The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015)

[BadassBlues]

The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015) - PubMed

Deprenyl/Selegiline (DEP), created by Joseph Knoll in the 1960s, registered in more than 60 countries to treat Parkinson's disease, Alzheimer's disease, major depressive disorder; and used as an anti-aging drug, achieved its place in research and therapy as the first selective inhibitor of...

pubmed.ncbi.nlm.nih.gov

The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015)​

I Miklya 1
Affiliations expand

• PMID: 27480491
• DOI: 10.1038/mp.2016.127

Abstract​

Deprenyl/Selegiline (DEP), created by Joseph Knoll in the 1960s, registered in more than 60 countries to treat Parkinson's disease, Alzheimer's disease, major depressive disorder; and used as an anti-aging drug, achieved its place in research and therapy as the first selective inhibitor of B-type monoamine oxidase (MAO-B). The demonstration that the DEP analog (-)-1-phenyl-2-propylaminopentane devoid of MAO inhibitory property, enhanced like DEP the activity of the catecholaminergic brain engine revealed that this effect is unrelated to the selective inhibition of MAO-B. β-Phenylethylamine (PEA), the important trace-amine in the mammalian brain, is known to be a releaser of catecholamines. Amphetamine and methamphetamine, the best known synthetic PEA derivatives are also releasers of catecholamines like their parent compound. DEP is a unique synthetic PEA derivative devoid of the catecholamine releasing property. As the releasing effect conceals the catecholaminergic activity enhancer (CAE) effect, it remained undiscovered until DEP uncovered that PEA is a natural CAE substance; and only releases catecholamines in high concentration. Discovering that tryptamine is a natural enhancer of catecholaminergic and serotonergic neurons catalyzed the development of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane (BPAP); the most potent and selective enhancer substance, and it exerts its enhancer effect in 0.0001 mg kg-1. DEP and BPAP initiated an analysis of the enhancer regulation in the mammalian brain. Studies regarding the nature of the enhancer regulation revealed that this regulation is enhanced after weaning and sex hormones return it to the pre-weaning level. Thus, sex hormones elicit the transition of the developmental phase of life into the post-developmental, downhill (aging) period. The aging-related, slow decline in the enhancer regulation of the catecholaminergic brain engine, the main activator of the cortex, is the prime factor of brain aging. The enhancer regulation's decay in the most rapidly aging dopaminergic system is, for example, mainly responsible for the decline in learning ability and sexual activity over time. According to the Knoll concept, based on two longevity studies performed on male rats, to keep the catecholaminergic brain engine, from the beginning of the downhill period of life, via the administration of a small daily dose of a CAE substance (presently DEP is the only available drug) on a higher activity level, thus to fight against the physiological aging-related slow decay of the catecholaminergic system, is a suitable anti-aging therapy. As our present knowledge regarding the enhancer regulation in the mammalian brain is like seeing a peak of an iceberg, the future of this new line of brain research looks promising from both theoretical and practical aspects.

 

[Gman86]

Took a dose this morning

 

[BadassBlues]

Deprenyl (update) - An Antiaging Aphrodisiac | Aging Matters Magazine

Deprenyl offers many life-extending and antiaging benefits for those who suffer with Parkinsons Disease, as well as others who take it for its antiaging effects

aging-matters.com

Deprenyl – an antiaging, life-extending aphrodisiac (update)​

June 14th, 2019
By Ward Dean, M.D.

Deprenyl (later known as selegiline) was developed by Professor Josef Knoll of Semmelweis University in Hungary in the 1950s. It was first used as an anti-depressant and was later used for the prevention and treatment of Alzheimer’s and (especially) Parkinson’s Disease. Deprenyl’s value initially was based on the belief only that it was a monoamine oxidase B (MAO-B) inhibitor. MAO-B is an enzyme that degrades the neurotransmitters dopamine, epinephrine, nor-epinephrine and serotonin in the brain. MAO-B levels rise with age (Fig. 1)1 and it was believed that this caused a decrease in these neuro-transmitters, which resulted in depression, Parkinsonism, and other neurodegenerative diseases. By selectively inhibiting MAO-B, deprenyl was theorized to maintain these neuro-transmitters at more youthful levels.

Life-extending effects

In 1983, Dr. Walter Birkmayer in Germany reported that Deprenyl, combined with L-dopa, not only improved the on-off phases and rigidity of Parkinson’s disease and reduced adverse reactions to L-dopa, but also prolonged the life expectancy of Parkinson’s patients!2 Birkmayer’s preliminary report was confirmed by ten-year long studies in nearly 1,000 Parkinson’s patients- who added deprenyl to their regimens after L-dopa had lost its efficacy.3-6 The L-dopa-plus-deprenyl-regimen significantly delayed the progression of Parkinson’s symptoms, and increased life expectancy compared to those on L-dopa alone.

Figure 1: Platelet MAO-B increases with age Figure 2: Straital dopaminergic neurons. The striatum is the main input nucleus of the basal ganglia and a key neural substrate for procedural learning and memory.
Autopsies showed that deprenyl prevented or retarded the degeneration of striatal dopaminergic neurons in the brain (see Fig. 2). Scientists in the U.S.7 and Finland8 recommended that Deprenyl treatment be started as soon as the Parkinson’s diagnosis was made.

But it wasn’t just Parkinson’s patients that were living longer with deprenyl. In 1988, Knoll rocked the gerontological community with a study that showed a dramatic extension of maximum lifespan of rats treated with deprenyl (Fig. 3).9

Figure 3: Extension of maximum lifespan in rats injected with deprenyl 3 times/week, beginning at the age of 24 months. Note that all the control rats died before the first deprenyl-treated rat died.
Knoll and his colleagues treated 132 24-month-old male rats, (equivalent to 60-year-old humans) with injections of saline or deprenyl three times/week. The average lifespan of the saline-treated group was 147 weeks. The oldest rat in the saline group was 166 weeks old when it died. In contrast, the first rat to die in the deprenyl group lived 171 weeks, (five weeks after the last control rat died), and the longest-living deprenyl-treated rat died in its 226th week! The average lifespan of the deprenyl-treated group was 198 weeks–i.e., higher than the previously-estimated maximum lifespan of the rat (182 weeks). Knoll claimed that this was the first time that administration of a drug or nutrient resulted in extension of a species’ known maximum lifespan.10

In addition to these dramatic findings, the scientists evaluated sexual functioning in the rats, as a measure of their brain striatal function. Because of the normal age-related decay of sexual function, none of the 2-year-old animals displayed full-scale sexual activity. In the saline group, the last signs of sexual activity had completely vanished by the 33rd week of treatment. In contrast, deprenyl treatment restored full-scale sexual activity in 64 out of 66 rats!11 Inspired by Knoll’s groundbreaking lifespan studies with deprenyl, researchers around the world began trying to duplicate his results in a variety of species. Researchers at the University of Toronto in Canada gave injections of deprenyl (0.25 mg/kg) or saline every other day to male Fischer rats starting at 23 to 25 months of age. The deprenyl-treated animals showed a significant increase in both mean and maximum survival.12 Scientists from the Tokyo Metropolitan Institute of Gerontology reported their results with 70 male Fischer 344, (F-344) rats treated with injections of deprenyl or saline 3 times a week from the age of 18 months until they died. Although their results were not as dramatic as Knoll’s, the average lifespan of deprenyl-treated rats after 24 months was 34% greater than saline-treated controls, lending support to the growing awareness of deprenyl’s life-extending properties (Fig. 4).13, 14



Figure 4: Extension of lifespan of deprenyl-treated rats (open circles) from the Tokyo Metropolitan institute of Gerontology. Treatment began at 18 months of age, resulted in 34% increase in the remaining life expectancy after 24 months.
In Germany, scientists treated 14 immunosuppressed mice- beginning at 2 ½ months of age, with half the group receiving deprenyl-laced food. The last mouse in the control group died at the age of 5 months (2.5 months after the study began). In contrast, the last mouse in the deprenyl group died at the age of 14.5 months–1 year after the beginning of the study, having lived nearly three times as long as the longest-living control mouse!15

Scientists at the Jackson Laboratory in Bar Harbor, Maine, conducted studies on 2 strains of mice, starting at mean ages of 26 and 18.5 weeks. In the study that began at 26 weeks, there was a 77-day increase in mean female lifespan, and an 84-day increase in mean male lifespan. For the mice that began treatment at 18.5 weeks of age, the mean longevities were increased only 59 days in females, and 56 days in males. Despite the inconsistencies, the authors concluded that since all studies found increased lifespans in deprenyl-treated mice, further research with deprenyl as a life-extending substance was justified.16

In 1997, a team from Mannheim, Germany, reported on deprenyl’s effect on the lifespan of Syrian Hamsters. At the age of 13 months, 36 pairs of hamsters were treated–half of which received 0.05 mg/kg deprenyl in their food. The scientists surprisingly found that deprenyl significantly increased life span in the females, but not in males (Fig. 5).17 This was especially significant as females of this species normally had a shorter lifespan than males.

Figure 5: Survival curves of female (A) and male (B) syrian hamsters. Female hamsters normally have shorter lifespans than males. After deprenyl treatment, the difference of lifespan between male and female hamster disappeared.

Two months later, the same journal published a study by scientists at the VA Medical Center in Denver, CO, using male Fischer 344 rats. They administered deprenyl in drinking water to 14 rats, beginning at 54 weeks of age (16 rats served as controls) (Fig. 6). Although there was no difference in the maximum lifespan due to deprenyl, the mean lifespan was significantly longer for the deprenyl-treated rats (110 vs. 103.5 weeks).18

Figure 6: extension of lifespan of male rats treated with deprenyl in their drinking water, compared to controls. Treatment was begun at 54 weeks of age. Deprenyl-treated rats exhibited higher survival rates at all time points after 62 weeks of age.
In the same year, thirty-three elderly beagle dogs between the ages of 10-15 years old were given 1 mg/kg of deprenyl or a placebo each day for 104 weeks by researchers in Overland Park, Kansas. Twelve of 15 (80%) dogs in the deprenyl group survived to the conclusion of the study, in contrast to only 7 of 18 (39%) of the dogs who received placebo. By the time the first deprenyl-treated dog died on day 427, five placebo-treated dogs had already succumbed–the first on day 295 (see Fig. 7). The authors concluded that daily administration of 1 mg/kg deprenyl could prolong the life of relatively healthy 10-15-year-old dogs.19

Figure 7: Survival of dogs, between 10 and 15 years old at the start of the study, treated with deprenyl for at least six months. Note that by the time the first deprenyl treated dog died on day 427, five of the placebo-treated dogs has already died.
The German team that three years previously had tested deprenyl on immunosuppressed NMRI mice (cited above) did another series of experiments using various combinations of deprenyl and lipoic acid in ten groups of 14 mice. They obtained the best results with doses of 75 mcg/kg deprenyl plus 9 mg/kg of R-lipoic acid. This combination resulted in nearly 200% increased maximum lifespan!20

Multiple mechanisms for Deprenyl’s benefits

Besides its known MAO-B inhibiting properties, scientists in the UK reported that deprenyl also induced increased levels of superoxide dismutase (SOD) and suggested this as the basis of deprenyl’s neuroprotective and life-extending effects.21

The Japanese team led by Kitani has probably done more ongoing research with deprenyl’s effect on lifespan than any other group. Kitani speculated that the life-extending effects of deprenyl were not due solely to its MAO-B inhibiting effects, but to a multiplicity of mechanisms. These included elevations of catalase as well as SOD (as found by the British team mentioned above). Other benefits attributed to deprenyl included immune system enhancement characterized by increased concentrations of cytokines such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, and natural killer (NK) cell functions. Kitani speculated that these humoral factors were responsible for deprenyl’s ability to prevent malignant tumors in rodents and dogs, and for its diverse antiaging and life-prolonging effects by enhancing homeostatic regulation of the neuro-immuno-endocrine axis.22-26

Researchers from the Department of Pharmacology, University of North Dakota School of Medicine and Health Sciences expanded upon deprenyl’s potential life-extending mechanisms by noting that deprenyl also enhances cyclic AMP; restores insulin-like growth factor I (IgF1); possesses neurotrophic-like actions and enhances the synthesis of nerve growth factor; and protects against peroxynitrite- and nitric oxide-induced apoptosis.27

Less may be more

When deprenyl was first clinically used, the recommended dose for Parkinson’s disease was 5 mg in the morning, followed by a second dose at noon. Prof. Knoll early-on recommended that those at risk of (or diagnosed with) Alzheimer’s disease “should take 10 mg daily for the rest of their lives.”28 This is probably still good advice for those suffering from these dementing illnesses.

However, Kitani and his associates found that with continued use, lower doses of deprenyl provided better effects with regard to optimizing antioxidant enzyme levels in the brain and maximizing the life expectancy and lifespan of experimental animals. They determined that the dosage used for any life span study was a critical factor, with the dosage differing widely depending on sex, age of the animal, and duration of therapy. In fact, Kitani’s team proposed that long-term treatment with deprenyl decreased the optimal dose by a factor of at least 5 in terms of upregulation of antioxidant enzymes.29, 30 Although Dr. Kitani had conducted more studies with deprenyl than any other scientist except Prof Knoll, there is no indication that he used deprenyl himself. He passed away unexpectedly on October 15th, 2008 at the age of 73 from colon cancer.31

Kitani’s conclusions agree with Knoll’s later recommendations. Whereas Knoll initially recommended dosages of up to 10 mg per day for those with Parkinson’s and Alzheimer’s diseases, he explained in his later work that deprenyl has enhancing qualities in “femto-picomolar concentrations,” which leave MAO-B activity unchanged. He believed that the activity of the catecholaminergic neurons in the brain stem and this previously unrecognized ‘enhancer effect’ is responsible for the unique therapeutic benefits of deprenyl. Consequently, Knoll suggested doses of as little as 1 mg/day as optimal for disease-prevention and life-extending purposes.32, 33

Prof. Knoll ‘practiced what he preached.’ Since January 1989, at the age of 64, he took 1 mg Deprenyl every day. At the age of 92, he continued his daily consumption of what he referred to as a catecholaminergic activity enhancer (CAE) substance. I first discussed this with him at the IAS-sponsored Monaco Anti-Aging Conference in 2002. He revealed that although deprenyl’s activity as a MAO-B inhibitor was its first-discovered and most highly-promoted mechanism, he described its most important mechanism as a “catecholaminergic receptor sensitizer”– sort of like a; “metformin for the brain” (he winked at me as he said that, as I had just given a talk on the multi-hormone receptor-sensitizing effects of metformin).

Until his death on April 17th, 2018 at age 94, Prof. Knoll continued to maintain his emeritus position as a Professor at Semmelweis University, conducted ongoing research and wrote books and articles. His only limitation was that he traveled less internationally than he had formerly done. He commented slyly in his book that his ongoing “self-experiment (1 mg of Deprenyl daily) augers very well.”33

 

[Gman86]

@BadassBlues Do u think taking 5mg/day orally is ok to take indefinitely? Based on what dr knoll has stated, u don’t think it’s too much to take over the long haul?

 

[Gman86]

@BadassBlues also, what do u make of this Reddit thread, and the links they posted? Anyone that’s done research on selegiline has heard that taking it sublingually decreases the amount of methamphetamine metabolites. But I think what they’re saying in this thread is that it’s a misinterpretation, and that the metabolites were only decreased when taking sublingually because with sublingual dosing u can take around 1/8th of the same dose as u would need orally, to elicit the same overall benefits. So with less of a dose, there’s simply less metabolites. What’s ur thoughts?

https://www.reddit.com/r/Nootropics/comments/2aa39u

 

[BadassBlues]

@BadassBlues Do u think taking 5mg/day orally is ok to take indefinitely? Based on what dr knoll has stated, u don’t think it’s too much to take over the long haul?

From my research, and personal experience, the dosage of selegeline is highly age related. At 66, 5 mg a day is perfect for me and has done wonders for my cognitive health, motivation, mood and sexual function. I understand that Dr. Knoll recommended a smaller and less infrequent dose, but current research and clinical practice have altered that based on age.

Deprenyl- A Multi-Functional Anti-Aging Drug | Antiaging Systems

Deprenyl is a ‘psychic energizer’ and antidepressant that has also seen success in treating Parkinson's Disease and as a preventative against aging.

www.antiaging-systems.com

DEPRENYL- DOSAGES FOR LIFE EXTENSION PURPOSES

As stated previously, Professor Knoll is a man who ‘practises what he preaches’ and reportedly takes two 5mg Deprenyl tablets per week. We (Dean, Fowkes and Morgenthaler) recommend the following age adjusted titrated dosage schedule in our book, Smart Drugs 2.

Age. Dosage

30-35 1mg twice a week
35-40 1mg every other day
40-45 1mg every day
45-50 2mg every day
50-55 3mg every day
55-60 4mg every day
60-65 5mg every day
65-70 6mg every day
70-75 8mg every day
75-80 9mg every day
80 plus 10mg every day

 

[BadassBlues]

@BadassBlues also, what do u make of this Reddit thread, and the links they posted? Anyone that’s done research on selegiline has heard that taking it sublingually decreases the amount of methamphetamine metabolites. But I think what they’re saying in this thread is that it’s a misinterpretation, and that the metabolites were only decreased when taking sublingually because with sublingual dosing u can take around 1/8th of the same dose as u would need orally, to elicit the same overall benefits. So with less of a dose, there’s simply less metabolites. What’s ur thoughts?

https://www.reddit.com/r/Nootropics/comments/2aa39u

A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition - PubMed

Seven randomised comparative studies were conducted in healthy volunteers to compare the pharmacokinetic and pharmacodynamic profiles of selegiline hydrochloride in a new formulation designed for buccal absorption "Zydis Selegiline" (1.25-10 mg) with conventional selegiline hydrochloride tablets...

pubmed.ncbi.nlm.nih.gov

Abstract​

Seven randomised comparative studies were conducted in healthy volunteers to compare the pharmacokinetic and pharmacodynamic profiles of selegiline hydrochloride in a new formulation designed for buccal absorption "Zydis Selegiline" (1.25-10 mg) with conventional selegiline hydrochloride tablets "conventional selegiline tablets" (10 mg). A total of 156 healthy volunteers participated in these studies. Plasma concentrations of selegiline and its primary metabolites, N-desmethylselegiline (DMS), l-amphetamine (AMT), and l-methamphetamine (MET) were measured using Gas Chromatography Mass Spectrometry (GCMS) and gas liquid chromatography (GLC) assays. Inhibition of monoamine-oxidase type B (MAO-B) and monoamine oxidase type A (MAO-A) activity was determined by measurement of as beta-phenylethylamine (PEA) by GCMS and 5-hydroxyindoleacetic acid (5-HIAA) by High Performance Liquid Chromatography (HPLC) assays. Almost a third (2.96 mg) of a 10 mg selegiline dose in Zydis Selegiline was absorbed pre-gastrically (predominantly buccally) within 1 minute. Mean [SD] area-under-the curve (AUC(0- infinity)) values following Zydis Selegiline 10 mg (5.85 [7.31] ng.h/mL) were approximately five times higher than those following conventional selegiline tablets 10 mg (1.16 [1.05] ng.h/mL). In contrast, plasma concentrations of metabolites were significantly ( p<0.001) lower following Zydis Selegiline 10 mg than following conventional selegiline tablets 10 mg. Plasma concentrations of selegiline and its metabolites increased in a dose-dependent manner over the dose-range Zydis Selegiline 1.25-5 mg. Bioavailability was determined using AUC and peak plasma concentrations (C(max)). The C(max) of selegiline was similar following administration of Zydis Selegiline 1.25 mg (1.52 ng/mL) or conventional selegiline tablets 10 mg (1.14 mg/mL). The range of values for AUC(0- infinity) and C(max) following Zydis Selegiline 1.25 mg were entirely contained within the range following conventional selegiline tablets 10 mg, with a much higher variability of plasma selegiline concentrations occurring after conventional selegiline tablets than after Zydis Selegiline. As expected, peak plasma concentrations for DMS, AMT and MET were consistently lower after Zydis Selegiline 1.25 mg (1.19, 0.34, 0.93 ng/ml, respectively) than after conventional selegiline tablets 10 mg (18.37, 3.60, 12.92 ng/ml, respectively). A significant (r=0.0001) correlation between daily PEA excretion (a measure of brain MAO-B inhibition) and the log-transformed AUC((0-t)) for selegiline was demonstrated. Mean daily PEA excretion was similar following Zydis Selegiline 1.25 mg and conventional selegiline tablets 10 mg (13.0 microg versus 17.6 microg). In contrast, there was no correlation between PEA excretion and selegiline metabolites, indicating that selegiline metabolites do not significantly inhibit MAO-B. Urinary excretion of 5-HIAA (used as a marker for MAO-A inhibition) was unrelated to plasma concentrations of selegiline or DMS following single or repeat dosing of Zydis Selegiline 1.25 mg or conventional selegiline tablets 10 mg. However, comparison of treatment groups revealed a significantly lower excretion of 5-HIAA in the conventional selegiline tablets 10 mg group than in the Zydis Selegiline 1.25 mg group after repeated administration over 13 days. In summary, by reducing the opportunity for first-pass metabolism, the absorption of selegiline from Zydis Selegiline was more efficient and less variable than from conventional selegiline tablets. Compared with conventional selegiline tablets 10 mg, Zydis Selegiline 1.25 mg yielded similar plasma concentrations of selegiline and degree of MAO-B inhibition, but markedly reduced concentrations of the principal metabolites. Thus, the lower but equally MAO-B inhibitory dose of selegiline in Zydis Selegiline 1.25 mg, which is associated with lower concentrations of potentially harmful metabolites, could offer a safer and more predictable treatment in the management of patients with Parkinson's disease.

 

[BadassBlues]

@BadassBlues also, what do u make of this Reddit thread, and the links they posted? Anyone that’s done research on selegiline has heard that taking it sublingually decreases the amount of methamphetamine metabolites. But I think what they’re saying in this thread is that it’s a misinterpretation, and that the metabolites were only decreased when taking sublingually because with sublingual dosing u can take around 1/8th of the same dose as u would need orally, to elicit the same overall benefits. So with less of a dose, there’s simply less metabolites. What’s ur thoughts?

https://www.reddit.com/r/Nootropics/comments/2aa39u

I believe you are correct in your theory that the lower dose is the reason for reduced metabolites.

Also, most of those Reddit threads are people taking regular tablets and cutting them into smaller doses to take sublingually. I don't know the efficacy of doing it that way. The only true sublingual that I have seen, and its not technically really a sublingual, but rather compounded drops to use for pets.

To be honest, I have no desire personally to take it sublingually, so I have never put much effort into searching for a sublingual product. If anyone knows of a legitimate sublingual Deprenyl / Selegeline product, please post the info in this thread.

 

[BadassBlues]

It's important to address the drug interactions and contraindications so people can have some responsible guidelines in researching and possibly taking this drug. I will attest to one thing not listed. Selegeline potentiates other stimulants. I am much more sensitive to caffeine than I was before taking it. Also Yohimbine. There are likely other stimulants in sports drinks and supplements that should be considered.

Selegiline - Drug Interactions, Contraindications, Other Rx Info

Selegiline - Drug Interactions, Contraindications, Other Rx Info

www.druglib.com

Here is a drug checker that can be used to search for interactions. Again, take the dosage into consideration:

Selegiline Interactions Checker - Drugs.com

511 medications are known to interact with selegiline. Includes amlodipine, gabapentin, lisinopril.

www.drugs.com

​ DRUG INTERACTIONS​ ​ Drug Interactions​ The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination (see CONTRAINDICATIONS). Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and selegiline and selective serotonin reuptake inhibitors and selegiline. (See WARNINGS for details.) One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine). ​

​ OVERDOSAGE​ ​ Selegiline​ No specific information is available about clinically significant overdoses with selegiline hydrochloride. However, experience gained during selegiline's development reveals that some individuals exposed to doses of 600 mg of d,l-selegiline suffered severe hypotension and psychomotor agitation. Since the selective inhibition of MAO B by selegiline hydrochloride is achieved only at doses in the range recommended for the treatment of Parkinson's disease (e.g., 10 mg/day), overdoses are likely to cause significant inhibition of both MAO A and MAO B. Consequently, the signs and symptoms of overdose may resemble those observed with marketed non-selective MAO inhibitors (e.g., tranylcypromine, isocarboxazide, and phenelzine). ​ Overdose with Non-Selective MAO Inhibition​ NOTE: This section is provided for reference; it does not describe events that have actually been observed with selegiline in overdose. Characteristically, signs and symptoms of non-selective MAOI overdose may not appear immediately. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur. Importantly, the peak intensity of the syndrome may not be reached for upwards of a day following the overdose. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring for a period of at least two days following the ingestion of such drugs in overdose, is strongly recommended. The clinical picture of MAOI overdose varies considerably; its severity may be a function of the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved. Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonus, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. ​ Treatment Suggestions for Overdose​ NOTE: Because there is no recorded experience with selegiline overdose, the following suggestions are offered based upon the assumption that selegiline overdose may be modeled by non-selective MAOI poisoning. In any case, up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians' Desk Reference (PDR). Treatment of overdose with non-selective MAOIs is symptomatic and supportive. Induction of emesis or gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, provided the airway has been protected against aspiration. Signs and symptoms of central nervous system stimulation, including convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated with intravenous fluids and, if necessary, blood pressure titration with an intravenous infusion of a dilute pressor agent. It should be noted that adrenergic agents may produce a markedly increased pressor response. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential. ​

​ CONTRAINDICATIONS​ Selegiline hydrochloride is contraindicated in patients with a known hypersensitivity to this drug. Selegiline is contraindicated for use with meperidine. This contraindication is often extended to other opioids. (See Drug Interactions.)​

 

[Wolverine]

Ive read that dopamine and testosterone have a bidirectional relationship. Is it ok take TRT and selegiline as the same time? Will dopamine increase too much? Tx

 

[electrify]

Selegiline which is an MAOB inhibitor at low doses actually mostly increases trace amines like PEA, not dopamine. Although PEA indirectly is a releaser of DA and NE as its basically endogenous amphetamine.

Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis - Experimental & Molecular Medicine

The inhibition of two forms of an enzyme that modulate key processes in the brain has different benefits for patients with Parkinson’s disease than previously thought. Monoamine oxidase (MAO) is present in the brain as MAO-A and MAO-B, both of which were thought to be involved in dopamine...

www.nature.com