19-Nortestosterone (nandrolone) is a well known anabolic – androgenic steroid. It has been approved by the FDA for wasting diseases and for treatment for anemia, since 1983. Among athletes it is one of the most favorable steroids for gaining strength and muscle. Its relatively low toxicity assures fewer side-effects with moderate use. Usually users report increased wellbeing after the initiation of nortestosterone treatment. Some doctors even believe nandrolone has abuse potential similar to narcotic drugs. What I am about to say in this article is how nandrolone affects wellbeing and possibly explains why users likely use this drug alone or in combination with psychoactive drugs.
The Serotonin System
The serotonin system in the mammalian brain has great impact. Serotonin regulates many crucial behavioral and endocrine characteristics. For many years it was not clear exactly how serotonin was involved in mood regulation. It is hypothesized that serotonin acts synergistically with dopamine. It is believed the mesolimbic area is the area where dopamine exerts most of its behavioral results. LSD experiments conducted in the 1960s brought scientists closer to the relationships between the two. Literally thousands of scientific experiments were conducted with LSD. The value of these experiments was tremendous to the development of psychopharmacology. At the same time organic chemists synthesized the first hallucinogenic phenetylamines and tryptamines that were fully synthetic ie. they were synthesized based on organic solvents only. Some of the most remarkable and relevant in my review were 2,4 methoxy substituted amphetamines STP, DOM, DOI and DOC otherwise know as Dox family. All invented by living legend Alexander Shulgin.
Why are they so unique among other PEAs? It’s because their remarkably pure selectivity to some of the serotonin subsystem. In other words they are very pure chemicals for clinical and scientific laboratory experiments. The relevant linkage between nandrolone and the Dox family is one of the central themes in this article. The factual data comes from the experiments where nortestosterone activity was measured with one of the most psychoactive drugs called DOI. Interestingly, through different measures and facts, nortestosterone use may be associated with changed DOI availability in the brain. Wow, is something flickering in your brain now? Basically if one relates to the other, then there must be a relation between them. An understanding of such a link was one of the most interesting and challenging ideas in putting this down on paper. The combination of nortestosterone and a serotonergic hallucinogen including LSD would increase the activity of the latter and possibly reduce the side effects of these mentioned drugs. Now that would be fun, but it isn’t.
The Three Main Regions in the Brain Where AAS Have Effects On
I’ve seen many people on Internet forums wondering how exactly AAS regulate one’s mood and behavior. Generally the answers vary between endocrine disturbances and sexuality and how these cause mood changes. Clearly none of these replies are enough to satisfy my curiosity. Albeit being quite new to the anabolic world I have graduated in biochemistry and genetics. The only reason I haven’t continued my education in neuroscience was the insecurity of my current knowledge and lack of insights at that time. Now that I have my own will to carry on my development I have the chance to invest my time exactly where it needs to be. So I will now discuss and analyze one of the recent discoveries in the anabolic world.
As I have delved into the neurophysiological world of anabolics I have come to realization that there are three distinctive areas where AAS exerts their effects. To give you a better understanding of what I am thinking I’ll try to explain and put into logical order and hopefully give some references as well.
The first place to look at of course is the hypothalamus. Although wellbeing may seem a small factor, it is found in one of the most complex parts of the brain. The hypothalamus is derived of many smaller compartments. From the data, I found out that the ventral medial part of the hypothalamus (VMH) is the part which exerts its projections to the cortex and mesolimbic system. Interestingly this site is heavily controlled by estradiol (8).
DeBold et al 1994 discovered that free progesterone injected into the VMH induced sexual behavior in female hamsters. The discovery was based on earlier speculation that progesterone exerts its effect directly on steroid receptors found on the cell membranes of VMH and VTA. When progesterone is conjugated with bovine albumine it loses its ability to attach to the steroid receptors; thus genomic alteration is not possible. Still, the sexual effect is there. DeBold discovered that sexual behavior derived from the VTA is not related to the genomic activation but VMH is. The most interesting hypotheses of the study was that progestins show some affinity to GABAA receptors or nearby receptors modulating GABAA in VTA. This theory suggests two distinctive activities of nandrolone in VTA and possibly elsewhere.
The assumption then is that every aromatizing AAS will affect VMH because they aromatize to estrogens. Over stimulation of VMH has three distinctive outcomes: aggression, female sexual arousal and appetite (7). Appetite is controlled through hypoglycemic signs. It receives signals from:
- from the VTA ie. the mesolimbic area; and
The aggression and sexual part are more of an afferent type but could act in both ways ie it sends and receives signals from the mesolimbic area and cortex where it is translated further.
The second would be the mesolimbic area. The mesolimbic area controls our wellbeing and state of salience. It is the region where dopaminergic starts from the ventral tegmental area (VTA) and ends in the amygdala. The mesolimbic area gets most of its afferent signals from the serotonergic fibers originating in the raphe nucleus mostly modulated through serotonin 5ht2 receptors (2). Blocking these fibers either with 5ht2 antagonists or 5ht1 agonist would reduce overall mesolimbic activity. Nandrolone according to the data, increases this regional activity, possibly leaning 5ht2/5ht1 activational ratio positively through genomic or/and nongenomic effects. Interestingly, all progestins activate this region according to the study (7), trenbolone included.
General data suggest that psychotic behavior is a result of increased mesolimbic activity. This would explain the intolerable anxiety accompanied with high dose of progestagenic drugs like nandrolone or trenbolone. Presumably, trenbolone affects this site more acutely because it doesn’t have any estrogen effect on VMH which would lessen or gas out the psychotic behavior elicited from the amygdala.
After a heavy state of chronic down regulations the mesolimbic area is one of the places affected. The genomic expression of dopamine and serotonin would be affected the most and the result would likely be similar to anecdotal‚ post cycle depression. Keeping the level of expression of these neurotransmitter levels at normal levels or slightly above, would yield a continuous state of emotional wellbeing and should be taken into account.
The third part consists of higher mental parts eg the hippocampus and prefrontal cortex. Logic, short term memory and complex memory are associated with these regions. These regions are abundant with neurotransmitter fibers, of which serotonin plays a major part, and derives from the hypothalamus, the mesolimbic area and nucleous accumbens. These areas are abundant with serotonin fibers derived from hypothalamus and mesolimbic area. These places are most sensitive to the harm because they depend directly of the two previous mentioned. These output pathways modulate our state of cognition, logic and also fear and emotional satiety. Interestingly, ventral striatum shares a lot with the mesolimbic structures and is mostly dopaminergic like the latter.
Back to the topic. DuRant et al., 1995 and Kindlundh et al,1999, 2001b reported that according to factual and analytical data AAS are used alone or in combination with psychoactive substances where in many cases this has been reported to cause disinhibitory and violent behavior (5, 6). Such a straightforward conclusion comes from the fact that there are abusive individuals who have become uncontrollably maniac with AAS use. But let’s go further with this statement and see what’s behind this complex change of behavior in these people. In other words, let’s look at the analytical data.
Effects on 5ht1 Subsystem
Simon et al., 1998 demonstrated that administration of 5-HT reuptake inhibitors, 5-HT precursors or5-HT1A or 5-HT1B agonists results in reduced aggression and impulsiveness. It is a well documented fact that stimulation of serotonin autoreceptors reduces aggressiveness in subjects. Stimulation of serotonin auto receptors may in fact increase harm of PTSS because of reduced ability to fight stress and fear. Interestingly propranolol has been successfully used of PTSS and as already stated it is potent 5ht1 antagonist.
Saudou et al 1994 demonstrated that male mice lacking functional expression of the 5-HT1B receptor gene are likely to be more aggressive than wild type controls (3). This is another example of conflicting data which may make more sense in different environments. Aggressiveness of what? Increased aggressiveness could be transformed into increased self-confidence and bravado. Nandrolone (1) is shown to facilitate the blocking effect of 5ht1 antagonists to serotonin system.
Data demonstrating the results of 2 weeks of treatment with nandrolone decanoate exhibited significant down-regulation of [125I]-iodocyanopindolol binding to the 5HT1B receptors at all doses (1, 5, 15 mg/kg/day) in the hippocampal CA1 and the MGP (Table). This isn’t a bad sign at all. Because up regulation of 5ht1 sites in hippocampus are related to reduced short-term memory retention. Interestingly, nandrolone can and should be used in cases were treatment of SSRIs have negatively rewired serotonin receptors in the hippocampus and prefrontal area. Many users have reported blunted emotions and reduced memory capacity after SSRI treatment. The subjective data puts SSRIs and other antidepressants clearly into bad perspective. Another interesting point is that the same reduction of or rewiring effect on SSRI activity could be achieved with either propranolol or pindolol treatment because they antagonise serotonin 5ht1a and 5ht1b receptors. Both sub-receptors are reducible for serotonin 5ht2 receptors and dopamine heteroreceptors in various regions in VTA and PFC. Administration of the highest dose of nandrolone significantly enhanced the [125I]-iodocyanopindolol binding in the Lateral Globus Pallidus(1).
Globus Pallidus is the part of the brain which sends GABAergic axons to other parts of the brain and receives glutaminergic signals. Remember this is the part I briefly mentioned in the II region. This part of the brain is sometimes subject to electrical stimulation for treatment of people suffering from Parkinson’s disease. Nandrolone does seem to be enhanced in this region, possibly through GABAA related mechanisms (1). Interestingly in this part of the brain nandrolone shares some activities of 5ht1 antagonist propranolol. This fact should be useful in general with geriatrics. Ever wondered about old people getting juiced?
Feldman et al., 1998; Rosenberg et al., 2000 proposed that 5ht2 antagonism is good for anxiety and depression. In general psychiatry these types of drugs have become very popular for treating various types of mental illnesses. Nandrolone exerts positive effect on 5ht2 modulation thus reflex the opposite route (1).
Clearly one cannot draw parallels from these because nandrolone is not a direct agonist to these receptors but rather modulates 5ht2 receptors through indirect ways. Thus it could even be used along with 5ht2 antagonist to minimize the side effects of the latter. This statement of course is not validated. One interesting point in serotonin 5ht2 antagonists is that they generally produce dose-dependent insulin resistance and sexual dysfunction. Turning this upside we could assume nandrolone which partly antagonized the 5ht2 antagonists could possibly reduce insulin resistance and increase sexual performance; especially the emotional part of sexuality. Again this is partially speculation so far.
Procognitive Effects of Nandrolone
One important quest is to understand whether nandrolone affects hippocampal andcortical activity. One study (1) showed significant decrease in the density of 5-HT1B receptors in hippocampus after two weeks of nandrolone treatment. The measured effect refers to increased serotonin perfomance in CA1 nerve terminals where the blocked 5ht1b receptors are located. In hippocampus 5ht1 receptors are situated mainly in the axonal terminals of CA1 pyramidal cells where they elucidate cognitive inhibition.
It takes little logic to understand the possible pro-cognitive effects of nandrolone elicited mainly via 5ht2 receptors. This would give us new perspectives for cures in cognitive declines and psychological disorders. To say the least, the possible positive outcome of nandrolone treatment in debilitated persons is very promising.
Nandrolone has been shown to have two distinctive effects on serotonin system. One is the suppressive effect on the 5ht1 subsystem and the other is the faciliatory effect on the 5ht2 subsystem. It is not clearly known whether these effects are due to steroidal or norsteroidal activity. The turnover of serotonin is shown to be increased in the hippocampus which indicates increased cognitive effect while the level of whole-brain serotonin metabolite doesn’t change compared to the littermates (1). There also seems to be a direct linkage of nandrolone between 5ht1 antagonists and 5ht2 agonists. Something which may sound surprising: many AAS users also use and abuse psychotropic agents. Whether this is good or bad is matter of choice.
I have shown that combining nandrolone with either 5ht1 antagonist or 5ht2 agonists would facilitate the anabolic effect and the psychological stimulus of nandrolone further than nandrolone alone. The possible pro-cognitive effect of nandrolone is promising and should be investigated further. The effects of progestagenic, estrogenic and androgenic of nandrolone suggest it is perhaps the best anabolic steroid for conducting and analyzing the effect of steroid affects on the central nervous system. Earlier CNS studies are very, very promising. I believe nandrolone is one of the major keys in the future of neuroscience due to broad effect on steroid receptors.
1. Kindlundh et al (2003) The anabolic-androgenic steroid Nandrolone induces alterations in the density of serotonergic 5HT1B and 5HT2 receptors in the male rat brain. Neuroscience 119 (2003) 113–120
2. Sasaki-Adams DM, Kelley AE (2001) Serotonin-dopamine interactions in the control of conditioned reinforcement and motor behavior. Neuropsychopharmacology 25:440–452.
3. Saudou F, Amara DA, Dierich A, LeMeur M, Ramboz S, Segu L, Buhot MC, Hen R (1994) Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science 265:1875–1878.
4. Sprouse JS, Aghajanian GK (1988) Responses of hippocampal pyramidal cells to putative serotonin 5-HT1A and 5-HT1B agonists: a comparative study with dorsal raphe neurons. Neuropharmacology 27:707–715.
5. Choi PY, Pope HG Jr (1994) Violence toward women and illicit androgenic- anabolic steroid use. Ann Clin Psychiatry 6:21–25.
6. Pope HG Jr, Katz DL (1990) Homicide and near-homicide by anabolic steroid users. J Clin Psychiatry 51:28–31.
7. DeBold F et al (1984) The relative effectiveness of progestins for facilitation and inhibition of sexual receptivity in hamsters Physiology & Behavior, Volume 32, Issue 5, May 1984, Pages 743-747
8. DeBold F et al (1982) Sexual receptivity: Brain sites of estrogen action in female hamsters Physiology & Behavior, Volume 29, Issue 4, October 1982, Pages 589-593