Alchemica

This one - the dragonfly - came to me in a time where I was embracing change - new place, new attitudes, new behaviour, new light "...change what needs to be changed, survive, become better, and flourish!"

Well said @Inyan Coming from only ever being interested in plants for medicinal aspects, to then finding the enjoyment of creating that nourishing connection to food, I always dismissed anything else as aesthetic gardening and pointless. Not saying food/medicine isn't important, I'm just surprised to find how the act of relationship with something that won't deliver a therapeutic brew or even food really breaks the addictive consumption mindset - something I was always struggling with

You can eat the kale, do the meditations, sip on the plant medicine but how healing is that really? I got disenchanted with 'plant medicine' as it was often turning into a bunch of band-aid experiences and pits of continuous self-medication. I saw lots of people embarking on the same loop, it seemed to be a pathway of less healing than expected. Anyone else found that? I think we've often lost some aspect of simply nurturing something that doesn't give back to us with food or medicine etc. A deeper connection to the Web of Life. I started growing some non-medicinals, things that weren't providing me with anything, and noticed something... From the butterfly attracting Milkweed to Milly's forget-me-nots to Acacias I'd never had any interest in... In the past, a plant's worth was dictated to me by what it could do for food or medicine, a very ego-centric view on the plant. There was nothing spiritual or worthwhile about a plant being simply a living entity, the essence of respect was often not there/not as deep - what did it do for us other than provide a bit of oxygen?!? It's "just a plant"... I was centred around always taking something from a plant, be it food, medicine, boosts in self etc. If we treat humans in such a way, constantly dictating their worth by what they can do "for me/us" and with limited respect for their unique worthwhile existence, that's a very unhealthy view that's all too prevalent in society - I believe our human relationships are often mirrored in the way we treat the Earth. If we flip that "for me/us" around into what we can do "for them" without expectation of something in return, that's the start of some healing. In that flip, you also seemingly make room for healthy natural reciprocity Today I see the worth of a plant beyond that narrow view. I'm starting to nurture something that I don't expect anything in return from. The essence of each plant has it's own gift, beyond a phytopharmacological or nutritional cocktail, and deserves respect - a more eco-centric and spirited view Looking forward to Trees for Life

Keep us in the loop on any improvements or anything you note @Xperiment. I doubt you got up to as much thiamine depleting shenanigans as I did but if you did, be liberal with doses... Longer term, I've noted it's not the panacea for me - don't expect it to be - if I get stressed I get symptom flares but they actually resolve over a bit of time whereas before nothing would shift a continuous spiral down.

This continues to deliver day by day. So much so I think the quest for some stability might be over I find the effects are very dose dependent in line with the dose-response noted above - using 500mg+ (I haven't noted side effects up to 1.5g) and keeping those levels elevated throughout the day has given me some good stability, I might be able to reduce doses soon. Why did my brain feel daily like it was being eaten alive, was pure negative affect constantly over-riding my emotional world, was I in pure dysphoria with constant fluctuations in mental state and deteriorating cognition? This seems to be the closest I've found to a solution and an affordable one at that The encouraging thing is that on returning to what was my first point of call but really upping the thiamine dose with just healthy dietary diversity and maintenance, it feels like there's nothing too much needing continuous time investment in attempting 'fixing' which has been a super challenging loop for me to break free from when minute to minute your mental state, memory and cognition is doing weird things. Hopeful I can maintain that. I'm currently having manageable stable-ish days without extreme and constant mood, emotional and other weird neuropsychiatric stuff happening. That said, it's been a long time of symptoms so there's likely been damaging effects from that. I'm not saying it's at all perfect but it's workable and stable 'good enough'. I can actually do some things I want to do for a few hours, particularly manage some family time, without it being absolute torture for my fluctuating brain state. Get on with living life.

Well modulating 5-HT did something helpful, temporarily... In a moment of impulsivity went back to what was my first point of call after abstinence. Cheap old thiamine, was my body really getting enough or could that help explain the scary deteriorating struggle town I was in each day? Not going to neglect the other vitamins see table in this article The B vitamins: nomenclature, dietary sources, coenzyme forms (roles), symptoms of deficiency, and risk factors (over and above low consumption). Of all the evidence based things I've tried to stay on top of, thiamine was one major legitimate concern. Thought I was including enough to try and cover that concern... but I upped the thiamine quite a bit.... and felt slightly better. A few days, even better. These days of supplements being so dodgy in quality, I'll only use simple cheap pharmaceutical grade thiamine I trust from the chemist not some novel derivative. B1 Thiamine - brain deficiency particularly seen in alcohol abuse, obesity Mild deficiency: irritability, emotional disturbances, confusion, disturbed sleep, memory loss Deficiency: Wernicke-Korsakoff syndrome (neurodegeneration, within the medial thalamus and cerebellum). Ataxia, abnormal motor function and eye movement, amnesia, apathy, confabulation - Thiamine deficient rats developed learning and memory deficits as well as aggressive behaviour - There was significant cognitive deteriorations in the psychoneurotic scales in thiamine deprived participants . - There was significant association between improved thiamine status and enhanced performance across a range of cognitive-function test [ref] Thought I was on enough but if you start getting weird neurological symptoms and cognitive decline, it seems to be a really good thing to knock out as a potential causative factor ASAP rather than fluffing around, particularly if you've been on anything thiamine depleting. Not just take a bit but saturate your system with it for awhile... Particularly when if you're getting changes in mental state and cognitive deterioration - disoriented, inattentive, agitated etc Any thiamine experts? How much thiamine is actually needed for abstinence recovery? How long do you need to maintain high-dose supplementation for? I used 100mg/day for a bit then I was using about 50mg/day. Maybe that simply wasn't enough Alterations of serotonergic parameters have been demonstrated in experimental thiamine deficiency. "...data suggest that 5-HT neurons, although structurally intact, are functionally affected early during the progression of thiamine deficiency. These alterations, which are likely a part of adaptive neuronal change consequent to thiamine dysfunction, may be important in the physiological manifestations and the learning deficits commonly encountered in experimental thiamine deficiency. " Stuck with it a few days, got out in the garden more. Feel just clearheaded, been more able to persist with goal-directed tasks, not irritable. Calm and collected in the most grounded way I've felt for awhile. Stability of mood. I've actually slept in past my usual 3.30am wake up time, too. With 50mg in healthy subjects: An improvement in thiamine status was associated with reports of being more clearheaded, composed and energetic. These influences took place in subjects whose thiamine status, according to the traditional criterion, was adequate. Once again, this seems to have antidepressant augmenting effects in human studies [1]. In a small study, thiamine supplementation significantly improved anxiety scores, general well-being and reduced fatigue in patients with Generalised Anxiety Disorder. "Interestingly these patients were able to discontinue taking anxiolytic and β-blocker medications." [2]. It has also been found thiamine supplementation shows a beneficial clinical effect on children with autism [3]. [1] https://www.ncbi.nlm.nih.gov/pubmed/26984349 [2] https://pdfs.semanticscholar.org/7c1b/53c8c4dbfdccf441a16bcc1464b2b26c9c55.pdf [3] http://article.sciencepublishinggroup.com/pdf/10.11648.j.ajpn.20130102.11.pdf "Thiamine is being used to improve brain function and it is also shown to help treat neurodegenerative disease such as Alzheimers and Parkinsons" It's established "thiamine supplemented abstinent rats made a faster recovery of hepatic and neuronal damage than in the abstinence group. Changes in neurotransmitter levels in brain were also reversed by thiamine supplementation. DNA damage was decreased and DNA content increased in thiamine supplemented group compared to abstinence group showing a faster regeneration" [1] It is claimed Steve Jobs took massive doses of thiamine when he was experimenting with other stuff and said both were about equally effective as idea stimulators, but B1 did not have the psychoactive effect. Thiamine compounds may act by boosting anti-oxidant cellular defenses and prevent stress-induced inhibition of hippocampal neurogenesis [2] Thiamine has antidepressant/anti-stress effects that are associated with reduced GSK-3β expression and conditioning of adverse memories [3] High doses have some utility in dementia potentially due to a cholinomimetic effect of thiamine in the central nervous system [4] Thiamine is required to synthesise acetylcholine (ACh). Thiamine is involved in the presynaptic release of ACh; thiamine binds to nicotinic receptors and exhibits anticholinesterase activity The treatment with thiamine led to a significant improvement of Parkinson's symptoms. Experimental findings showed an increased dopamine release in rat striatum after the intrastriatal thiamine administration and "high doses of thiamine, could lead to an increase of synthesis and release of the endogenous dopamine, to an increase of activity of the thiamine-dependent enzymes" [5] A thiamine derivative promotes voluntary activity through dopaminergic activation [6] The same derivative has been found to make mice engage in more passive cuddling-type behaviours. Likewise acute sulbutiamine induced a modulatory effect on glutamatergic and dopaminergic cortical transmissions in the rat brain It has anticonvulsant effects [7] One report of a healthy subject taking mega-doses: "I have been using megadoses of Thiamine (Vit. B1) on and off for over a year and am greatly impressed. I always take a 250 mg or 300 mg B1 pill with a Vitamin B Complex (100 mgs/mcgs of the various B Vitamins) usually twice per day (once with breakfast and once with lunch). Good things about Thiamine megadoses: - Greatly improves my attention to detail on reading tasks. Without it I often struggle reading through pubmed articles for example, with it I read every single word quickly and understand what the article is about without giving up (I often 'give up' without this given that I have inattentive type ADD). - Greatly improves ability to do 'boring' mundane tasks. For example, when doing boring checking tasts at work, this helps me rip through them better than anything else. Also lets me rip through chores easily. - Improves my motivation. It allows me to follow a more disciplined lifestyle (eating healthier, sticking to routines, doing boring chores without too much hassle, etc.) - Gives me more mental energy and I feel more awake generally in the daytime." [8] [1] https://www.ijpp.com/IJPP archives/2013_57_4_Oct - Dec/406-417.pdf [2] https://www.ncbi.nlm.nih.gov/pubmed/28506637 [3] https://www.ncbi.nlm.nih.gov/pubmed/27825907 [4] http://www.ncbi.nlm.nih.gov/pubmed/8251051 [5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828997/ [6] https://www.nature.com/articles/s41598-018-28462-2 [7] https://www.ncbi.nlm.nih.gov/pubmed/28766407 [8] https://www.longecity.org/forum/topic/65238-megadosing-thiamine-for-motivation-and-sexual-arousal/ I've learned with a potential deficiency ie thiamine, don't skimp on doses of the safe ones. Doses of high magnitude for longer periods are required to replenish many B vitamin levels and correct enzymatic activity, particularly with those who have restriction in their ability to absorb them. There is a linear dose response following single oral doses of thiamine in terms of whole blood and plasma levels up to the maximum administered dose of 1500 mg (corresponding to more than 1000 times the RDA). Higher doses have also been used such as 3g. It's seemingly better to get those levels up. "Epidemiological evidence suggests that the benefits of B vitamins extend well beyond the accepted biochemical cut-offs for deficiency or marginal deficiency" Other B deficiencies from [ref]: B2 Riboflavin Fatigue, personality change, brain dysfunction B3 Niacin - Particularly seen in alcohol abuse Depression, anxiety, progressing to vertigo, memory loss, paranoia, psychotic symptoms, aggression (Pellagrous insanity) B5 Pantothenic acid Encephalopathy, behaviour change, demyelination B6 Vitamin B6 (referring to: pyridoxal, pyridoxamine, pyridoxine) Particularly seen in Alcohol abuse, age-related malabsorption, contraceptive medications Irritability, impaired alertness, depression, cognitive decline, dementia, autonomic dysfunction, convulsions B7 Biotin - particularly seen in Type II diabetes, poor gluco-regulation Depression, lethargy, hallucinations, seizures B9 Folic acid/folate - particularly seen in Common genetic polymorphisms (inc. MTHFR C667T) Low Riboflavin and B12 B12 Vitamin B12 - particularly seen in age-related malabsorption, vegetarians, vegans, genetic polymorphisms Both cause affective disorders, behaviour changes, psychosis, cognitive impairment/decline, dementia (inc Alzheimer’s disease and vascular dementia) Observational and controlled trial research being focused disproportionately on just three of the vitamins—folate and vitamins B6 and B12. "Unfortunately, there is a general dearth of controlled trial research into the effects of the remaining B vitamins on brain function"

Switching this around, how do we use the social to modulate monoamines? Is 5-HT something that is successfully modulated by the social? That's the other thing that causes a drastic reduction in symptoms for me - nourishing social interaction. The serotonergic system itself is highly responsive to social influences and social isolation has been shown to affect endogenous 5-HT release and 5-HT turnover and leads to a reduction in the excitability of DRN 5-HT neurons. Sure, initially the elevated serotonergic states where nice but eventually things seem to return to a homeostasis, likely as seen in clinical studies with Trp augmentation "During the first week of treatment, there was a significantly greater decrease in depression scores. No significant differences were noted at later time points." and if you're adding additional Trp, are you potentially providing extra fuel for an activated kynurenine pathway? Upping the monoamines helped but... I mean really, is fancy supplementation really alleviating issues at the source and improving life, or just a band-aid for real problems, like persistent social isolation? Part of me says, fix the aberrant underlying deficits and you'll start having better social approach and try more socialising whereas in reality, each "band-aid" is directing life force away from actively tackling the root causes. The bidirectional effects of the social on the biological could be more effective and stable than trying to up monoamines with anything. I've tried that approach before, a few times, but it's worth a retry. Riding through the nastiness of 'augmentation cost cutting', feeling quite extra crap, and more attempted action even though I feel crap. Often the only way that works... I'm at the point Trp isn't doing much more, other than inducing side-effects and becoming very blunting. More so than just switching favour between hedonic short-term rewards in favour of longer-term ones, actually feeling extremely anhedonic. It switched the impulsivity down, tackled negative emotional dysregulation well, for a bit. PRN stuff it feels. Do social factors induce cascading serotonergic abnormalities? It seems very difficult to climb back to any level of health if you condition social defeat and isolation. We too easily isolate and subordinate people with lower mental health, as they do to themselves, how much does that cascade into crippling mental illness? How much of a role does the serotonergic system play in that? Serotonin is probably most central in its relation to social status functioning [1] Changes in serotonergic function seems to directly affect perceived social status. "Social subordination leaves one fidgety, easily perturbed, and their behaviour seems to be largely controlled by external stimuli rather than being self-directed. [they are] prone to impulsive behavior including impulsive aggression." 5-HT appears - important in developing nourishing social contacts - contributes to the appraisal of the social emotional cues - increases the perception/interpretation of social stimuli - It stimulates pro-social behaviour, which leads to high levels of cooperation and improved perception of social cues In a simplistic framework: "Serotonin levels are not innate and inflexible. They are themselves the product of social status. The higher your self-esteem and social rank relative to those around you, the higher your serotonin level is. Experiments with monkeys reveals that it is the social behavior that comes first. Serotonin is richly present in dominant monkeys and much more dilute in the brains of subordinates. Cause or effect? Almost everybody assumed that the chemical was at least partly the cause: it just stands to reason that the dominant behavior results from the chemical, not vice versa. It turns out to be the reverse: serotonin levels respond to the monkey’s perception of its own position in the hierarchy, not vice versa." “Contrary to what most people think, high rank means lower aggressiveness, even in vervet monkeys. The high-ranking individuals are not especially large, fierce or violent. They are good at things like reconciliation and recruiting allies. They are notable for their calm demeanor. There is little doubt that the monkeys mood is set by its high serotonin levels. If you artificially reverse the pecking order so the monkey is now a subordinate, not only does its serotonin drop, but its behavior changes, too. Moreover, much the same seems to happen in human beings." - Genome The activity of 5-HT neurons is highly vulnerable to stress. Stress → social withdrawal/low mood → social isolation and continuous social subordination. Each of those declines is another hit to the functionality of the serotonergic system. It forms a negatively re-enforcing cascade. [1] https://www.ulm.edu/~palmer/TheBiochemistryofStatusandtheFunctionofMoodStates.htm "Serotonin dysregulation found in depression and other psychiatric disorders may go hand-in-hand with deficits in initiating social interaction, impaired learning from social interaction experience and making adverse decisions in social situations."

Thanks @tarenna and @LikeAshesWeFade for the kind words Still going with the Trp. Finding it really quite useful. It's not so much a mood boost as what I need Modulating 5-HT more given me a view on 5-HT beyond it being a way of increasing personal "happiness". I'm not more "happy" - it's deeper than that. It's also deeper than 5-HT making octopi cuddly with empathogens, too. I like the model where "Serotonin influences social behaviour by shifting social preferences in the positive direction, enhancing the value people place on others’ outcomes." Trp augmentation may "influence the way they feel and think about themselves in a social context" and "serotonin function is related to positive social preferences, that is, the positive valuation of others’ outcomes" Serotonin's effects appear to depend on the social context: "serotonin amplifies neural representations of positive social preferences, whereas serotonin depletion shifts neural value computations toward selfish or even negative social preferences" "Serotonin is concentrated in discrete brain regions known to regulate social cognition and decision-making that have been collectively called “the social brain”. Depleting serotonin in normal individuals shifts their behaviour toward lack of impulse control and short-term gratification at the expense of long-term benefits. Enhancing brain levels of serotonin causes people to become more averse to harming others" Depleting brain serotonin levels in normal individuals results in a shift away from cooperative behavior in favor of short-term gain and results in antisocial behaviour, increased uncontrolled aggressive behavior, feelings of anger, quarrelsome behavior, and self-injury Low functioning "compromises the decision-making process by altering the ability to distinguish the magnitude of differences between immediate versus long-term rewards" and increases the tendency to choose the less probable outcome Low Trp manipulations result in the use of more self-references, more negative words, and fewer positive words Reduced serotonin function indeed impairs ones empathic abilities. Serotonin is important for promoting behavioural suppression or withdrawal in the face of aversive predictions Serotonin modulates human concerns for harm and fairness Serotonergic activities might strongly influence the sharing effect of emotions. It plays important roles in the regulation of individual behaviours that organize social group dynamics. Read How serotonin shapes moral judgment and behavior Vitamin D and 5-HT I'm a month into the L-methylfolate with the later added amino acids. It's reduced some symptoms quite nicely but it's pricey when I have house expenses. Trp will definitely remain as a useful amino acid for me but I'm keen for more affordable monoamine modulating vitamin options - maybe massive doses of L-methylfolate aren't needed and I can just use a mg/day or something. I also note how much the sun does for me... when I get out there properly "Vitamin D acts not only to induce serotonin synthesis, but also functions at an indirect, molecular-genomic stage to mimic SSRIs and MAO inhibitors" [1] "Fine-tuning serotonin concentrations in the synaptic cleft, vitamin D may be able to steer neurological control of such processes as social behaviour and depression." It is "hypothesized that an association between vitamin D insufficiency and low central serotonin concentrations represents a common denominator in a myriad of neuropsychiatric disorders." How does this apply to health? The core symptoms of ASD fluctuated in severity with changes in serum vitamin D levels in children: high-dose vitamin D3 regimens may ameliorate the core symptoms [2, 3] "...core symptoms of ASD were remarkably improved during the vitamin D3 supplementation period when serum 25-hydroxyvitamin D [25(OH)]D levels reached over 40.0 ng/mL. However, symptoms reappeared after the supplementation was stopped, when serum 25(OH)D levels fell below 30.0 ng/mL but were again improved with re-administration of vitamin D3 after the interruption, when serum 25(OH)D levels exceeded 40.0 ng/mL." Vitamin D supplementation is associated with lower depressive and anxiety symptoms in psychotic illness [4] and addition of vitamin D to conventional antidepressive agents can improve antidepressive effect [5] I was always on the lower end dose when supplementing. A daily vitamin D intake of 1000–4000 IU (25–100 micrograms) should be enough to ensure optimal blood levels for most people [6] Anyone attest to benefits dosing higher? [1] https://www.ncbi.nlm.nih.gov/pubmed/30008960 [2] https://www.ncbi.nlm.nih.gov/pubmed/29629638 [3] https://www.ncbi.nlm.nih.gov/pubmed/27868194 [4] https://www.ncbi.nlm.nih.gov/pubmed/30245372 [5] https://www.ncbi.nlm.nih.gov/pubmed/29460820 [6] https://www.healthline.com/nutrition/how-much-vitamin-d-is-too-much

The recent dietary modification has given me baseline stable state where it feels feasible to attempt simple meditations, started that and try and incorporate that each morning, whereas before the dysregulation was something I couldn't at all over-ride. In SUDs, there is a brain-state shift from a hippocampal and PFC- mediated regulatory state to a more primitive and dysregulated amygdala and insula-mediated state underlying emotion dysregulation Few things I've noticed: Trp influences behaviour along the agonistic–affiliative axis, it regulates the tone of interactions along the axis that runs from agreeable to quarrelsome to overt aggression. Tryptophan - promotes prosocial behaviour. - promotes interpersonal trust. - causes greater sharing and helpfulness, greater perspective taking and emotion recognition. - improves control over antisocial behaviour - It allows regulation of aggression and positive social interactions, as well as emotional processing Serotonergic signalling impacts the two-way interaction between each of the following pairs: mood and social behaviour, mood and cognition, social behaviour and cognition and increases prosocial behaviours - Enhanced serotonergic function might promote effortful control over underlying action tendencies - Enhancing serotonergic function should decrease reliance on habitual, reflexive forms of self-regulation and increase the use of effortful, reflective forms of behaviour regulation - Enhanced 5-HT leads to blunted evaluative responses to both positive and negative stimuli Manipulations of serotonergic tone affect reward [1] and decision making [2]. Depleted states cause one to be significantly more perseverative over choices and (acutely) significantly less sensitive to reward (lower reward magnitude) For me, the impulsive reward chasing loops start to seemingly undergo some changes (serotonin has been proposed as a possible encoder of reward and facilitator of reward extinction): you go from impulsive action to greater conscious choice but it doesn't feel as impulsively rewarding to do things. It feels a little blunting. So those healthy addictions, for me gardening and daily walking, start to feel more effort-driven than impulse driven and require more effort in. If you're not careful, you can become content with inaction. Depletion of 5-HT enhances behavioural and brain responsiveness to aversive signals, while disinhibiting previously rewarded but now aversive behaviours [3]. Dysfunction by the serotonergic system in impulse control disorders reflect inhibitory impairment of the prefrontal cortex [4]. You want 'better'. It has been proposed "5-HT encodes beneficialness, and may signal motivation to either maintain or switch current behaviour, for example displayed by 5-HT’s role in facilitating patience for future rewards" [1] https://www.frontiersin.org/articles/…/fnhum.2017.00484/full [2] http://www.jneurosci.org/content/32/17/5833 [3] https://www.ncbi.nlm.nih.gov/pubmed/18069045 [4] http://europepmc.org/articles/PMC4117279 Imagine, after a long time of not knowing/feeling emotions or self-regulating them, you are now unable to avoid the blunt edges of tough emotions which are, after so long, alien influences. Sadness, anger, disappointment, frustration, boredom, annoyance, confusion, disgust, surprise, anxiety, guilt, shame, embarrassment. There is no more avoidance. Your escape route has gone. ‘Feeling all the feels’ is like being on a furious roller coaster, particularly when your emotional regulation route has always been psychopharmacological. There's not just the array of problems induced by self-medication but also over a decade of often supratherapeutic doses of potent psychotropics/ECT, including over neurodevelopmentally-sensitive timeframes when the prefrontal networks and skills in emotional regulation should have been developing. I'll attest that attempting meditation when all emotional regulation is in tatters and you have pure negative affect is plain frustrating, studies show that greater intact emotional regulation when meditating produces more benefits in affect regulation You can use attentional bias modification: mindfully focus on their breath, or on emotions. Breathing meditation and emotion-focused meditation may constitute effective emotion regulation strategies to deal with negatively valenced emotional states [1] Short meditation [2] enhanced mood (i.e., total mood disturbance, anxiety, and fatigue), cognition (i.e., attention, working memory, and recognition memory), and improved the response to acute stress Simple 13 min meditation [they used Journey Meditation (http://www.journeymeditation.com/) for 8 weeks has been studied. 8 weeks of brief daily meditation relieves feelings of negativity by decreasing levels of mood disturbance. It exhibited a similar range of cognitive benefits as the effects previously reported following longer duration, more intense meditation training If you get through regulating and managing persistent negative emotion, you start to feel the good ones in all their glory too. All of the lovely positive emotions such as; satisfaction, joy, elation, excitement, love, contentment, gratitude, hope, amusement, inspiration, awe, interest. [1] https://www.ncbi.nlm.nih.gov/pubmed/30146138 [2] https://www.ncbi.nlm.nih.gov/pubmed/30153464 The world of emotions Key to this employment of equanimity to reduce emotional reactivity is the intentional cultivation of awareness towards emotional information. I was shutting down that world. "Limiting cognitive elaboration in favor of momentary awareness appears to reduce automatic negative self-evaluation, increase tolerance for negative affect and pain, and help to engender self-compassion and empathy in chronically dysphoric individuals" [1] - cognitive elaboration often automatically triggers negative self-judgments that cannot be voluntarily overridden "Dysregulation of fronto-limbic control regions may lead to maladaptive, ruminative, and egocentric attention contributing to depressive affect. In mood disorders, cognitive control appears to be impaired, there is compromised connectivity between the PFC and limbic regions such as the amygdala. Thus, activating PFC regions in efforts to reappraise negative feelings may backfire, bringing attention to focus on dysphoric mood without a commensurate reduction in the intensity of negative feelings." Instead, you begin observing, describing, acting with awareness, being nonreactive, and being nonjudging. When emotional information is consciously attended, you evoke less of an amygdala response and engaged greater prefrontal cortical resources. By deploying attentional resources to recruit a network that limits habitual elaboration and self-referential narrative "automatic recruitment of temporally-extended, self-referential narrative generation may undergo a form of neural extinction, restoring autonomy to the central executive system and freeing it from its habitual applications For me, some of the skills I'm trying to bolster are: 1. Acceptance of emotional responses (ACCEPTANCE) 2. Engaging in goal directed behavior (GOALS) 3. Impulse control (IMPULSE) 4. Emotional awareness (AWARENESS) 5. Emotion regulation strategies (STRATEGIES) Mindful emotion regulation can be construed as a process of ‘turning toward’ momentary experience - attention is positively directed towards present moment sensation, providing a non-conceptual and non-threatening focus for attention 6. Emotional clarity (CLARITY) Improving the self-regulation of attention might reduce the negative emotionality associated with ruminative thought patterns and the tendency to suppress thoughts, both of which have been associated with craving and relapse in addictive behaviours [2] The development of an attitude of acceptance (i.e. a nonjudging/nonattached view of experiences) could reduce negativity affectivity by reinforcing distress tolerance abilities in relation to several experiences (e.g. craving, stress, anxiety) [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303604/ [2] https://www.ncbi.nlm.nih.gov/pubmed/30216741 Tryptophan and ASD I always had strong affinity for serotonergics but addressing it at the dietary level is so much more sustainably promising for me than other approaches. Trp, B-vitamins and magnesium have been used. While radically boosting prosociality through empathogens is being researched for autism, I feel it often needs to be addressed at a more fundamental and sustainable level. A slow and steady, easily integratable and sustainable induction of mood, emotion and greater prosociality can seemingly be had through safer dietary serotonergic interventions. "Low brain tryptophan availability… could be one of the possible mechanisms involved in the alteration of serotonergic function in autism.” "Serotonergic abnormalities were reported in ASD. Research indicates that the reduced levels of serotonin are correlated with the occurrence of impulsive and aggressive behavior, fatigue, depression episodes, insomnia and increased sensitivity to pain. There is evidence that pharmacological treatment is aiming the reduction of the serotonergic neurotransmission results in worsening of autistic symptoms" [1] "Often, families observe that anxiety and subsequent frustration leading to aggression can be better controlled by administering this supplement on a daily basis. Likewise, more focus and attention may accompany administration of tryptophan" [2] It seems to have quite prominent socio-emotional qualities in the way I'm using it that have not really been researched in ASD "BDNF and tryptophan metabolism appear to take part in the pathophysiology of autism spectrum disorders and their phenotypes." [3] Lower tryptophan and KA levels were characteristics of both childhood autism and intellectual disability disorder. Lower 5-HT synthesis were hallmarks of AS [1] https://link.springer.com/article/10.1007/s11011-017-0045-x [2] http://www.theautismdoctor.com/tryptophan-to-treat-autism/ [3] https://www.ncbi.nlm.nih.gov/pubmed/30033880 It also targets another issue for me: Recent findings suggested the serotonin system may be an effective target for prevention and treatment of mild cognitive impairment “Now that we have more evidence that serotonin is a chemical that appears affected early in cognitive decline, we suspect that increasing serotonin function in the brain could prevent memory loss from getting worse and slow disease progression.” Researchers have tried with limited success to treat Alzheimer’s disease and cognitive impairment with antidepressants such as SSRIs What if it's as simple as tryptophan as a starter? I was skeptical about simple tryptophan, assuming it could worsen pathology through often noted disturbed tryptophan metabolism. L-Tryptophan (TrP) enriched diet protect against memory deficits during physiological aging 5-HT modulates BDNF mRNA levels. TrP significantly elevates the number of 5-HT immunoreactive fibers and this correlated with BDNF increase in the FC and hippocampal region "...enhanced TrP intake and the consequent increase in 5-HT neurotransmission may act as a modulator of BDNF system suggesting a possible mechanism for the protective role of serotonergic system on memory impairment occurring along normal aging process." [1] "data suggest that enhanced TrP intake, and in consequence a potential increase in 5-HT neurotransmission, might be beneficial in preventing age-related detrimental features by inhibition of hippocampal apoptosis." [2] https://www.healio.com/.../serotonin-may-play-important... [1] https://www.ncbi.nlm.nih.gov/pubmed/26444078 [2] https://www.ncbi.nlm.nih.gov/pubmed/27889579 Targeting alexithymia Working through spectrums of emotions and getting some quite pleasant positive ones for once. My emotional world has consistently much improved, as has the range of accessible emotions, I have to learn to put words to them more. Finally looking forward to the new place now that I'm not stuck with such negative unprocessed emotions over-riding me. I like this take. "Alexithymia, a personality trait involving difficulties in identifying and describing one’s own emotional feelings and an externally oriented or concrete thinking style, has been reported to be strongly associated with alcohol misuse" [1] "We argue that emotion processing deficits result in a diminished ability to put words to emotions, or articulate feelings, with the consequence that feelings cannot be acted on with goal directed behaviour, but are instead treated as undifferentiated emotion distress, prompting repetitive compulsive behaviours." In alexithymia, "Instead of dampening amgydaloid activity (and subsequent neuro-endocrine release) in order to identify and label emotion in order to cognitively process, alexythmics may do the opposite. They appear to increase amgydaloid and neuro-endocrine activity, which recruits more automatic, implicit and motoric regions in responding to affective stimuli. Emotion is thus not labelled as a resource to be cognitive processed but almost treated in a compulsive threat or “fight or flight” stimulus; an undifferentiated emotion distress" [2] [1] https://www.jstor.org/stable/10.5406/amerjpsyc.131.1.0041 [2] https://insidethealcoholicbrain.com/2018/07/06/addiction-as-a-brain-disorder-of-emotion-regulation-part-4/

How do you modulate your serotonin system with dietary factors? I wanted to try and address persistent issues at the most fundamental dietary level possible - amino acids, vitamins. I tried some challenge doses with tyrosine and tryptophan and the later seemed to provide the most robust improvements. I keep on top of B-vitamins but assumed tryptophan in dietary protein was going to be enough... I've been abstinent from deleterious things for a long time now but it didn't mean health was improving. I couldn't shift a worsening phenotype of persistent emotional and mood dysregulation, cognitive decline, multiple night time awakenings and poor sleep quality, uncharacteristic uncontrollable verbal aggression (to the point of coprolalia), impulsiveness, intrusive thoughts, obsessiveness and plain dysphoria. SSRIs alone were not getting at the issue sufficiently. Diet, exercise and meaningful activity wasn't stopping the roller-coaster. Studies have found disturbances of tryptophan metabolism and their association with depression in alcoholics. Particularly, a decreased tryptophan ratio to other amino acids competing with tryptophan for brain entry has been investigated - diminished supply of tryptophan would lead to serotonin deficiency and thus contribute to depression in alcoholics Depressed alcoholics had significantly decreased ratios of plasma tryptophan to amino acids sharing with it the same transport carrier into the brain (tryptophan ratio). This ratio has been shown to predict the brain serotonin concentration. It is not presently known whether amino acid modifications disappear after a period of abstinence or persist [1]. Patients who had exhibited violent behavior were observed to have tryptophan ratios lower than patients with no history of violence. Research has demonstrated a robust response to increasing plasma Trp/LNAA ratio, stimulating a significant affective response. Unexpectedly Trp supplementation not only improved central serotonergic functioning but improved the profile of tryptophan metabolism [2]. [1] http://grantome.com/grant/NIH/R01-AA006510-02 [2] https://patentimages.storage.googleapis.com/50/94/8b/2fef42545c61d4/WO2005049012A2.pdf Using the amino acids is not just addressing pathology but providing some vital things: A source of believable hope, when things feel hopeless A source of day-to-day stability and connection to something when other sources of connection are non-existent or volatile A sense of being in control, when things feel out of control A secure quasi 'attachment relationship' to something when these might not elsewhere exist A safe displacement onto healthier behaviours for residual impulsivity and craving A placebo effect synergistic with added active effects. Placebo effects themselves can be potent medicine, as seen in many illnesses, from depression to Parkinson's. Sure it's better to find these things in other ways but it's often the most stable, permanent connection in times of illness and volatility one can find In recovery: “Glutaminergic-Dopaminergic Optimization Complex Therapy”, has been well-researched in many clinical trials and shown to provide gentle activation of dopamine across the brain reward circuitry in abstinence. Additionally, significant increases in resting state functional connectivity have been demonstrated in human and animal models using state of the art resting state fMRI measurements [1] Amino acid based therapies have led to: Improved Physical and BESS (behavioural, emotional, social and spiritual) Scores Reduced craving, relapse rates and enhanced recovery Stress reduction lead to improved sleep, enhanced energy, and improved focus and performance, reduced appetite, loss of unwanted weight, decreased body inches, and enhanced well-being Cognitive processing speeds were enhanced Significant results were observed for weight loss, sugar craving reduction, appetite suppression, snack reduction, reduction of late night eating, increased energy Research is needed regarding the potential for return of well-being in recovery by the gentle induction of “dopamine homeostasis;” balancing serotonergic, endorphinergic, cannabinergic, glutaminergic, dopaminergic mechanisms and restoring healthy brain function and connectivity. While I'm just using simple aminos and vitamins, one such version that has been extensively researched is KB220Z which is composed of the following ingredients: 10 mg (500%) vitamin B6, 15 mg (1,033% of daily value) thiamine, 200 mcg (166%) chromium poly nicotinate, and a fixed dose of synaptose. Synaptose is a combination of amino acids and herbs. The amino acids include L-tyrosine, DL-phenylalanine, L-glutamine, and 5-hydroxytryptophan. The herbs include passionflower extract and a complex containing astragalus, arabinogalactans, N-acetylglucosamine, aloe vera, white pine bark extract, frankincense resin, Spirulina, Rhodiola [1] https://dx.doi.org/10.1080%2F10826084.2016.1244551 What if the serotonergic dimension needs more urgent addressing? I tried L-methylfolate 15mg/day (+B12 1mg) with slight improvements for a short time, then also added some tryptophan [1] to the diet. A few days into adding the Trp and the coprolalia waned, emotional regulation started to return. I started to get malleable non-intrusive thinking again. Mood started to improve. See what happens longer term Folate for Depression, Schizophrenia and Dementia: Folate supplementation may be beneficial for severe mental health problems Folate deficiency seems to be an important contributor for the onset and progression of neuropsychiatric diseases [2]. L-methylfolate addresses hyperhomocysteinemia, lower methylation reactions and tetrahydrobiopterin levels [3]. Brain folate abnormalities causes diminished production and availability of tetrahydrobiopterin (BH4) which is a critical cofactor for the rate-limiting enzymes involved in the synthesis of the monoamine neurotransmitters and may be targeted by L-methylfolate. L-methylfolate should cause, in an over-simplistic framework: -Activation of tryptophan hydroxylase initiates a cascade that leads to the synthesis of serotonin, and -Activation of tyrosine hydroxylase initiates a cascade that leads to the synthesis of dopamine and norepinephrine [1] http://journals.sagepub.com/doi/abs/10.1177/0269881111430744 [2] https://www.ncbi.nlm.nih.gov/pubmed/25939915 [3] https://www.ncbi.nlm.nih.gov/pubmed/27068282 Why L-methylfolate? Many users find it quite effective - some users get quite rapid responses "Within 1 day, I felt like my internal motor that had been idling along at a 5 out of 10 had been turned up to a 10 for the first time in a long time. I had more energy, clearer thoughts, happier disposition..." "I felt better the first day. I feel like normal people feel. I have hope, motivation, freedom. I am completely happy." "Within just days of my first dose, I could fell a huge, positive difference. My mind and speech were clearer, my anxiety was nearly unrecognizable, and I was just plain happy." "...my lows vanished within first week on 15mg/day." "Within one week of taking L-methylfolate, I had absolutely NO anxiety. It was so quiet in my soul that I almost felt anxiety about not having anxiety! It was foreign to me; the steady drip, drip, drip of adrenalin rushing through my system was shut off." "Within 10 days, I felt more alive, motivated, energetic, and at peace then I had EVER felt in my life. " 15 mg eight days ago and I feel absolutely wonderful. Mood is great, anxiety has improved significantly, and I feel so peaceful. My energy level is up, and I feel hopeful and full of life again. I am so relieved and happy I could cry." I am able to finally really smile and laugh. I have not been able to find humor in things for years. I have more of a sense of well being I have more serenity I have an increased amount of time I feel better emotionally and mentally There is some support for the efficacy of both standard folic acid and L-methylfolate as an augmentation agent for depression [1]. The lowest dose of MTHF studied in depression to augment antidepressant treatment is 7.5 mg, roughly equivalent to 52 mg of folic acid. Synthesis of the monoamine neurotransmitters serotonin, dopamine, and norepinephrine is regulated by L-methylfolate, which can cross the blood brain barrier. "Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs" [2]. It shows promise against negative symptoms in psychotic illness [3]. "Clinical improvement in depressed patients treated with an SSRI and l-methylfolate (0.5 to 1 mg) was 30 percent greater than that in matched patients treated with an SSRI only. A systematic review of controlled studies (total N = 247) concluded that folate augmentation (1 to 15 mg per day) enhanced the efficacy of conventional antidepressants." "Does folate supplementation relieve symptoms of depression? A ten-week trial of 127 participants compared 0.5 mg/day folic acid (standard folate) augmentation of fluoxetine to placebo augmentation, and found that folic acid significantly outperformed placebo in terms of treatment response rate (38% vs. 18%) and overall improvement on the Hamilton Depression Rating Scale. However, the advantages for folic acid were not seen until ten weeks into treatment. In a smaller trial, patients with depression or schizophrenia were given either 15 mg methylfolate (equivalent of 7.5 mg L-methylfolate) or placebo in addition to their existing medication regimen. Though hampered by a small sample size (24 depressed patients and 17 patients with schizophrenia), there was a statistically significant benefit on a general clinical outcome scale and there were trends toward a significant benefit on other outcome measures in the six-month study" Administration of MTHF may have significant advantages over administration of folic acid to augment antidepressants in depressed patients who do not respond adequately to their antidepressant treatment. Such patients may or may not be folate deficient, may or may not have the inefficient form of the genotype. "Biomarkers associated with inflammation or metabolism (higher BMI) and genomic markers associated with L-methylfolate synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with L-methylfolate" [4]. "Patients with schizophrenia who take daily folic acid in the form of methylfolate 15 mg together with an antipsychotic may have fewer positive symptoms (e.g. hallucinations and delusions) and fewer negative psychotic symptoms (paucity of thought, social withdrawal) and may respond more rapidly" [5] [1] https://pro.psychcentral.com/l-methylfolate-for-depression-the-real-deal/ [2] https://www.ncbi.nlm.nih.gov/pubmed/23212058 [3] http://www.schizophreniaforum.org/news/l-methylfolate-shows-promise-against-negative-symptoms-schizophrenia [4] https://www.ncbi.nlm.nih.gov/pubmed/24813065 [5] https://www.psychologytoday.com/us/blog/integrative-mental-health-care/201709/folate-depression-schizophrenia-and-dementia Addressing homocysteine and potential B9/B12 deficiencies While I keep on top of B-vitamins generally... Stress can increase homocysteine levels (HCy). Higher levels of hostility were associated with higher levels of homocysteine [1]. People high in hostility are known to report more life stress, it is possible that homocysteine concentrations are elevated among these individuals due to increased stress [2]. Elevated levels of homocysteine have been associated with major depressive illness (and positively correlated with anger and length of depressive episode), bipolar disorder (both during manic and depressive episodes and in euthymic state) and various other mental conditions. "Studies of subjects with a wide range of cognitive functions showed increased plasma Hcy and decreased serum folate and enzymatic cofactors involved in methionine and Hcy metabolism are associated with the risk of cognitive dysfunction" Supplemental use of these vitamins has shown a slowing cognitive decline and also improvement in clinical status in patients with cognitive impairment, particularly in those with high baseline levels of serum Hcy [3]. A high circulating concentration of homocysteine has been implicated as a risk factor for Alzheimer's Disease and its prodromal stage, mild cognitive impairment. Cognitive and psychosocial impairment has been associated with increased levels of homocysteine [4]. While not a specific marker for schizophrenia, hyperhomocysteinemia occurred in our schizophrenia patients with poor social and relational functioning [5]. Elevations of serum homocysteine levels are a consistent finding in addictions. Hyperhomocysteinemia could enhance the substance consumption increasing the severity of craving in a circular self reinforcing mechanism. [6,7] MTHFR variants and smoking behaviour were associated with homocysteine plasma levels [8] Folate deficiency is associated with depression, attention issues, and other neuropsychiatric disorders, along with irritability and behavioural problems. Cerebral folate deficiency has been linked to self-injurious behaviour. In ASD, "In clinic I have certainly seen some very beneficial effects of using the active forms of folate in ASD" [9] Inflammation induced by by low folate concentrations can significantly be attenuated through treatment with appropriate supplementation and result in cognitive function improvement and decrease of peripheral inflammatory cytokine levels B12 deficiency has been "linked to agitation, irritability, negativism, confusion, disorientation, amnesia, impaired concentration and attention and insomnia; while psychiatric disorders that may be diagnosed in patients having vitamin B12 deficiency include depression, bipolar disorder, panic disorder, psychosis, phobias and dementia". B12 deficiency has presented in younger patients with “irritability, regressive behaviour, apathy, crying and truancy” [1] https://news.osu.edu/hostility-anger-linked-to-chemical-that-may-cause-heart-disease/ [2] https://www.ncbi.nlm.nih.gov/pubmed/14724053. [3] https://www.ncbi.nlm.nih.gov/pubmed/29936555 [4] https://www.ncbi.nlm.nih.gov/pubmed/29306698 [5] https://www.ncbi.nlm.nih.gov/pubmed/26017629 [6] https://www.ncbi.nlm.nih.gov/pubmed/28527647 [7] https://www.ncbi.nlm.nih.gov/pubmed/26885351 [8] https://www.ncbi.nlm.nih.gov/pubmed/23285280 [9] http://www.allnaturaladvantage.com.au/home/wp-content/uploads/2014/11/Cerebral-Folate-Deficiency.pdf Addressing serotonergic aspects The emotional dysregulation was intense. It seemed to be hypothetically a very 5-HT deficient state Both fear/terror and anger/rage are here further assumed to be low-serotonergic. Aggression has also been coupled to serotonergic deficit in many studies, supporting the placement of anger/rage on the low-serotonergic side A first approach would involve the administration of tryptophan and/or BH4. Lack of tryptophan in the diet has been linked to decreases in tissue tryptophan and in brain serotonin - changes in tryptophan availability have a direct impact on the rate of 5-HT synthesis Tryptophan enriched diets in animal models have led to increased prefrontal activation, these results seem to suggest that activation of the PFC could be related to a decrease in anxiety/diminishing amygdalar activity and to decrease in depression-related symptoms L-tryptophan has shown efficacy as an isolated substance in the treatment of depressed patients (it lifted the mood of participants and affected the function of brain regions known to be associated with mood regulation), addition of tryptophan to fluoxetine was associated with a greater improvement within the first week of treatment. It also lessened the fluoxetine-induced decrements in slow wave sleep. There were no cases of serious toxicity of the combination; it was very well tolerated overall [1]. Serotonin syndrome resulting from augmentation of antidepressants with L-tryptophan is ‘rare’ It has found use in OCD as an augmentation strategy [2] L-tryptophan was found to be a well tolerated and useful adjunct and standalone antidepressive agent in treatment-resistant unipolar depressed borderline personality disorder patients, with positive effects on sleep, suicidality and social engagement. [3] [1] https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/11022398/ [2] https://www.ncbi.nlm.nih.gov/pubmed/9393391 [3] https://www.sciencedirect.com/science/article/pii/S221296261500036X Trp as a dietary manipulation "Impulsive, violent and suicidal behaviours have repeatedly been shown to be associated with a reduction in serotonergic activity in the central nervous system. Tryptophan supplementation may be most effective in reducing aggression during times of stress. Tryptophan, an essential amino acid, is the dietary precursor to serotonin, and several lines of evidence have suggested that the amount of tryptophan in the diet relates closely to aggressive behavior. For example, rats given a diet almost lacking in tryptophan develop aggressive behavior In a group of depressed alcoholics, those with a history of aggression, including suicide attempts, also had the lowest tryptophan ratios When hospitalized male schizophrenics were given tryptophan, only those patients with high levels of hostility and a high lifetime frequency of aggressive incidents benefited; these patients showed a lessening of hostility and depression, a reduction in ward incidents and improvement on a standardized psychiatric rating scale." Note: A diet high in Trp, but with a large amount of LNAAs (leucine, isoleucine, tyrosine, phenylalanine, and valine), will not result in higher brain Trp levels, and may even decrease Trp uptake into the brain. An intervention rich in Trp relative to other LNAAs (including is needed in order to boost uptake of Trp, and consequently serotonin production, in the brain. It may be more difficult for the prefrontal cortex to control negative emotional responses that are generated within the amygdala under low serotonin, meaning Trp may help [1] Low tryptophan levels may significantly affect the mood and may contribute to anti-social, aggressive and impulsive behaviours [2] Tryptophan metabolism is disturbed in abstinence Experimental lowering of serotonin (5-HT) neurotransmission by acute tryptophan depletion (ATD) induces a transient depressed mood in 50–60% of patients treated with a selective serotonin reuptake inhibitor (SSRI) who are in remission from depression [3]. It has been claimed by some that simple dietary manipulation is not an effective method to increase brain Trp and 5-HT. The effect of an SSRI on extracellular 5-HT are dependent on the nutritional availability of Trp. Moreover, increased availability of TRP affects behaviour in a manner similar to SSRI administration. While caution is advised, it's being explored as an augmentation strategy [4] "...nutritional factors play an important role in the biosynthesis of 5-HT. Increasing 5-HT levels by increasing the availability of TRP might augment the therapeutic efficacy of SSRIs, whereas malnutrition may render patients refractory to SSRI treatment.” Studies suggest long-term effects of dietary Trp on stress responsiveness Acute tryptophan depletion caused a significant decrease in perceived control and increase in interfering thoughts at the time of provocation in OCD. "Successful selective serotonin reuptake inhibitor treatment of obsessive-compulsive disorder may involve the ability of serotonin to switch habitual responding to goal-directed behaviour." and it has been proposed tryptophan or 5-HTP may augment the effectiveness of antidepressants. Trp supplementation seems to improve control over social behaviour in patients and individuals suffering from disorders or behaviours associated with dysfunctions in serotonergic functioning - in healthy humans supplementation seems to promote social behaviour [5]. Review: Effects of tryptophan loading on human cognition, mood, and sleep [1] https://www.cam.ac.uk/research/news/serotonin-levels-affect-the-brain’s-response-to-anger [2] https://www.salubrainous.com/tryptophan-for-alcoholism/ [3] https://www.sciencedirect.com/science/article/pii/S0165032705000182 [4] https://link.springer.com/article/10.1007/s00213-003-1632-6 [5] https://doi.org/10.1016/j.neubiorev.2016.02.022 Part of the fun with effectively bolstering serotonergic activity is that positive beliefs come on line (or feel positively amendable), what were heavy cognitive self-referential processes taper down there's a socio-emotional dimension that comes on line and cognitive/behavioural flexibility bolsters. Studies show that the relationship between the activation of serotonin and subsequent behaviour is highly dependent on the belief about the circumstances [1] Self-referential processing is a key cognitive process, associated with the serotonergic system and the default mode network (DMN). "Typically, depressed individuals endorse more negative adjectives as self-referential than non-depressed individuals. This bias in self-referential processing is also present in individuals who have remitted depression, suggesting that negative cognitive biases persist even when symptoms are no longer evident." "Analytical self-focused rumination (thinking analytically about self and symptoms) is maladaptive - This cognitive style is associated with overgeneral autobiographical memory, global negative self-judgments, greater negative future thinking, and dysphoria." It appears to reflect DMN connectivity which can be modulated by TRP [3] [1] https://www.eurekalert.org/pub_releases/2018-06/oios-wfi053018.php [2] https://www.sciencedirect.com/science/article/pii/S016801021002835X There are a few 'side effects' to Trp While "involvement of 5-HT in rewarding and aversive processing, hedonic experience, mood and higher cognitive functions such as consciousness or self reflection are undisputed" and there seems to be a good level of "contentedness" and mood/emotional regulation... Manipulations of serotonergic tone affect reward [1] and decision making [2]. Depleted states cause one to be significantly more perseverative over choices and acutely significantly less sensitive to reward (lower reward magnitude) For me, the impulsive reward chasing loops start to seemingly undergo some changes (serotonin has been proposed as a possible encoder of reward and facilitator of reward extinction): you go from impulsive action to greater conscious choice but it doesn't feel as rewarding to do things. It's a little blunting. So those healthy addictions, for me gardening and daily walking, start to feel more effort-driven than impulse driven and require more effort in. If you're not careful, you can become content with inaction. Depletion of 5-HT enhances behavioural and brain responsiveness to aversive signals, while disinhibiting previously rewarded but now aversive behaviours. [3] You start to seemingly have a layer of higher order self-reflection come in. You want better choices. It has been proposed "5-HT encodes beneficialness, and may signal motivation to either maintain or switch current behaviour, for example displayed by 5-HT’s role in facilitating patience for future rewards" [1] https://www.frontiersin.org/articles/10.3389/fnhum.2017.00484/full [2] http://www.jneurosci.org/content/32/17/5833 [3] https://www.ncbi.nlm.nih.gov/pubmed/18069045

Do any of the nornicotine dominant Nicotiana have a history of traditional interesting use? I'm trying to suss out the novel tobacco's. I'm sick of relapsing on boring NRT nicotine only. From what I can find, N. tabacum, N, rustica, N. alata, N. langsdorffii all contain nicotine; N. sylvestris and N. rusbyi [N. tomentosiformis] contain nornicotine, while N. glauca contains anabasine. I've used N. glauca cautiously but didn't get heavily into it [covered the potential anti-addictive nature of anabasine in [1]] and the major nicotine containing Nicotianas. I want something different. I want to know what nornicotine is like as a dominant alkaloid? Exploring some cotinine would be neat, the predominate metabolite of nicotine, which has been "shown to reduce depression, anxiety, and fear-related behaviour as well as memory impairment in animal models of depression, PTSD, and Alzheimer's disease." [2]. "Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine." [3] Note: the nornicotine in Duboisia hopwoodii has been stated in one (albeit old) paper to be d-nornicotine contrary to what is found in Nicotiana, which may be more toxic, potentially giving rise to the statement "Twentieth century chemical analysis found that both nicotine and nornicotine, a drug four times as toxic as nicotine, are usually present in Duboisia" [4]. Nornicotine occurs in several species, such as Nicotiana sylvestris and some Australian species [5]. N. sylvestris contained 0.44% alkaloids in one study but in another, had a total alkaloid concentration of 1%, nornicotine comprising 95% of the alkaloids [6]. Another reference [8] gives 4.8mg/g alkaloids, 82.2 % of that being nicotine. Nicotiana langsdorffii contained 0.22% alkaloids, 73% being nicotine, the rest nornicotine [7]. It is the dominant alkaloid in N. thyrsiflora (94.3% of the 5.1mg/g total alkaloids). It is said "The heated leaves of Nicotiana thrysiflora are used for rheumatism." In Nicotiana tomentosiformis, nornicotine makes up 79% of the 1.1mg/g total alkaloids. N. glutinosa contains 7.4mg/g with 77.4% of that being nornicotine [8]. "About 0.8% of nicotine is metabolized to nornicotine in the periphery. However, the biotransformation of nicotine to nornicotine also appears to occur locally in the brain, and brain concentrations of nornicotine have been shown to exceed those in the periphery" [9]. Nornicotine is proposed to result in additional activation of a7-type receptors, which may be important for effects on cognition and attention. Nornicotine inhibits striatal DAT function via a nAChR-mediated mechanism [10]. "The nAChRs mediating the nornicotine-induced inhibition of DAT function appear to be different from those activated by nicotine which increases DA clearance" Both nicotine and nornicotine were relatively potent partial agonists of rat α7 receptors with efficacies of approximately 60% and 50%, respectively, compared with ACh The efficacies of nicotine and nornicotine for α4β2 receptors were relatively low, compared with ACh, although nicotine was rather more potent than nornicotine and ACh. Nicotine was relatively efficacious for α3β4 receptors, although less potent at α4β2 receptors. Nornicotine was a relatively poor agonist for α4β2 and α3β4 receptors. The half-life of nornicotine in brain is 166 min, which is three times longer than that of nicotine (52 min) [1] http://www.shaman-australis.com/forum/index.php?/topic/45354-n-glauca-and-anabasine-as-anti-addictive-agents-some-theory/ [2] https://en.wikipedia.org/wiki/Cotinine [3] https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+8034 [4] https://en.wikipedia.org/wiki/Pituri [5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727613/ [6] https://academic.oup.com/jee/article-abstract/30/5/724/2201756?redirectedFrom=fulltext [7] https://naldc.nal.usda.gov/download/IND43969765/PDF [8] https://www.degruyter.com/downloadpdf/j/cttr.1990.14.issue-6/cttr-2013-0610/cttr-2013-0610.xml [9] https://pdfs.semanticscholar.org/6a2f/0b3328d07bab7dc4bd6164172bcecb9e25b5.pdf [10] https://www.ncbi.nlm.nih.gov/pubmed/17146768 For more nicotine containing plants: For a breakdown of normal tobacco: Nicotiana tabacum Alkaloids 11.462 mg/g Nicotine 94.8% Nornicotine 3.0% Anabasine 0.3% Anatabine 1.9% N. alata is generally very low on nicotine but allows the other non-alkaloid constituents of tobacco's medicine to be explored. N. megalosiphon contained 0.22% alkaloids, 100% being nicotine N. quadrivalvis had in one study a nicotine content of approximately 0.16% in one study. It was the main native tobacco that was once widely cultivated by numerous tribes for medicinal and religious purposes Another reference gives Alkaloids 7.76 mg/g Nicotine 94% One early trier found the such tobacco "very pleasant," adding, "it does not affect the nerves in the same manner..." Nicotiana clevelandii Alkaloids 8.945 mg/g Nicotine 98.5% Nornicotine 0.3% Anatabine 1.2% Thanks @Micromegas

Ethnopharmacology of Love Background: Elixirs conferring eternal youth or inducing amatory and erotic attraction have been searched for without success. Lovesickness is a widespread affliction resulting from unrequited love and/or the impossibility for physical and emotional union. The symptoms are reflections of altered dopamine, serotonin, noradrenaline, testosterone and cortisol levels and range from frenzy and intrusive thinking to despair and depression, sharing traits with the neurochemistry of addiction and compulsive behavior disorder. Although it can seriously impact the quality of life, lovesickness is currently not considered in official disease classification systems. Consequently, no official therapeutic guidelines exist, leaving subjects to seek the cure on their own. Methods: We review literature of the past 2000 years dealing with the concept, diagnosis and the healing of lovesickness and contextualize it with neurochemical, ethnomedical, and ethnographic data. Since neurobiological and pharmacological connections between the love drive and the sex drive exist, we review also the literature about herbal an- and aphrodisiacs, focusing on their excitatory or calmative potential. Results: An overall consensus regarding socio-behavioral regimes exists for dealing with lovesickness from historical through contemporary literature. The herbal drugs used for treating lovesickness or inducing love passion do not possess the alleged properties. The pharmacological effects of aphrodisiacs are heterogeneous, including dopaminergic and adrenergic activities, but there is no evidence for any serotonergic effects. The libido-regulating properties of anaphrodisiacs seem to be associated with sedative and toxic effects or decreasing testosterone levels. CB2 receptors expressed on dopaminergic neurons of the ventral tegmental area, part of the brain’s reward circuit, implicated with addiction, orgasm and strong emotions such as love, might constitute a new therapeutic target. Conclusion: The common food additive and CB2 agonist β-caryophyllene might have the potential to attenuate dopaminergic firing, quenching the reward and thus motivation associated with romantic love. From Greek mythology to modern history, cultural expressions and implications of love, sex and procreation is and was organized along hierarchical lines that put men on top. The neuronal predispositions and activities associated with falling in love will probably forever remain nature’s and Eros’ secret. Copaiba oil, ~50% β-caryophyllene, appears safe orally at low doses An update on the pharmacology of BCP - orally active potent CB2 full agonist and PPARα/γ agonist. - Analgesic, anti-inflammatory, anti-amyloidogenic, insulin-sensitising, anti-alcoholism, anti-cancer, cardioprotective, hepatoprotective, gastroprotective, neuroprotective, nephroprotective, antioxidant, antimicrobial and immune-modulator effects - Exerts anxiolytic and the anti-depressant effects via CB2 agonism - Activates TrkA receptors and induces neuritogenesis by a mechanism independent of NGF or cannabinoid receptors - potent antagonist of α7-nAChRs - exhibits synergy with µ-opioid receptor dependent pathways - Neuroprotection via prevention of microglial activation and inflammatory cytokine and chemokine expression: β-caryophyllene reduced astrogliosis and microglial activation as well as the levels of COX-2 protein and the mRNA levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the cerebral cortex, inhibits pathways triggered by the activation of toll like receptor complex - CB2Rs modulate striatal dopamine release - PPARγ activation prevents the negative emotional effects of stress and exerts anxiolytic actions - CB2 agonists may provide therapeutic possibilities to treat metabolic diseases associated with lipid dysregulation. β-caryophyllene is an attractive molecule with therapeutic potential for the treatment of pain, Alzheimer's disease, anxiety, depression, Parkinson's, schizophrenia, various neurodegenerative conditions, brain injury, diabetes and metabolic disorders

Yeah, feel you on that, sorry to hear things are a struggle for you. I got disconnected again and the only way I've recently been able to reconnect is through plants. It takes my head off the social situation which is hard to manage with anxiety, social anhedonia and not finding common ground etc. Churned out a bunch of Ashwagandha tubestocks through winter that did well in the greenhouse, ready for spring. Joined the local grow free group. I've been forcing myself to connect with new people, even strangers, by giving the plants away. It just makes an awkward social encounter more positive. A reason to try. Just breaking that pattern of isolation through a plant can be potent. You can rebuild some social skills etc. Transfer interests from one domain to another etc

Tomorrow, spike those ketones in the name of a healthy brain experiment and see what I think of it as a "neurotherapeutic" and "promising anxiolytic strategy" [1], see if there are hints of enjoyable prosociality which would be nice. "Use of βHB as an efficient neurotherapeutic relies on increasing blood βHB levels so as to encourage entry of βHB to the brain." [2] The main problem with using βHB as a therapeutic lies in being able to deliver sufficient βHB to the brain, due to the limited uptake of βHB across the blood brain barrier and the difficulty in sustaining high enough levels of βHB in the blood - uptake can be increased by instigation of dietary changes, such as a high fat diet or regular ingestion of medium chain fatty acids. Any keto nuts suggest better (other than ketone esters) than BHB+MCTs? I want to feel it as acutely as possible... Thinking to go from intermittent fasting/low carb to using short term BHB + MCTs as my diet for a bit. Ketone bodies upregulate neurotrophins, reduce neuroinflammation and hyperexcitability, causing potent neuroprotection. They also drive growth and myelination, enhance synaptic plasticity, cognition and neuronal stress resistance, improving learning and memory. Exogenous ketones also improve oxygen utilisation, especially in the central nervous system There are concerns regarding the level of Ca and K provided by supplementing BHB salts, which can rise to toxic levels if excessive doses are administered, so adherence to dose recommendations is required [3] In the body, "Exogenous ketone supplementation causes blood glucose to decrease significantly, likely due to the acute increase in insulin sensitivity. Therefore, exogenous ketones may present a potential therapy for type-2 diabetics via regulation of blood glucose.". "BHB + MCT raises blood BHB levels much higher than BHB or MCT in isolation, with a peak just over 1.30mmol/L. Even more important is that blood BHB levels do not seem to readily fall back to the normal levels of 0.2mmol/L. Even after 8 hours blood BHB levels are 0.5mmol/L, which is over double the normal level, and they look to be only very gradually falling. Blood BHB levels look like they will be elevated for the best part of a day, but the most significant rise being between 1 and 4 hours after ingestion." [4] Consumption of MCTs produces a mild ketosis which has been estimated to contribute up to 8–9% to brain energy metabolism and it is well tolerated. In comparison, "In human tests, 30ml of MCT oil was able to raise blood BHB levels to about 0.55 mmol/L. This is just over half the effect that BHB salt supplementation had. MCT oil supplementation spiked blood BHB levels at just under an hour, and drops to normal levels after 3 hours. Interestingly, BHB levels continue to fall below normal levels of 0.20mmol/L to 0.12mmol/L. The low blood BHB levels show no real indication of normalising after 8 hours." While the low ketone levels generated by MCT supplementation have been demonstrated to partially reverse the memory deficits of Alzheimer’s dementia, exogenous ketones have the potential for greater memory-improving effects, with maximum effect likely occurring at a beta-hydroxybutyrate blood level of 4 mmol/L or higher, the level at which ketone transport into the brain is maximised. Human pilot studies and case studies suggest that ketogenic diet and ketogenic supplement-induced ketosis is a potential therapeutic approach in the treatment of epilepsy, Alzheimer's disease, autism spectrum disorder, and schizophrenia Ketone bodies may exert their effects through modulation of GABAergic, glutamatergic, and adenosinergic system. Administration with no need for energy restriction might also be a promising intervention to improve the neuronal activity and ameliorate the degeneration of CNS. Noted antidepressive and anxiolytic effects It an efficient mitochondrial fuel, improving energy metabolism Enhances GABAA receptor function, upregulates GABAergic activity [may increase GABA concentration], enhances inhibitory glycine receptors Decreases brain glutamate, alters the response of NMDA receptors, L-type Ca2+ channels, reduces neuronal firing rates, mediated in part by Katp channel activity and GABAB signaling It interacts with an inflammasome in immune cells to reduce production of inflammatory cytokines and reduce inflammation. inhibitor of histone deacetylases resulting in upregulation of genes involved in protection against oxidative stress and regulation of metabolism Supplementation with βHB has been shown to extend the lifespan of C. elegans by 20% [1] https://www.frontiersin.org/articles/…/fnmol.2016.00137/full [2] https://www.ncbi.nlm.nih.gov/pubmed/27826689 [3] https://blog.undoctored.com/beware-exogenous-ketones/ [4] https://ketosource.co.uk/exogenous-ketones-how-they-work/ By afternoon, I'm normally crashing in mood, grumpy and tired, not that the morning is much better. I got a paradoxical lift changing my diet for once, but then the typical diet shift anergia kicked in. From a couple of days of IF, gave the BHB salts a whirl. Solid dose, 12g BHB and some MCTs. Really, the ketone elevations offered by even large doses of the salts aren't that huge but "can help your body transition into ketosis with less misery and hunger pangs." potentially. The combo of MCTs and BHB is said to be better for BHB elevations. Beta hydroxybutyric acid is antidepressive and anxiolytic. It enhances inhibitory glycine receptors at concentrations observed in humans clinically. In addition, beta-hydroxybutyric acid enhances GABAA receptor function at these concentrations. Subanesthetic concentrations may contribute to lethargy and impairment of consciousness [1] and has abilities to alter physical properties of cell membranes [2] [1] https://www.ncbi.nlm.nih.gov/pubmed/17717222 [2] https://www.ncbi.nlm.nih.gov/pubmed/23339286 By 45min, there's a very mild energetic lift, wouldn't say much more than MCTs alone. Some restoring energy, stability of mood again and a little potential anxiolysis. Functionally nice as a mild meal tonic. Enough to get another bout of exercise in, which seemed to attune me to it more. It was pleasant exercise. Just a calm, centred functional bit of exercise. Didn't feel so neurotic. Got for another bit of exercise - just level headed. All in all, maybe the BHB salts are useful but not likely to be problematic. It may be therapeutically useful to for the times I crave alcohol (I've now been abstinent quite awhile), "In ethanol dependence, it is suggested the following occurs "energy deficiency (“starvation”) of the brain → stimulation of production of ketone bodies → partial transition of the brain from exclusive using of glucose as the energy substrate to partial use of ketone bodies as such substrate. Under such conditions, the brain begins to be dependent, to a significant extent, on the level of these bodies in the blood, i.e., on the degree of ketonemia. With any decrease in this index, the biological requirement to replenish the amount of these compounds develops. Since rapid synthesis of ketone bodies can be readily initiated by introduction of ethanol into the organism, this organism tries to realize the corresponding behavioral reaction, i.e., to consume alcohol." [1] MCTs themselves compensate for the brain energy deficits in direct proportion to the level of plasma ketones achieved. MCT-fed rats exhibited reduced anxiety-like behaviors and enhanced social behaviour [2] Data on the neuroprotective capacity of MCT-derived medium chain fatty acids (MCFA) suggest 8-carbon and 10-carbon MCFA may have cognition-enhancing properties which are not related to ketone production [3] [1] https://link.springer.com/article/10.1007/s11062-016-9596-4 [2] https://www.ncbi.nlm.nih.gov/pubmed/29908242 [3] https://www.ncbi.nlm.nih.gov/pubmed/27517611

Recently got into the fasting. I like the mood stability and uplift. Firstly has anyone used the commercial 'BHB exogenous ketone' salts and got an acute nice noteworthy mood reaction? There are commercial βHB salt products - quite pricey - but I want to know if anyone has heard of the cheap ketone esters, particularly super cheap (and fragrant!) ethyl acetoacetate, being used safely orally? I'm not going to slack off using will power to fast for my added uplift but I'm curious... it could be quite nice as an acute quite enjoyable mood lifter. Is it the βHB, or is acetoacetate a nice mood lifter? Ketones, particularly BHB, upregulate GABAergic tone but are they 'enjoyable' acutely orally administered? "...researchers don’t know the exact cause of these [euphoric] feelings. Acetoacetate, acetone and BHB, or any of their metabolites, may all be involved, as well as the effects of low blood sugar, which can cause euphoria and giddiness." People felt remarkably well, and experienced a mild intoxication: not dissimilar to the effects of ethanol. Bloom speculated that acetoacetate had caused the inexplicable jubilation. [1] Aside from acute prosocial anxiolytic effects which I deem as an important therapeutic area to address in many conditions, I'm also primarily looking for sustainable better health in my life, as are many people with epilepsy, Alzheimer's disease, autism spectrum disorder, and schizophrenia etc. My intermittent fasting is proving interesting, mood stabilising and uplifting in conjunction with other measures, pushed that quite a bit but it's personally not sustainable to run an extreme 'deprivation diet'. Just skipping breakfast and healthy meals at the other times with my exercise is probably my best bet. There are a few suggestions on ways to stay in a fasting state during IF [1]. Caved in and thought I had to try the most economical βHB salts, to get a gauge on it's effects. Probably get around to doing some trials with that this week. It is suggested elevations of β-hydroxybutyrate may partly mediate the beneficial effect of IF in CNS conditions. "Brain BHB concentration increased from a nonfasted level of 0.05 +/- 0.05 to 0.60 +/- 0.26 mM (after second day of fasting), increasing further to 0.98 +/- 0.16 mM (after the third day of fasting)" [2] While βHB salts or other supplements "aren’t a great fat loss tool – they’re simply ways of increasing your blood ketones" and increase energy in, I'm more generally looking for the therapeutic benefits of ketones on the brain for the moment. Both would be nice - I'm getting really good kJ intake reductions and maintaining my exercise so hoping. Unfortunately, with exogenous ketone administration, blood βHB reached low levels (<1 mM) and a high amount of salts, consumed βHB, was required to achieve ketosis. That said, this is still roughly equivalent to three days of fasting. That said, gastrointestinal symptoms were reported in a large number of participants. βHB has antidepressant and antianxiety-like effects and results in modulation of multiple systems, including GABA, Glu, adenosine, neurotrophic etc and even in the presence of glucose exerts beneficial CNS effects, also exerting epigenetic effects (β-hydroxybutyrate is a HDAC inhibitor). Dietary ketone salts are often racemic mixtures of the two optical isoforms of βHB, despite the metabolism and actions of L-βHB being poorly understood ~12 or ~24 g orally administered ketone salts elevated D-βHB concentrations (D-βHB Cmax 1.0 mM) which returned to baseline within 3–4 h. [3] [Another study found 0.5 g/kg bw at 2 h elevated D-βHB, with a mean value of 0.598 ± 0.300 mM [4], 0.38 g/kg bw caused only a rise to 0.3-0.4 mM βHB in trained athletes [5]. The ketone salts contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h. L-βHB is still neuroprotective but not much is known about it's CNS effects More cheaply, one can increase βHB in the brain 90 minutes after ingesting coconut/MCT oil, which improved paragraph recall in adults with impaired memory. Preliminary studies also show ketones can improve working memory in both young and old subjects [1] http://siimland.com/what-breaks-a-fast-while-intermittent-fasting/ [2] https://www.ncbi.nlm.nih.gov/pubmed/11043913 [3] https://dx.doi.org/10.3389%2Ffphys.2017.00848 [4] https://www.ncbi.nlm.nih.gov/pubmed/29850235 [5] https://www.ncbi.nlm.nih.gov/pubmed/29966721 "Conversion of ketone bodies (KBs) to ketone esters (KEs) eliminates KB acidity, making the KEs suitable vehicles for the delivery of KBs to the blood circulation via the gastrointestinal route. Ingestion of KE can directly increase plasma KBs to levels within the range achieved during fasting. The degree of KB elevation attained is readily controlled by the dose size Studies have demonstrated that orally or intravenously administered 1,3-butanediol or glycerol esters of βHB are safe and well tolerated in animals and that the orally administered 1,3-butanediol monoester is also safe and well tolerated in humans" [2] While 1,3-butanediol esters are ideal as they are readily metabolised in a manner similar to ethanol without the deleterious effect of ethanol metabolism, with subsequent conversion to βHB and, eventually (at the peripheral tissue level), to AcAc, I'm curious if ethyl acetoacetate might be healingly enjoyable orally administered? While using diet is superior for weight loss than supplementation, there are a few people talking of acute βHB effects @12g of the salts: "...there was an unmistakable uplift in mental clarity, mood and energy. This continued for a number of hours. The energy & focus was clean" It seems βHB is nicely anxiolytic in studies but maybe not intoxicating, the anxiolysis correlated with increased level of βHB . Human pilot studies and case studies suggest that ketogenic diet and ketogenic supplement-induced ketosis is a potential therapeutic approach in the treatment of epilepsy, Alzheimer's disease, autism spectrum disorder, and schizophrenia. Ketone bodies may exert their effects through modulation of GABAergic, glutamatergic, and adenosinergic system It has also been demonstrated that administration of exogenous ketone supplements (normal food + ketone supplements and/or medium chain triglyceride/MCT), such as ketone ester (KE), ketone salt (KS) or their combination with MCT oil (e.g., KSMCT) induce rapid and sustained nutritional ketosis https://www.frontiersin.org/.../10.../fnbeh.2018.00029/full "Administration with no need for energy restriction might also be a promising intervention to improve the neuronal activity and ameliorate the degeneration of CNS" [6] Just curious, couldn't spot it done anywhere... From risk assessment of Ethyl Acetoacetate Acetoacetate is an endogenous product of accelerated fat metabolism. Absorption of ethyl acetoacetate via the oral route is demonstrated in animals It may be anticipated that ethyl acetoacetate is partially cleaved already in the gastrointestinal tract due to acidic pH values or by bacterial activity. In a first metabolic step the absorbed portion of ethyl acetoacetate will be hydrolysed into 3-oxobutanoic acid and ethanol by the unspecific esterases of the blood. The acid moiety is an endogenous product within the lipid metabolism and is further metabolized predominantly to carbon dioxide and water; ethanol will be metabolized on known pathways. In animals, acute toxicity by the oral, dermal, and inhalative routes is low as judged by tests with rats. The substance demonstrated no or only mild skin irritation and mild eye irritation in tests with rabbits. Valid human or animal data on sensitization are not available. Following repeated oral exposure of ethyl acetoacetate in rats, no treatment-related adverse effects (including haematology, clinical chemistry, gross necropsy and histopathology) were reported up to 1,000 mg/kg bw/d. Note: Levels above 10 mmol/L of ketone bodies are associated with ketoacidosis.