of developing new treatments for social dysfunctions.” [24]

Chelerythrine is a benzophenanthridine alkaloid present in the plant Chelidonium majus (greater celandine). It is a potent, selective, and cell-permeable protein kinase C inhibitor and “Improves PFC working memory” [25]


Myricitrin, a nitric oxide (NO) and protein kinase C (PKC) inhibitor, demonstrates antipsychotic-like effects [26]

Myricitrin structure

A small study found benefits from sulforaphane administration [27]: “Sulforaphane (SFN) is a molecule belonging to the isothiocyanate group of organosulfur compounds found in broccoli sprouts. It is known to have potent anti-oxidant and anti-inflammatory activity. Previously, we reported that SFN attenuated behavioral abnormalities in mice after administration of methamphetamine or phencyclidine, suggestive of a potential therapeutic potency in schizophrenia. Recently, we found that SFN improved cognitive deficits in phencyclidine-treated mice”.


EGCG-like polyphenol nutraceuticals (contained in “green tea” and chocolate) may be clinically useful in protecting against the adverse behavioral dissociative and cortical glutamate stimulating effects of NMDA antagonists, acting as inducible nitric oxide synthase inhibitors [28].


Addition of Yi-Gan San/yokukansan to antipsychotics has potential benefits.

Other traditional medicines used by healers are detailed here

Is there any evidence to support herbal medicines as an adjunctive treatment for schizophrenia?

High quality evidence shows that treatment with Ginkgo biloba in combination with antipsychotics improves total symptom severity to a greater extent than antipsychotics alone in people with chronic schizophrenia in studies conducted in China.

Moderate quality evidence suggests various traditional Chinese herbal medicines combined with antipsychotics may result in greater improvement in global state and mental state and better retention in treatment compared to antipsychotics alone.

Moderate to low quality evidence suggests traditional Chinese medicine (SuoQuan Wan) but may be more effective than doxepin (antimuscarinic) for reducing clozapine-induced hypersalivation and may cause less constipation.