S-Adenosyl Methione (SAMe) is a methyl-group donor in the biosynthesis of hormones, neurotransmitters, nucleic acids, proteins, and phospholipids.[4] SAMe is sometimes also referred to as Ademethionine.
1.1. Endogenous Regulation
SAMe is involved in the latter stages of the regulatory pathway involving folic acid (Dietary Folate) and cobalamin (Dietary B12). Folate converts to 5-methyltetrahydrofolate (5-MTHF; bioactive folate) which converts circulating homocysteine back into the amino acid methionine (a process that uses Vitamin B12 as a cofactor to proceed in); L-Methionine then binds to an Adenosine group from ATP to create S-Adenosylmethionine (SAMe), which is used to donate methyl groups to a variety of reactions that degrade SAMe into S-Adenosylhomocysteine to be fed back into the aforementioned cycle (after dissociating from Adenosine to become Homocysteine once again).[4][5] This cycle is sometimes referred to as the one-carbon cycle.
SAMe is involved in a methylation cycle with Folate and B12, and serves to travel around the body to donate methyl groups to allow other bodily reactions to proceed
In regards to other compounds of the one-carbon cycle after supplementation of SAMe, it appears that when 400mg of SAMe is supplemented and raises plasma SAMe by 9.6-fold (Cmax values, as AUCs were weighted and may be misleading) that increases also occur in 5-MTHF (1.95-fold) and S-adenosylhomocysteine (2.9-fold) yet both Homocysteine and Methionine are unaltered.[6] No increase is seen either with 800mg over 4 weeks.[7]
May influence other compounds in the one-carbon cycle, but not homocysteine
1.2. Deficiency and Excess (Correlations)
SAMe tends to be regulated in the serum within a wide range of 60-120nmol/L (24-64ng/mL).[8]
Relative deficiency states (when circulating levels are found to be less than the above physiologically maintained range) are seen in patients with depression (averaging 44+/-25nmol/L)[9] and in persons with HIV suffering from depression[10] and more severely with pnemonia (4nmol/L).[11] Lower than normal serum levels have also been noted in a subset of persons with Dementia that are specifically undergoing Alzheimer's Disease.[12]
One study in controlled diabetics undergoing various stages of nephropathy (pathology of kidney failure associated with diabetes) noted that the normal relationship between SAMe and 5-MTHF were dysregulated (mostly in advanced cases of nephropathy) and that serum SAMe decreased inversely to a rise in S-adenosylhomocysteine.[13]
SAMe levels in serum appear to be lower during depression, and may be lower in HIV infected individuals
Schizophrenic patients tend to show higher than normal SAMe levels in serum[14][15] with one intervention quantifying serum levels of 16 Schizophrenic patients (using antipsychotic medication) at 255.4-273.8ng/mL (+/-52.1 to 71.8 variance), with subsequent supplementation causing further increases.[16]
One study on elderly persons with a cobalamin deficiency has noted elevated SAMe as a clinical sign, which is accompanied by elevated S-adenosylhomocysteine, Methylmalonic acid, and Homocysteine; these abberations were normalized after cobalamin treatment.[17]
Some situations are associated with than normal serum SAMe levels, such as Schizorphenia and cobalamin deficiency
Men appear to have a significantly higher erythrocytic SAMe level than do women without supplementation.[18] Women may experience a quicker plasma peak of SAMe after oral administration when compared to men, currently unknown as to why this occurs;[19] it is possibly related to lower serum levels of SAMe at baseline observed in women relative to men.[20]
Some gender differences as it pertains to SAMe in the body and in response to supplementation
1.3. Stability
SAMe is produced biological in the S/S form, and can convert into an R/S form passively over time (both appear to be biologically active, but differently so[21]) and the pure S/S form racemizes into an equilibria of S/S and R/S in equal parts.[22] It is contested as to whether or not this equilibria matters practically, but some studies suggest that S/S is the biologically active form in regards to methyltransfering[23][24][25] while R/S acts to inhibit methyltransferase actions.[26]
At least one study exists where a reduced potency of SAMe was noted during the study, and a new shipment needed to be achieved; the authors thought conversion to R/S may play a role, but did not perform analysis to confirm.[27]
It is possible that, over time, SAMe may lose its potency secondary to degradation of the active component into a less active form
2.1. Bioavailability
Conventional forms of SAMe appear to have a bioavailability of 0.5-1.0% after oral ingestion without enteric capsules, thought to be due to poor intestinal permeability.[28] This study based these conclusions on intestinal and hepatic cellular uptake rates.[28]
SAMe at 100mg given as a tosylate disulfate salt (enteric capsules) appears to have enhanced bioavailability of 2-3%.[29]
Appears to be poorly absorbed in the intestines
2.2. Serum
400mg or SAMe orally (in the form of AdoMet bis(sulfate)-p-toluenesulfonate) in 14 otherwise healthy persons can elevate plasma levels from 38+/-13.4nmol/L to a Cmax of 361.8+/-66.4nmol/L at a Tmax of 4.3+/-0.3 hours.[6] The weight adjusted Area-Under Curve (to account for baseline levels) in response to nothing (control) was 6.8+/-2 while 400mg AdoMet gave an AUC of 194.8 +/- 41.3nmol/L/h,[6] and SAMe appears to have a half-life of 1.7+/-0.3 hours in otherwise healthy persons when at 400mg.[6]
In healthy persons give an acute dose of 1000mg of SAMe (16.8+/-1.3mg/kg) in a fasted state (tosylate disulfate salt) notes a Cmax of 2.37-2.50umol/L (+/-1.58-1.83) at a Tmax of 5.2-5.4 hours.[29] AUC24h was 8.56+/-5.16 and 10.3+/-8umol/L/h in men and women respectively, which is thought to be due to differences in body weight; a half-life of 6.06-6.2 (+/-1.8-2.6) hours was noted.[29]
There appears to be a dose-response in SAMe elevation of plasma concentrations, with oral supplementation able to increase serum SAMe above normal concentrations in healthy persons
After repeated dosing of 1000mg SAMe, the Tmax of SAMe in serum appears to decrease nonsignificantly from 5.3+/-1.25 hours after the first dose to 4.20+/-1.87 hours after 5 days.[29]
2.3. Distribution (Serum, Cellular)
SAMe has been noted to effectively cross the blood-brain barrier after intravenous administration.[12]
It has been noted that binding of SAMe to serum proteins is negligible.[30]
Does not appear to bind to serum proteins
On the level of the cell, transport of SAMe across the cellular and mitochondrial membrane does not occur passively but occurs via a high-specifity transporter[31] of the Folate Biopterin Transporter (FBT) family.[32] This transporter (SAMC, encoded by the SLC25A26 gene) is saturable, inhibited by S-adenosylhomocysteine,[33] and although mRNA for this transporter is expressed at relatively equal amounts in the liver, brain, heart, lungs, kidney, and skeletal muscle it has 7-fold higher expression in testes and slightly lower levels in the spleen (relative to liver); these may not necessarily reflect transporter activity.[31]
SAMe has its own cellular transporter known as SAMC
2.4. Excretion
Clearance rates of 3.7+/-0.5 and 3.1+/-0.2mL/min for intravenous injections of 100mg and 500mg SAMe (respectively) have been noted in healthy volunteers.[30]
One study administering 1000mg SAMe orally in otherwise healthy persons each morning for 5 days, with measurements on the first and final day, failed to note any apparent build-up effect of SAMe over time.[29]
3Interactions with Neurology
3.1. Acetylcholine
SAMe can convert Nicotinamine into N-methyl-nicotinamide (NMNA) via Nicotinamide N-methyltransferase, NMNA which can prevent choline efflux from the brain and neurons.[34] Additionally, some in vitro studies have suggested increase acetylcholine muscarinic receptor density following SAMe administration to both young[35] and old rats.[36] These two mechanisms may underlie the importance of SAMe in regulating cholinergic function in the brain,[37] and may underlie possible therapeutic effects to Alzheimer's Disease.[38]
3.2. Depression
SAMe is thought to be related to depression due to being an intermediate of the one-carbon cycle (abnormalities in this cycle in general tend to be associated with depression[5][39] and folate deficiencies appear in 10-30% of depressed persons[40]) while low SAMe levels have been noted in cerebrospinal fluid of depressed persons[12] and a positive correlation existing between the degree of depressive improvement and an increase in serum SAMe levels when using other anti-depressant drugs.[9]
Some abnormalities have been noted in the enzyme methionine adenosyltransferase which manufacters SAMe in the body in depressed schizophrenic patients while not being noted in manic counterparts at certain times, suggesting a link to depressive disorders.[41][42][43]
Due to positive correlations with well-being and SAMe (with lower levels associated with depression and higher levels not associated with depression) SAMe has been investigated for usage in Depression; the above results only note correlation however, and not causative roles
A review of trials assessing oral doses of SAMe between 200mg and 1600mg notes that they appear to have similar efficacy to Tricyclic Antidepressants (a currently outdated pharmaceutical option for depression) and more effective than placebo,[4] these conclusions were again reached in a later meta-analysis of trials.[44] When assessing brain-wave function of infusions of SAMe in otherwise healthy indivdiuals, the result of SAMe infusion is similar to that observed with imipramine and with TCAs.[45]
In regards to speed of onset, a review of trials[46] notes that SAMe has been associated with some improved depressive symptoms in a few days when standard Tricyclic Antidepressants took up to two weeks (although this study used parental),[47] and that the addition of SAMe to TCA therapy improved the rate of which persons reported a bettering of symptoms.[48]
By itself, SAMe appears to have some degree of efficacy in treating depression that rivals the efficacy of Tricyclic Antidepressants
One study has been conducting investigating SAMe at 1600mg daily (two divided doses) as adjunct therapy alongside SSRIs for 6 weeks and found that improvements in depressive symptoms as rated by HAM-D (rating scale) improved from 17.6% to (a reported) 36.1% and remission rates were improved from 11.7% to (a reported) 25.8%;[49] these numbers were noted elsewhere to be miscalculations[50] and were actually 46.1% and 35.8%, respectively. This study suggested efficacy for SAMe in SSRI-resistant populations (although it was not a mandatory inclusion criteria), and side-effects were not different between groups which were mixed gender.[49] This study was built off of a previous pilot study where augmentation of SSRI therapy in non-responders or partial-responders was noted with 800-1600mg SAMe.[51]
One of the few nutritional supplements to be found to augment SSRI therapy, alongside creatine supplementation
A 12-week double-blind subsample of another study of people with major depressive disorder found a significant effect for 1600-3200mg SAMe daily compared to placebo and also superior to 10-20mg escitalopram at weeks 2,4, and 6, but not weeks 8-12 as the escitalopram arm experienced a slow but steady improvement over time which eventually caught up with the SAMe arm.[52] Response rates (defined as a 50% or greater reduction in HAMD-17 score) were 45% of the SAMe group, 31% in the escitalopram group, and 26% in the placebo group.[52]
SAMe may be similar to an SSRI (escitalopram) in efficacy for up to 12 weeks.
In studies on non-depressed individuals where depressive symptoms are measured, 800mg of SAMe for 8 weeks in Schizophrenics was unable to influence depressive symptoms any more than placebo (baseline serum SAMe within normal range).[16]
3.3. Schizophrenia
One studynotes that SAMe at 800mg daily for 8 weeks (doubleblind) in addition to standard antipsychotic medication was able to improve quality of life (QLS rating scale) and reduce aggressive behaviour (assessed by Overt Aggression Scale) in a subset of Schizophrenic patients with low-active Catechol-O-Methyltransferase (COMT) activity; placebo noted a 43% decrease while SAMe noted a 77% decrease, but high variability was also noted.[16] A low-active COMT enzyme polymorphism (158met) is associated with aggressive behaviour in Schizophrenia[53][54] and the authors hypothesized that these effects were due to increased COMT activity from methylation, but aside from baseline genotyping there was no assessment of COMT although SAMe had an decrease in serum catecholamines.[16]
3.4. Parkinson's Disease
A small (n=11) of depressed persons with Parkinson's disease noted that variable doses of 800-3600mg SAMe for 10 weeks was associated with highly significant improvements in depression as rated by the Hamilton Depression Scale, with 10/11 patients reporting over 50% improvement and the average score dropping from 27.09+/-6.04 to 9.55+/-7.29 (65% improvement).[55] This study was unblinded.
3.5. Cognition
1600mg oral SAMe daily in two divided doses of 800mg in otherwise healthy adults (25.2+/-0.8yrs) noted that both phosphocreatine (bioactive form of creatine) were increased by 9.2+/-3.3% while beta-nucleoside levels (of which includes ATP) were decreased by 7.9+/-3.6%; no changes were noted with inorganic phosphate or pH.[20] These effects as similar to those seen with 31P MRS studies on creatine supplementation, and may be due to SAMe donating a methyl group to Guanidinoacetate (GAA, precursor of Creatine) to accelerate its synthesis.[20]
In otherwise healthy young adults, SAMe may have benefits similar to those seen with creatine supplementation in the brain
One trial in persons with depression who failed to respond to SSRI therapy taking 400mg SAMe twice a day (800mg total) for two weeks with a doubling of dose (1600mg) for the next 4 weeks noted significant improvements in memory recall and a trend towards enhanced word finding as assesssed by a cognitive and physical symptoms questionnaire (CPFQ).[56] This study failed to note significant benefits to focus, mental acuity, wakefullness, or ability to focus.[56]
May have weak cognitive enhancing effects in depressed persons, which tend to be more prone to cognitive deficit
In a study (double-blind crossover) testing either 400mg or 1600mg SAMe for 15 days in otherwise healthy elderly persons (57-73yrs) noted that the higher dose was associated with drowsiness 6 hours after consumption which may have preceded the reduced performance in numerical memory; 15 days of consumption of 400mg was associated with elevated mood but reduced numerical memory.[57]
Mixed results in otherwise healthy and non-depressed older persons
4.1. Endothelial Function
After controlling for Homocysteine concentrations (known to be adversely correlated with endothelial health) and other cardiovascular risk factors, SAMe levels in serum as well as 5-methyltetrahydrofolate (5-MTHF) are positively related to blood flow and smooth muscle function with high SAMe being associated with better blood flow and low 5-MTHF being associated with lower blood flow.[58] This study assessed and divided 608 persons into tertiles and compared the highest and lowest tertiles of SAMe against each other.[58]
This apparent association is not explained by Nitroglycerin-mediated dilation,[58] a test that reflects smooth muscle function.[59]
4.2. Homocysteine
A study conducted in otherwise healthy individuals administering 800mg SAMe daily for 4 weeks failed to find a significant increase in plasma Homocysteine levels nor high sensitivity C-Reactive Protein.[7] A case study from this study that had elevated homocysteine levels at baseline (13.1umol/L) actually experienced a decrease at the end of the study by 19%.[7]
One study investigating, retroactively, whether SAMe was associated with increases in serum Homocysteine (known to be a risk factor for cardiovascular incidents) noted that SAMe treatment was not associated with an increase in Homocysteine from baseline to the end of the trial; this study did note significant differences between groups (SAMe and placebo) at baseline, which limits conclusions.[60] Administration of 1600mg daily for 4 weeks also failed to increase homocysteine, although a small (and deemed insignificant) increase in formaldehyde was noted in a few subjects tested.[61]
Supplemental S-Adenosylmethionine does not appear to influence serum Homocystine levels significantly
5Interactions with Skeletal Muscle
5.1. Fibromyalgia
Fibromyalgia is a non-specific pain disorder of the musculoskeletal system (muscles and skeleton), sometimes accompanied by disturbances in sleep and stiffness/fatigue. One pilot study using 200mg Intravenous SAMe noted improvements in mood parameters and ratings of muscle tenderness in Primary Fibromyalgia[62] and benefits with intravenous SAMe have been replicated.[63] These results were followed up with an oral SAMe (800mg) double-blind trial on Primary Fibromyalgia (Fibrositis) where highly significant benefits were seen to tenderness, some benefit to morning stiffness, and no apparent benefit over placebo for muscular strength over 6 weeks and independent of other medications.[64] This study also noted significant improvements on self-rated soreness and fatigue (via 5-point VAS) with a trend to benefit overall well-being and no apparent benefit to sleep disturbances.[64]
Overall, one review on the subject matter noted that there is weak evidence for the reduction of Fibromyalgia symptoms with SAMe treatment,[65] ranking higher than NSAIDs while lower than SSRIs.
Appears to be some efficacy for Fibromyalgia, but no comparative studies nor replicated oral studies for assessment of 'how' effective it is
6The Liver and Hepatology
6.1. Fatty Liver and Cirrhosis
SAMe is investigated for its role in the liver due to steatohepatitis (fatty liver) being associated with reduced rates of the one-carbon cycle and subsequent methylation in the liver.[66] Additionally, SAMe appears to be able to normalize levels of Glutathione in measured erythrocytes (red blood cells) after IV administration;[67] Gluthione of which is abnormal during liver damage due to modifications in sulfur metabolism[68] and serves to protect the liver from damage.[69]
One large multicenter study noted that treatment of persons with cirrhosis of the liver over 2 years with 1200mg SAMe daily was able to reduce the rates of liver tansplantation or death form cirrhosis from 29% to 12%; more benefit was noted in persons with less pathology of cirrhosis compared to late-stage cirrhosis.[70] The difference actually failed to reach statistical significance when the 8 subjects (out of 123) with late-stage cirrhosis were included in the analysis.[70]
6.2. Liver Enzymes
One study in 52 healthy persons given 800mg SAMe for 8 weeks recorded a slight increase in serum ALT that was notable in magnitude (22%) but statistically insignificant (P=0.29).[7]
In persons undergoing chemotherapy who subsequently experienced liver toxicity, SAMe supplementation was associated with an attenuation of liver enzymes (AST, ALT, LDH) that were increased in response to toxicity; it did not appear to interfere with the goals of chemotherapy in this unblinded pilot study.[71]
6.3. Cholestasis
One study using 1000mg of intravenous SAMe noted that, in comparison to standard Ursodeoxycholic Acid (UDCA; 750mg) oral therapy for pregnancy-related cholestasis, that over 12 days prior to deliver SAMe underperformed relative to UDCA but combination therapy led to faster improvements (without significantly affecting magnitude).[72]
A more practical intervention (less than 36 weeks of gestation) using oral SAMe at 1000mg (divided into two doses) compared against 600mg UDCA (two divided doses) noted no significant differences in clinical signs of pruritis but UDCA again outperformed SAMe in reducing serum bile acids, bilirubin, and liver enzymes.[73] Oral administration of both agents also shows additive effects, similar to the aforementioned intravenous SAMe study,[74] and at least two studies note no significant improvements in cholestasis in pregnant women following oral consumption of SAMe.[75][76]
Appears to be somewhat effect at attenuating the effects of cholestasis in pregnant women, but routinely underperforms relative to Ursodeoxycholic Acid (UDCA). Improvements in pruritis seem similar though, and therapies are additive
6.4. Viral Responses
Pegylated IFNa is a medication sometimes used in treatment of Hepatitis C infections during the early stages of infection, due to the importance of IFNa in the virological response; methyl donors such as SAMe and betaine (derivative of choline) appear to enhance signalling of IFNa to the nucleus via JAK-STAT[77] since the virus itself overexpresses Protein Phosphatase A2 (PP2Ac)[78] which suppresses PRMT1 (a molecule that preserves the action of STAT1 in the JAK-STAT pathway via methylation[79]); adding other methyl donors is thought to circumvent this inhibition[77] and in a pilot study on persons with Hepatitis C where there was initially only 14% of persons achieving an early virological response SAMe at 1200mg (and betaine at 6g) was able to enhance this number to 59% when paied with IFNa/ribavirin standard therapy, but did not significantly benefit the sustained virological response (10%).[80] Another study on this topic notes that 53% of persons were able to sustain an early virological response following 1200mg SAMe in isolation with 48% of previous nonresponders experienced no detectable HCV mRNA after 48 weeks when SAMe was combined with standard therapy.[81]
Due to its methyl donor properties, SAMe may have a role as adjunct therapy for Hepatitis C
6.5. Interventions
One study using 1200mg SAMe (400mg for three doses) daily for 24 weeks in person suffering from alcoholic liver disease (temporarily forbade from alcohol) failed to find any difference in bilirubin, ALP, AST, or ALT; this study also failed to note alterations in serum SAMe.[82]
7Immunology and Inflammation
7.1. Osteoarthritis
One large multicenter study (n=734) consisting of rheumatologic and orthopedic clinics of knee and hip osteoarthritis noted that 1200mg SAMe (400mg thrice a day) was as effective as 750mg Naproxen when measured at 30 days, but not at 15 days; at 30 days SAMe was significantly better than placebo.[83] When rating the following on a scale of 1-4, improvements at 30 days were noted functional limitations (24% improvement from baseline), diurnal pain (40%), and standing up from a seat (23%).[83]
In comparison to Celecoxib (selective COX-2 inhibitor for treatment of osteoarthritis), SAMe appears to be as effective as Celecoxib on pain control, swelling of the knee, and functional movement after 2 months of treatment, but not one month, when dosed at 1200mg taken twice daily at 600mg.[27]
Two meta-analysis' have been conducted on SAMe on Osteoarthritis that have found comparable effects to Ibuprofen[84] or pooled studies on 'NSAIDs'.[84][85] The meta-analysis from Soeken et al.[85] builds off a 1987 meta-analysis which, although it investigated 12 trials of over 22,000 persons, found benefit with SAMe but was heavily influenced by 97% of patients participating in an open-label design.[86] It found that the benefit of SAMe on Osteoarthritis relative to placebo (on an assortment of 11 studies with average Jadad score of 87.5%) was highly significant for 1,442 subjects when it came to improving functional movement (Effect Size of .31 and 95% CI of .099-.520) but only trended towards being significant on reducing pain when paired against placebo with no significant differences when compared to NSAIDs.[85] This meta-analysis noted that most studies used thrice daily dosing of 400mg (totalling 1200mg) with 3 studies using 600mg and one using 400mg and also noted that the dropout rate from studies using NSAIDs (6.9%) was significantly higher than with SAMe (2.6%) which was said to be due to less side-effects.[85]
A Phase IV trial in persons over 18 with Osteoarthritis comparing the effects of SAMe (1200mg in three doses) against the established drug nabumetone (1000mg) for 8 weeks noted that there were no significant differences in pain relief, rescue medication usage, side-effects, or withdrawal from the study.[87] Pain at baseline was rated 56.6+/-15.2 (on a possible rating scale of 100 on a Visual Analogue Scale) with reductions to 49.4+/-19.1 (13% reduction) at week 4 and 44.2+/-22.5 (22% reduction) at week 8.[87] There were some differences in pain at week 4 in favor of Nabumetone in regards to pain and this apparent delay has been noted in studies comparing SAMe to Naproxen[83] and the COX-2 inhibitor Celecoxib;[27] this suggests benefits with SAMe to rival pharmaceutical options may take up to 8 weeks to be of effectiveness.
In studies assessing SAMe against placebo, SAMe treatment at doses between 400-1200mg appear to be significantly better than placebo at improving limb functionality and reducing pain in persons with diagnosed Osteoarthritis; with more relative efficacy towards functionality
In comparative studies, SAMe is of similar potency to a variety of pharmaceutical options of Osteoarthritis (Nabumetone, NSAIDs, Naproxen, Celecoxib) although it appears to take a longer period of time to 'kick in', from 30-60 days after the start of taking SAMe
8Interactions with Hormones
8.1. Testosterone
Methylation in the testes appears to be important for testosterone product per se, as impairment of methylation in vitro (using S-Adenosylhomocystine) reduces the effects of Luteinizing Hormone (LH) stimulated androgen production by 48% (while incubation with SAMe increases activity 28%), which appears to be through modulating the amount of surface receptors for LH.[88]
Testosterone itself appears to beneficially influence SAMe production and utilization in the body (assessed by mouse studies), where in the kidneys (not observed in liver tissue) testosterone can increase SAMe content via inducing the S-Adenosylmethionine synthase enzyme;[89] the rate-limiting enzyme for SAMe production.[90] This enzyme is regulated in prostate and seminal tissues as well,[91][92] where orchidectomy (removal of testicles) can reduce levels of SAMe synthase by 34% after 3 days and further decreases after a week but is preserved with low-dose testosterone injections.[93]
Testosterone itself appears to regulate SAMe levels in the testes secondary to manipulating the rate limiting enzyme, where proper SAMe levels preserve testicular function; it is not known how supplemental SAMe affects the testes or testosterone
9Nutrient-Nutrient Interactions
9.1. Folate
The cognitive deficit associated with folate deficiency can have its symptoms temporarily abolished following supplementation of SAMe, as many symptoms of folate deficiency are mediated through a reduction in SAMe.[37]
9.2. Levodopa
Levodopa (brand name for L-DOPA) appears to increase serum levels of SAMe after oral administration at 125mg (when paired with a peripheral L-DOPA metabolism blocker, in this case benserazide).[94]
10.1. Case Studies
At least one study on depression has noted that a single individual experienced manic episodes without having a history thereof; this was thought to be related to the treatment.[95]
