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Bacopa monnieri (Brahmi)

INTRODUCTION

Bacopa monnieri is a perennial creeping plant distributed in warm, marshy areas of South Asia, Africa, Australia, Europe, North and South America [1]. It is known as an important herb in Ayurvedic medicine, and has been used for a long time as a treatment for many health conditions [2]. It is said to possess adaptogenic, cognitive-enhancing, mood-brightening, anti-anxiety, anti-epileptic and sleep inducing properties [3]. It is widely available today as a supplement and is marketed primarily for its effects on brain health. It is sold in the form of herbal powder or extract prepared from the whole plant, known as “brahmi”. However, it should not be confused with another herb, Centella asiatica (Gotu kola), that is also called brahmi and used for the same purposes (and often combined with Bacopa monnieri) [3].

Pharmacological effects of the whole extract of Bacopa monnieri and its individual constituents have been investigated in animal and human studies, revealing many beneficial properties. Preclinical evidence supports use of Bacopa as an alternative antidepressant, nootropic and anxiolytic, although conclusive evidence for its effects on human emotional health is insufficient. Neuroprotective actions can be attributed to some alkaloids present in the herb, but mostly to its specific saponins, particularly bacosides, which are often used to standardize Bacopa extracts [3].

EFFECTS ON MOOD AND COGNITION

Animal studies

Standardized methanolic extract of Bacopa monnieri demonstrated a significant antidepressant effect on rats in a study using forced swim test (FST) and learned helplesness models, in the oral doses of 20 and 40 mg/kg daily, and was said to be comparable to that of imipramine [4]. Study on mice found antidepressant actions of brahmi (in the oral doses of 10, 20 and 30 mg/kg daily) to be greater than that of imipramine in FST and shock induced depression model (SID) after 7 days of treatment, but failed to detect any effects in the tail suspension test (TST) [5]. B. monnieri extract (BM) was evaluated for acute vs. chronic antidepressant effects in FST and TST in doses of 50 and 100 mg/kg. The effects were significant in mice treated with 50 mg/kg in chronic study (drug administration for 10 days), but not in acute study (drug given 1 hour before the procedure), while treatment with 100 mg/kg showed antidepressant properties comparable to imipramine in both the acute and chronic study [6]. Another study evaluated effects of BM on the expression of BDNF protein and mRNA in the hippocampus and frontal cortex of rats. BDNF is a signaling molecule critical for neuronal survival and growth. Reduction in BDNF levels has been correlated with stress induced changes in neural plasticity that accompany depressive-like behaviours, while successful antidepressant treatment typically upregulates BDNF and reverses dendritic atrophy in the brain areas involved in regulation of mood. Rats subjected to chronic unpredictable stress routine (CUS) for 28 consecutive days developed depression-like state, manifested in the form of anhedonia (indicated by reduced sucrose consumption), diminished exploratory activity and failures to escape from stressors. Feeding of BM in the doses of 80 and 120 mg/kg during the course of experiment counteracted the behavioral effects of stress and restored BDNF mRNA and protein levels in the hippocampus and frontal cortex [7]. A precise mechanism of BM action was not explored.

BM produced anxiolytic effects in rats at doses of 5, 10 and 20 mg/kg. Higher doses were reported to be comparable to lorazepam [8].

BM is capable of decreasing plasma corticosterone and attenuating the depletion of serotonin, norepinephrine and dopamine in the rat cortex and hippocampus after chronic stress [9]. Thus, its antidepressant and anxiolytic effects might be due to its actions on the monoaminergic system. BM constituents known as Bacopaside I and Bacoside A were shown to inhibit MAO-A and MAO-B enzymes in an in-vitro study [10]. Modulatory actions of BM on 5-HT2C receptor expression have been reported, including its down-regulation in the hippocampus [11]. 5-HT2C antagonists are known to produce rapid antidepressant effects by disinhibition of dopamine cells in the ventral tegmental area [12].

BM has inhibitory effect on acetylcholinesterase (AChE) enzyme [13], increases the levels of acetylcholine and the density of cholinergic neurons in the hippocampus [14]. AChE inhibitors are used to improve cognitive function and mood in the treatment of Alzheimer’s disease. BM was demonstrated to reverse the cortical reduction of GABA receptors in the model of epilepsy [15]. Activity on the GABAergic system might prove to be useful in the treatment of depression, since this illness has been associated with low cortical GABA [16]. In animal models, decreased GABA receptors have also been correlated with depressive-like behaviour [15].

Human studies

Many clinical studies have been performed on the effects of B. monnieri on various cognitive abilities and mood. Most of them were conducted on healthy adults, for the period of 12 weeks, using 300 mg of BM extract daily [17]. Improvements in learning rate, memory formation and retention, working memory, verbal skills, attention, energy and mood, as well as anxiety reductions were reported in the studies [3]. However, no research has been done on patients suffering from actual depression or anxiety disorder. A recent review of high quality studies on Bacopa concluded that there is some evidence that BM improves memory in free recall, but claims of enhancements in other aspects of cognitive functioning are not well supported [17]. It also noted that studies used very similar doses over similar time frames and focused primarily on memory, ignoring other cognitive domains. Therefore, more studies exploring higher doses, longer supplementation periods and different mental functions are required.

OTHER PROPERTIES

BM exhibited potent antioxidant effects in studies and was shown to increase the activity of antioxidant enzymes such as superoxide dismutase, catalase and peroxidase in the brain and other organs [19, 20, 21]. It also has anti-inflammatory properties [21], which are primarily attributed to its constituent betulinic acid [22], and has shown potential for the treatment of rheumatic conditions [23]. Various fractions of Bacopa extract demonstrated antibacterial and antifungal effects [24].

SAFETY

Bacopa monnieri is a safe and beneficial supplement. It has been used as medicine for a long time with no reports of toxicity or dangerous side-effects. However, a number of gastrointestinal side-effects such as diarrhea, nausea and abdominal cramping were found in some studies, using doses of 300 mg daily [25, 26]. Intestinal complaints were milder and less frequent in a study where BM was taken in escalating amounts [27]. Interaction of MB can occur with drugs phenobarbital and chlorpromazine, potentiating their sedative effects [2]. A new study reported inhibition of human cytochrome P450 enzymes (CYP1A2, CYP3A4, CYP2C9 and CYP2C19) by BM, which would occur mostly in the gut, less in the liver [28]. Therefore, caution is advised when taking Bacopa alonsgide other drugs metabolized by the same enzymes.

DOSAGE

Wide range of BM doses produced antidepressant effects in animal studies, with higher doses exhibiting more significant effects. Doses showing efficacy in both FST and TST models in mice (50-100 mg/kg) correspond to 243 – 486 mg daily for a 60 kg human (when converted to human equivalent dose, HED). Doses within this range (300-450 mg) are recommended by supplement manufacturers, and have been tested in most clinical studies for potential nootropic properties. In the rat study, the most effective BDNF-raising dose was found to be 80 mg/kg, corresponding to human 778 mg daily. More research is needed to show if such doses can be considered safe and tolerable.

CONCLUSION

There is a considerable amount of preclinical evidence for antidepressant and anti-stress properties of Bacopa monnieri extracts. Human studies have consistently found pro-cognitive effects of BM, but haven’t produced any good evidence of mood brightening effects. However, neither conventional antidepressants affect mood significantly in healthy individuals and often cause undesirable cognitive side-effects. BM’s antidepressant actions are most likely due to its MAO inhibiting, GABA-ergic, and possibly anti-inflammatory and antioxidant properties. As is the case with most antidepressants, it would need to be taken chronically, over a long period of time (several months or more), in order to notice any change. Due to potential unpleasant side-effects, it would be advisable to gradually increase the dose (for example, over several weeks) until the desired amount is reached.

REFERENCES:

[1] Bacopa monnieri. (2015, June 2). In Wikipedia, The Free Encyclopedia. Retrieved 12:17, June 2, 2015, from http://en.wikipedia.org/w/index.php?title=Bacopa_monnieri&oldid=665160273

[2] Gohil, Kashmira J., and Jagruti A. Patel. “A review on Bacopa monniera: Current research and future prospects.” International Journal of Green Pharmacy 4.1 (2010): 1.

[3] Abascal, Kathy. “Bacopa for the Brain.” ALTERNATIVE AND COMPLEMENTARY THERAPIES (2011).

[4] Sairam K. Antidepressant activity of standardized extract of Bacopa monniera in experimental models of depression in rats. Phytomedicine. 2002;9:207–211. doi: 10.1078/0944-7113-00116.

[5] Kadali SRM, M.C. D, Rao A.S.R. S, Sri G K. Antidepressant Activity of Brahmi in Albino Mice. Journal of Clinical and Diagnostic Research : JCDR. 2014;8(3):35-37. doi:10.7860/JCDR/2014/7482.4098.

[6] Sindhu, Pabba, et al. “Evaluation of Antidepressant Activity of Bacopa Monnieri in Mice.” International Journal of Pharmacy 4.3 (2014): 144-148.

[7] Banerjee, Ritabrata, et al. “Chronic Administration of Bacopa Monniera Increases BDNF Protein and mRNA Expressions: A Study in Chronic Unpredictable Stress Induced Animal Model of Depression.” Psychiatry investigation 11.3 (2014): 297-306.

[8] Bhattacharya, S. K., and S. Ghosal. “Anxiolytic activity of a standardized extract of Bacopa monniera: an experimental study.” Phytomedicine 5.2 (1998): 77-82.

[9] Sheikh, Naila, et al. “Effect of Bacopa monniera on stress induced changes in plasma corticosterone and brain monoamines in rats.” Journal of ethnopharmacology 111.3 (2007): 671-676.

[10] Singh, Rajbir, et al. “In Vitro Evaluation of Bacopa monniera Extract and individual constituents on human recombinant monoamine oxidase enzymes.”Phytotherapy Research 28.9 (2014): 1419-1422.

[11] Krishnakumar, Amee, M. S. Nandhu, and C. S. Paulose. “Upregulation of 5-HT 2C receptors in hippocampus of pilocarpine-induced epileptic rats: Antagonism by Bacopa monnieri.” Epilepsy & Behavior 16.2 (2009): 225-230.

[12] Opal, M. D., et al. “Serotonin 2C receptor antagonists induce fast-onset antidepressant effects.” Molecular psychiatry (2013).

[13] Tembhre, Manju, et al. “Inhibitory Potential of Acephate and Ethanol Extract of Bacopa Monnieri on AChE in Rat Cortex and Hippocampus.” International Journal of Bioscience, Biochemistry and Bioinformatics 5.1 (2015): 45.

[14] Mathew, Jobin, et al. “Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A.” J Biomed Sci 19.25 (2012): 1-13.

[15] Sanacora G, Mason GF, Krystal JH: Impairment of GABAergic transmission in depression: new insights from neuroimaging studies. Critical Reviews in Neurobiology 2000, 14:23-45.

[16] Uabundit N, Wattanathorn J, Mucimapura S, Ingkaninan K. Cognitive enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer’s disease model. J Ethnopharmacol 2010;127:26–31.

[17] Pase, Matthew P., et al. “The cognitive-enhancing effects of Bacopa monnieri: a systematic review of randomized, controlled human clinical trials.” The Journal of Alternative and Complementary Medicine 18.7 (2012): 647-652.

[18] Bhattacharya, S. K., et al. “Antioxidant activity of Bacopa monniera in rat frontal cortex, striatum and hippocampus.” Phytotherapy research 14.3 (2000): 174-179.

[19] Kapoor, Radhika, Saurabh Srivastava, and Poonam Kakkar. “Bacopa monnieri modulates antioxidant responses in brain and kidney of diabetic rats.”Environmental toxicology and pharmacology 27.1 (2009): 62-69.

[20] Ghosh, Tirtha, et al. “In vitro antioxidant and hepatoprotective activity of ethanolic extract of Bacopa monnieri Linn. aerial parts.” Iranian Journal of Pharmacology & Therapeutics 6.1 (2007): 77-85.

[21] Channa, Shabana, et al. “Anti-inflammatory activity of Bacopa monniera in rodents.” Journal of ethnopharmacology 104.1 (2006): 286-289.

[22] Viji, V., et al. “Betulinic acid isolated from Bacopa monniera (L.) Wettst suppresses lipopolysaccharide stimulated interleukin-6 production through modulation of nuclear factor-κB in peripheral blood mononuclear cells.”International immunopharmacology 10.8 (2010): 843-849.

[13] Viji, V., S. K. Kavitha, and A. Helen. “Bacopa monniera (L.) wettst inhibits type ii collagen‐induced arthritis in rats.” Phytotherapy Research 24.9 (2010): 1377-1383.

[24] Ghosh, T., et al. “Antimicrobial activity of various fractions of ethanol extract of Bacopa monnieri Linn. aerial parts.” Indian Journal of Pharmaceutical Sciences 69.2 (2007): 312.

[25] Morgan A, Stevens J. Does Bacopa monnieri improve memory performance in older persons? Results of a randomized, placebo-controlled, double-blind trial. J Altern Complement Med 2010;16:753–759.

[26] Stough C, Downey LA, Lloyd J, et al. Examining the nootropic effects of a special extract of Bacopa monniera [sic] on human cognitive functioning: 90 day double-blind placebo-controlled randomized trial. Phytother Res 2008;22:1629–1634.

[27] Pravina K, Ravindra KR, Goudar KS, et al. Safety evaluation of Baco- Mind in healthy volunteers: A phase I study [clinical report]. Phytomedicine 2007;14:301–309.

[28] Ramasamy, Seetha, Lik Voon Kiew, and Lip Yong Chung. “Inhibition of human cytochrome P450 enzymes by Bacopa monnieri standardized extract and constituents.” Molecules 19.2 (2014): 2588-2601.

Lycium barbarum fruits (Goji berries)

INTRODUCTION

Lycium barbarum is a deciduous shrub that grows 1-3 meters high and is widespread in warm climate regions, from Southeast Europe to China [1]. It is cultivated mostly for its edible berries, orange-to-red in color and 1-2 cm in length, known as wolfberries or Goji berries. Majority of Goji berries on the world market come from North China.

Lycium barbarum has been used in the traditional Chinese medicine for thousands of years [1]. Its berries (fruits) have been claimed to nourish liver, kidneys and lungs, to promote sexual health and fertility, cure vision problems, reduce fatigue and headache, and increase longevity [1, 2]. History of the traditional use has been taken as evidence of its extraordinary health benefits by various alternative medicine practitioners and commercial distributors, who have promoted Goji as a quasi-miraculous cure for medical conditions and an anti-aging product [1]. Goji berries have been heavily advertised recently and became a popular item on the health food market [1]. They are mostly sold as raw dried fruits, but also as juice, or in the form of powder or tablets. Some scientific studies have indeed found interesting and potentially useful pharmacological properties in the Lycium barbarum fruits, however, the conclusive evidence for their benefits to humans is still lacking.

Goji fruits are abundant in several classes of compounds. The most important are polysaccharides, carotenoids and flavonoids. They also contain essential fatty acids, free amino acids and vitamins B1, B2 and C [1]. The polysaccharide fraction is relatively characteristic for L. barbarum and has been investigated for potentially beneficial health effects.

ANTIDEPRESSANT AND NEUROPROTECTIVE EFFECTS

One study has shown that Lycium barbarum polysaccharides possess significant antidepressant properties [3]. Depressive-like behaviour was induced in rats by repeated injections of corticosterone (the main glucocorticoid hormone in rodents, equivalent to human cortisol). Increased glucocorticoid signaling has been identified in both animal and human studies as one of the most common physiological changes in depression and anxiety disorders, accompanying characteristic brain abnormalities and behavioral symptoms. As would be expected, corticosterone treatment resulted with dendritic atrophy of pyramidal cells and decreased levels of neurogenesis in subgranular zone of the hippocampus. Oral administration of Lycium barbarum polysaccharides (LBP) in doses from 1 mg/kg to 10 mg/kg for 14 consecutive days reversed this effects, increasing both neurogenesis and dendritic spine density. Important synaptic proteins (PSD-95 and synaptophysin) were also found to be upregulated. Moreover, LBP produced a significant antidepressant response in the forced swim test. However, further experiments showed that the increased synaptic plasticity alone, not the altered rate of neurogenesis, was responsible for the antidepressant effects of LBP. It was pointed out in the study that LBP treatment exerted a more potent effect than volontary physical exercise (wheel running) in the corticosterone model of depression, which was evaluated in the previous study by the same authors [4].

Neurogenesis enhancing properties of LBP were also found in another study that examined its effects on sexual behaviour in male rats [2]. Corticosterone administration was used to induce defects in sexual motivation and performance, and was shown to decrease neurogenesis in the hippocampus and the subventricular zone of the olfactory system (SVZ), as well as suppress testosterone levels. LPB treatment was found to reverse this, rescuing neurogenesis in both regions, increasing testosterone and restoring normal sexual behaviour. LBP was also capable of enhancing sexual performance in healthy male rats not treated with corticosterone. Neurogenesis was shown to be essential for both normal sexual functioning and the beneficial, pro-sexual effect of LBP.

Several other studies confirmed LBP’s pro-neurogenic effects. Treatment of rats with LBP before and after subjecting them to severe trauma reduced cognitive and behavioral defects attributed to hippocampal cell death (apoptosis) and impaired neurogenesis. LBP alleviated those cellular changes and restored the hippocampal volume [5]. Similar observations were made in the study of hypoxia-induced injury to the hippocampus; LBP showed neuroprotective effects against oxidative damage, suppressed inflammation and apoptotic signaling, improved neurogenesis and reduced deficits in spatial memory [6]. Its protective effects in ischemia and reperfusion injury were also reported in several studies [7, 8].

Possible beneficial effects of wolfberry on subjective states and neurological functioning have also been investigated in clinical studies. Daily consumption of Goji fruit extract was reported to increase the quality of sleep, decrease fatigue, dizziness, chest distress and anorexia in elderly subjects [9]. In another study, a commercial Goji juice was found to improve the subjective well-being, neurological performance and gastrointestinal functioning in young healthy adults [10].

OTHER BENEFITS

Antioxidant properties of Goji fruit extracts or purified polysaccharides have been in the focus of many studies. Protective effects of LBP against oxidative stress in animal cells and tissues have been demonstrated both in vivo and in vitro [11, 12, 13]. In the single clinical study, consumption of Goji juice increased serum antioxidant markers in healthy participants [14]. Animal studies have shown that LBP can improve insulin sensitivity and exert hypolipidemic effects (lowering cholesterol and triglycerides) [15]. A lot of research has focused on its immunostimulatory and antitumor properties [16, 17], including one clinical study on cancer patients where LBP in combination with immunotherapy resulted with increased remission rates [18].

TOXICITY

Goji berries can be regarded as safe, even when consumed in large quantities. They have been used for a long time as food and folk medicine, with no reports of adverse effects [1]. Recently, there have been only a few cases of allergic reactions, and adverse interactions have been documented in patients taking warfarin [19].

VALIDITY OF RESEARCH

It should be noted that almost all research on pharmacological properties of wolfberry was done by Chinese scientists. Clinical studies have been conducted exclusively in China, and have not been of highest quality [1]. Typically, studies were limited by small size, lack of statistical analysis and poor controls. Some were conducted by scientists either affiliated with or directly sponsored by the company selling Goji products. Independent research is needed.

CONCLUSION

Preclinical evidence suggests that Goji products (berries, extracts or juice) might be beneficial in the treatment of depression and other neurodegenerative disorders. Clinical evidence is still insufficient, proper studies are yet to be conducted. Regular consumption of wolfberry might potentially bring some improvement in the hedonic function, in combination with other strategies and substances. Since the fruit is not toxic, one could freely experiment with different dosages to find if it could produce a mood enhancing effect, while enjoying many other health benefits.

REFERENCES:

[1] Potterat O. Goji (Lycium barbarum and L. chinense): phytochemistry, pharmacology and safety in the perspective of traditional uses and recent popularity. Planta Med. 2010;76:7–19. doi: 10.1055/s-0029-1186218.

[2] Lau BW-M, Lee JC-D, Li Y, et al. Polysaccharides from Wolfberry Prevents Corticosterone-Induced Inhibition of Sexual Behavior and Increases Neurogenesis. Borlongan CV, ed. PLoS ONE. 2012;7(4):e33374. doi:10.1371/journal.pone.0033374.

[3] Zhang E, Yau SY, Lau BW, Ma H, Lee TM, Chang RC, et al. Synaptic plasticity, but not hippocampal neurogenesis, mediated the counteractive effect of wolfberry on depression in rats (1) Cell Transplant.2012;21:2635–49.

 [4] Yau S. Y.; Lau B. W.; Tong J. B.; Wong R.; Ching Y. P.; Qiu G.; Tang S. W.; Lee T. M.; So K. F. Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats. PLoS One 6(9):e24263; 2011.

[5] Gao J, Chen C, Liu Y, Li Y, Long Z, Wang H, Zhang Y, Sui J, Wu Y, Liu L, Yang C. Lycium barbarum polysaccharide improves traumatic cognition via reversing imbalance of apoptosis/regeneration in hippocampal neurons after stress. Life Sci. 2015 Jan 15;121:124-34.

[6] Lam C-S, Tipoe GL, So K-F, Fung M-L. Neuroprotective Mechanism of Lycium barbarum Polysaccharides against Hippocampal-Dependent Spatial Memory Deficits in a Rat Model of Obstructive Sleep Apnea. Ma D, ed. PLoS ONE. 2015;10(2):e0117990. doi:10.1371/journal.pone.0117990.

[7] Li S-Y, Yang D, Yeung C-M, et al. Lycium Barbarum Polysaccharides Reduce Neuronal Damage, Blood-Retinal Barrier Disruption and Oxidative Stress in Retinal Ischemia/Reperfusion Injury. Ko B, ed. PLoS ONE. 2011;6(1):e16380. doi:10.1371/journal.pone.0016380.

[8] He M, Pan H, Chang RC-C, So K-F, Brecha NC, Pu M. Activation of the Nrf2/HO-1 Antioxidant Pathway Contributes to the Protective Effects of Lycium Barbarum Polysaccharides in the Rodent Retina after Ischemia-Reperfusion-Induced Damage. Gallyas Jr. F, ed. PLoS ONE. 2014;9(1):e84800. doi:10.1371/journal.pone.0084800.

[9] Li DY, Yuan XL, Xia HF, Ma L, Guo ZY, Shen YY, Rong QZ. Preliminary clinical observations for effects of Ning Xia wolfberry extract on old peoples. Chin Tradit Herb Drugs 1989; 20: 26–28

[10] Amagase H, Nance DM. A randomized, double-blind, placebo-controlled, clinical study of the general effects of a standardized Lycium barbarum (Goji) juice, GoChi™. J Altern Compl Med 2008; 14: 403–412

[11] Shan X, Zhou J, Ma T, Chai Q. Lycium barbarum Polysaccharides Reduce Exercise-Induced Oxidative Stress. International Journal of Molecular Sciences. 2011;12(2):1081-1088. doi:10.3390/ijms12021081.

[12] Liu L, Lao W, Ji Q-S, Yang Z-H, Yu G-C, Zhong J-X. Lycium barbarum polysaccharides protected human retinal pigment epithelial cells against oxidative stress-induced apoptosis. International Journal of Ophthalmology. 2015;8(1):11-16. doi:10.3980/j.issn.2222-3959.2015.01.02.

[13] Zhang L, Gu J, Chen Y, Zhang L. A Study on Four Antioxidation Effects ofLycium Barbarum Polysaccharides In Vitro. African Journal of Traditional, Complementary, and Alternative Medicines. 2013;10(6):494-498.

[14] Amagase H, Sun B, Borek C. Lycium barbarum (goji) juice improves in vivo antioxidant biomarkers in serum of healthy adults. Nutr Res 2009; 29: 19–25

[15] Ming M, Guanhua L, Zhanhai Y, Guang C, Xuan Z. Effect of the Lycium barbarum polysaccharides administration on blood lipid metabolism and oxidative stress ofmice fed high-fat diet in vivo. Food Chem 2009;113: 872–877

[16] Chen Z, Tan BKH, Chan SH. Activation of T lymphocytes by polysaccharide-protein complex from Lycium barbarum L. Int Immunopharmacol 2008; 8: 1663–1671

[17] Gan L, Zhang SH, Yang XL, Xu HB. Immunomodulation and antitumor activity by a polysaccharide-protein complex from Lycium barbarum. Int Immunopharmacol 2004; 1: 563–569

[18] Cao GW, Yang WG, Du P. Observation of the effects of LAK/IL-2 therapy combining with Lycium barbarum polysaccharides in the treatment of 75 cancer patients. Zhonghua Zhong Liu Za Zhi (Chin J Oncol) 1994;16: 428–431

[19] Ge B, Zhang Z, Zuo Z. Updates on the Clinical Evidenced Herb-Warfarin Interactions. Evidence-based Complementary and Alternative Medicine : eCAM. 2014;2014:957362. doi:10.1155/2014/957362.

The Case for Hedonic Engineering

“Hedonic engineering” can be defined as development of a hypothetical highly advanced biotechnology, preferably in the form of gene therapies, targeted to specific structures, nuclei and cell types of the human brain, with the aim of radical enhancement of human emotional and hedonic capacities. Such therapies would be designed to modulate the excitability of the so-called “hedonic hotspots” in order to elevate (what is presently considered) the normal mood far beyond the level of today’s highest peak experiences. With biomanipulation it should be possible to produce sustainable and profound changes in the function and activation states of the emotional networks in the brain, and therefore accomplish a great boost in the quality of everyday experiences – while not only keeping the cognitive processes intact, but also enhancing the abilities for rational thought, focus and creativity.

What would be the concrete goals of hedonic engineering?

a) Elimination of human suffering and dysfunctional behaviors, augmentation of all positive affective states. Rooting out depression (as one of the extremes of human suffering) from the human emotional repertoire entirely, and elevation of the hedonic setpoint – a basal level of pleasure and motivation that is maintained in the “background” of our everyday lives, in the absence of particularly intense positive or negative stimuli, around which all our experiences oscillate (peaks and troughs of life).

b) Stable and lasting, highly elevated mood coupled with the sensations of warmth, satisfaction, vigor and happiness just for being alive. Hedonic engineering would be able to stabilize human experience in the state of permanent positive, blissful mood, far more intense and more beautiful than anything imaginable today.

c) Ability to sustain strong feelings of motivation, interest, fascination, curiosity, amazement, creative drive, sexual desire, and feelings of meaning and purpose – with the maximally expanded range of activities experienced as interesting and exciting. (Appetitive motivation, “wanting”)

d) Ability to sustain intense sensations of pleasure with the maximally expanded range of activities experienced as pleasant. Increased capacities for aesthetic pleasure, increased ability to enjoy intellectual work, acquisition of knowledge, creation and innovation, participation and social interaction, expression of thought and feelings. Elevated capacity for love, tenderness, for sensuality and sexuality, for pleasure in physical activity, in play and recreation, in food and drink.. (Pleasure, “liking”)

e) Strong feelings of empathy, capacity for the experience of trust, warmth and intimacy.

Positive and productive emotional states should penetrate every single moment of human existence. Moments of boredom, “deadness” and “greyness” should be wiped out from our lives. Normal, basal mood should rise to the level of pure ecstasy, far more intense than any peak experience imaginable today. Every aspect of the outer and inner human reality should gain emotional color and weight, everything should become meaningful, interesting and motivating, everything should stimulate exciting, creative and complex thought.

Positive affective states that drive everyday behavior of normal, euthymic individuals are usually weak and mostly incomparable to their hedonic and motivational peaks, like sexual excitement, orgasm or feeling of “being in love”. Average human emotions are pale, “anemic” and shallow in comparison to the peaks of passion that can be experienced only a few times in a lifetime. Most of human life is usually spent in the affective stupor, wasted on the half-conscious state of routine and “functioning”. However, it doesn’t have to be that way. The very existence of intense pleasures like orgasm clearly shows that something far greater is possible. Subjective feelings are not intrinsically and inseparably tied to any specific stimuli, nor to any sensory modality within which they appear. Theoretically, it should be possible to rewire cortical projections and modify the pleasure centers in the way that would link positive anticipation and excitement – equal in intensity to sexual drives – to intellectual activity, and ensure that pleasure equal to orgasm in strength rewards every – even the smallest – result of mental effort. Such feelings would be entirely non-sexual and would resemble euphoria or the mental ecstasy, depending on the type of activity, invested effort, and the accomplished result. They could also be engineered to lack any significant somatic, distraction-producing component.

Only a tiny minority of people today is capable of sustaining an intrinsic motivation adequate for mastering complex subjects like natural sciences, while for the majority of people a system of extrinsic rewards and punishments is necessary. Inclinations towards the complex fields of science and technology are usually developed early in the life of rare gifted individuals, while for the most people such interests never outgrow childish dreams and curiosities, and never become a significant force driving their education and career. Consistent learning and exercising creativity in challenging fields is hard and the progress is slow, while the pleasure derived from it almost never approaches the level of even the simplest of life pleasures like those in food, recreation, play and social interaction. Indeed, to many people education stands only for pain and frustration, and for the most, a profession is only a way to make money instead of a life calling. There is a disappointingly small number of children that spontaneously begin expressing strong interest for demanding subjects, that rather study and write than kick a football in the playing field. The reason for that lies in our past. Humans have not evolved as mathematicians, historians or economists, but rather as hunters & gatherers, warriors, explorers and adventurers. Behaviors that come naturally to us are exactly the ones that modern society attempts to suppress under all costs. Men are naturally fascinated with combat, hunting and danger. Natural behaviors of boys are fights, exploration, war games, building of simple weapons, and formation of aggressive groups that seek conflicts with other groups. Natural behaviors of girls, on the other hand, involve activities necessitating patience and precision, for example preparation of food and manufacture of simple ornamental objects. During our evolution, children never had to sit quietly for hours in boring classrooms, they never had to spend a lot of time indoors under coercion and threats, under tyranny of deadlines and schedules. Humans never had to study consciously, never had to solve mathematical equations or produce objects more complex than bow and arrow. Although we were up to such tasks intellectually, for the lack of evolutionary pressures adequate motivations and intrinsic rewards have never developed. Without human needs for security, economic well-being and desire for higher status, education would have been a utopian goal.

Humans are characterized by a fundamental lack of adaptation to a life in modern civilization. Society cannot be adapted for human needs any more; the only form of society truly in tune with human nature would be a group of hunter-gatherers. Basic characteristics of human nature, like territorial, sexual, competitive and vengeful aggression, ethnocentrism, xenophobia, neophobia and intolerance, envy, narrow circle of empathy, drive for power and status, adrenalin-seeking, inclinations towards mystical and irrational beliefs, are entirely incompatible with the needs of rapidly advancing, highly technological and globalized world. The most important activities in our modern society, the ones that are the key for personal success and happiness, are also the ones that receive almost no help at all from our natural drives and intuitions – the ones that we feel the least motivated for, the ones that provide us with the least amount of pleasure and comfort. Although there is no individual or social phenomenon that isn’t, directly or indirectly, determined by some of the basic aspects of human nature, our natural motives provide an extremely poor fuel for the growth of civilization. To that realization also points the fact that in 10 000 years since the birth of civilization, true progress in the quality of life for the average human being has only started to become evident in the last 200 years. Human history has been described as history of spilling blood, tears and sweat. Advances in scientific discoveries, technological and social solutions were made slowly and pioneers of progress always faced fierce resistance from human natural intuitions, beliefs, fears and general ignorance. Even today, the major brakes on progress are still irrationality, fear of change, lack of interest in education, mysticism, tribe mentality, authoritarianism, being at peace with the “status quo”, idealization of natural, depression and passive attitudes towards politics and progress, lack of empathy and altruism, egotism and greed.

Running on economic competition, on desires for the acquisition of wealth and drives for higher social status as its main fuels, modern society has attained a high level of technological growth. Unlike it’s technology, however, humanity hasn’t advanced much. Human mental and physical abilities in the 21. century still aren’t much above those of Pleistocene hunter-gatherers that feasted on woolly mammoths and painted cave walls. Man is still basically a primitive animal that lives in a technological cage of its own creation. In spite of all the progress, there is no reason to believe we are happier than our distant ancestors.

Emotional misadaptation in the modern world results in suffering. In the absence of thrills and sources of pleasure that characterized early human existence, in the situation where most needs are satisfied only indirectly, where pain can’t be expressed and stress can’t be acted upon (by fight or flight), and where there is marked powerlessness of individual compared to society, many people don’t feel “alive enough”. Global capitalism provides us with the examples of extreme success, wealth and fantastical possibilities for meaningful work and entertainment that are still unavailable to great majority of people. As a result of this chronic gap between dreams and reality, a large number of individuals experiences frustration and “social defeat”, which slowly pushes them into mild depression. Incidence of depression rises and it has been predicted that this illness will become the leading cause of work disability by 2020. On the other side, a small minority of highly successful professionals manifests enviable motivation, energy and ability to deeply enjoy work they consider a “true calling”. Most talented and productive people claim that the key for happiness and success in life is the ability to retain curiosity and fascination with the world around yourself, to feel constant passion for research, for knowledge and creation. How can they sustain these passions and others can’t? A logical answer is that it’s because people are not born equal, but are rather endowed with different mental and emotional capacities. A huge body of research shows that personality traits and mental abilities are highly heritable. From the large pool of possible variations, a small percentage of individuals inherited a lucky combination of traits that made them highly functional and successful. People differ widely in their abilities to experience pleasure, motivation and interest, just as they differ in their abilities for concentration, memorizing, in verbal fluency, in social skills, or mathematical skills. Obviously, individuals with lower hedonic set-points will be less happy, just as individuals with the “wrong feelings”. On the one end of the spectrum, there are people who suffer from intense, agonizing treatment-resistant depression, whose every day is a true hell on earth. On the other end, there are hyperthymic or hypomanic people who enjoy high levels of energy and satisfaction, and experience powerful drive towards success. However, even the differences within the limits of psychological normalcy are substantial enough to secure happiness for some, and condemn others to chronic failure and frustration.

Modern capitalism in the prosperous western countries is often portrayed by its proponents as a system of great opportunities that provides everyone with equal chances. It is usually said that there is no level of wealth and success that an ordinary individual, on the basis of exceptional effort, would not be able to attain. However, it is still pointless to insist on “equal chances”. That’s because people are not born equal. Success and happiness of an individual is not ultimately determined by his environment; it’s not determined by economic situation nor by parental nurture. “Equal chances”, for the term to have sense, would have to mean not just equal starting conditions and opportunities in life, but also equal abilities. Nature, of course, is not equally generous to all. In fact, there is nothing so unjust, so cruel and blind as is the “natural order of things”. Many people, unfortunately, idealize “natural” and speak of nature as of some deity that we should all submit to and offer sacrifice to. In the mind of some people, evolution has optimized everything so well that any interference in the “natural design” can only produce disaster. This is simply wrong. Evolution is blind, wasteful, slow and cruel, it doesn’t try to fulfill any purpose and it doesn’t result with “universal perfection”. Evolution is not progress either, it is just the process of adaptation to specific conditions, driven by natural selection. Human brain is not a perfect design, it’s only a product of long-term adaptation to a specific way of life in a specific environment. Evolution couldn’t care less about our happiness or suffering. Our mental capacities did not develop so that we could understand the fabric of the cosmos, nor did our emotions come to be what they are so that we would be happy (or unhappy). Traits that are selected for are the ones that provide advantage in the struggle for survival and reproduction. During our evolution, negative affective states often had a far greater role in promoting survival than positive states, because it was more important to escape a predator or defend oneself successfully than to exploit every single opportunity for feeding or sex. There will always be a second chance for obtaining a meal or finding a mate, but there probably won’t be a second chance for saving your life. That’s why no positive emotion can match the intensity and duration of strong fear, anger or deep sadness. Psychiatric disorders of mood and emotion defined by negative emotions running wild (deep persistent anxiety, anger problems, sadness, agonizing chronic depression) are too common, while the ones where positive mood is elevated (hyperthymia, hypomania) are extremely rare. This also points to the conclusion that our brains are biased towards suffering.

Many aversive states can serve an adaptive role during mammal evolution. For instance, chronically anxious mothers might be more successful in protecting their offspring from danger. Depression can be adaptive for pack or herd animals. When strong alpha males rule the pack, weaker males sometimes transition into the state of behavioral passivity, which helps them avoid potentially harmful conflicts with dominant individuals. Depression-like behaviors are also adaptive in the conditions of scarcity, when it is necessary to conserve energy instead of wasting it on non-survival related behaviors.

Nature is extremely ungenerous on pleasure. The entire hedonic spectrum known to un-enhanced humans is only the tiny piece of what is possible. This is clearly shown by some emotional peaks that are rarely experienced, as well as by many psychotropic substances. Cocaine and amphetamines cast off depression instantly and produce a highly energized state of euphoria where everything seems colorful, exceptionally interesting, exciting, meaningful and important. Other drugs, like MDMA and GHB, induce euphoria, feelings of well-being, intense empathy and connectedness (thus called “empathogens”), while the effects of opioid substances include pleasure, analgesia and sedation. While they last, such effects are more pleasant than anything possible in the natural, drug-free mental states. Why is this so? Why can’t we enjoy sustainable natural “highs”? The answer is that well-being beyond certain point was simply maladaptive during our evolution, and mechanisms of “hedonic treadmill” had to develop – to ensure that mood always consistently returns to the genetically predetermined, basal level – the hedonic set-point. Like a hedonic “thermostat” or a “hedostat”, this mechanism provides a constant suppression of perturbations in this basic hedonic state, extinguishing both intense happiness and intense pain. Unfortunately, it seems that the set-point is often located “off-center”, lower in the mood spectrum, closer to the suffering end.

All pleasures – natural or induced – create tolerance and adaptation. Natural stimuli, just like synthetic drugs, activate the same neurobiological negative-feedback mechanisms in the pleasure centers of the brain – receptor desensitization and internalization, dendritic arborization (branching) and the kappa/ dynorphin system which provides inhibition to dopamine neurons. Hedonic set-point is highly stable. Our neurobiology doesn’t allow us to change our basic level of happiness, no matter how hard we try. Neither the most beautiful experiences, nor the worst traumatic events in life, do not permanently influence the hedonic treadmill. The initial exhilaration of lottery winners gradually diminishes, and their mood returns to their normal level, leaving them no happier then they were before. Horrible trauma, like a quadriplegia-inducing accident, can result with a suicidal depression in many cases. However, research has shown that patients usually return to their normal, pre-accident mood within six months after the trauma, without a significant effect on their long-term life satisfaction.

Psychotropic drugs are toxic and addictive precisely because they “hack” into the neurobiological hedonic control centers, and switch them to the “overdrive”. Short lasting but intense positive affective states induced by drugs overstimulate the feedback system which quickly turns emotional “peaks” into “troughs”, producing unpleasant symptoms of withdrawal. The same happens to the natural pleasures, although to a lesser degree. Passion of a love-affair gradually wanes away, until it turns to boredom and frustration, and comes “crashing down”. A favorite movie is little less exciting each time it is repeated, experience is weaker, until the point where it makes no sense to watch it again. We get used to the changes for the better. Excitement and fascination in professional fields, just as in hobbies, sports and entertainment, social interaction or travel – slowly diminish to low and stable levels, and one never captures the original feeling again. Everything in life comes down, eventually even the life itself.

Hedonic treadmill is important. It suppresses repetitive behaviors and forces us to constantly seek new and different sources of stimulation. However, there is no fundamental reason why this basal, stable level of un/happiness that we always return to couldn’t be set much higher. If we recalibrated our hedonic set-points, adjusting them to a much higher value, we would still seek novelty and progress, but in the same time we would be much, much happier with what we already have. Our normal moods would match the most beautiful experiences of present, and our stimulus-driven feelings and peak pleasures would go beyond anything imaginable today.

The capacities for happiness and satisfaction in life are set to different levels in different individuals. We are not born equal, and we cannot all be equally happy. Nature, sometimes in combination with nurture, has set for each individual how happy, how motivated and creative he can be, just as how intelligent he can be and how much focus he can achieve. Some are endowed with strong curiosity and energy, and later they become successful scientists, engineers or artists that deeply enjoy their lives and their work. Others can’t get enough motivation for even the simplest of activities and are destined to a lifetime of failure and poverty. Some people spend their lives in severe agonizing depression, unable to experience any joy, any positive desire, any meaning. The moments of pleasure are almost non-existent for them, their minds are consumed by all-pervasive, intense sensations of emptiness and pain. In some cases, they can’t even speak, eat or get out of bed, and they must be fed artificially. On the other hand, people suffering from mild to moderate depression can be relatively functional, although unhappy, particularly if driven by anxiety. Dysthymic individuals, although less affected than depressive ones, suffer from a chronic low mood, but usually don’t seek treatment, unaware that better life is even possible.

There is a grave injustice in the natural state of things. Human life is a deep tragedy, filled with meaningless pain and suffering, ending with meaningless death – into the oblivion. During our history, countless generations of miserable, powerless people lived their short lives of poverty, disease, back-breaking labor, oppression and sometimes unimaginable cruelty. The were born to suffer and die without any real chance, without any realistic hope. They couldn’t create anything or influence anything; they left nothing behind, it is like they never existed in the first place. We think of them as of “historical masses”, but they were individuals whose lives were as real as ours today. They are gone forever now – we can never make things right for them. But maybe we can help people who are suffering today. We are not helpless against the injustice of nature any more. We live in the time when we finally hold enough knowledge and enough technological power to start resisting the tyranny of natural forces and limitations, and take control of our own evolution. Neuroscience and biotechnology provide us with the means to sabotage the hedonic treadmill, root out human suffering and secure emotional well-being for all. There is no reason why states of extreme happiness – with adequate biomedical manipulations – couldn’t eventually be made sustainable in the human mind. If the worst forms of pain and suffering can be maintained for months, years, even lifetimes, why couldn’t happiness be? There is no physical law that would prevent it. Engineering of human nature is possible, necessary and desirable. Even more – it is a moral priority.