Notes from ADHD Meds research

Adderall is a mix of dextro-amphetamine & l-amphetamine.
Vyvanse is lisdexamphetamine, it is a prodrug that’s processed by the body into dextro-amphetamine.
Oct ’21 dose: Aderall XR 15mg, IR 10mg. When I moved to Vyvanse did I get an appropriate dose?
Stimulant Comparisons
50mg Vyvanse = 20mg Adderall XR
The “conversion rate” is measured at 0.2948, meaning 30mg Vyvanse is equal to 8.85 mg dextroamphetamine, or 11.8 mg Adderall.

Consistent with the pharmacokinetics, the subjective and cardiovascular stimulant effects of lisdexamfetamine also occurred later compared with d-amphetamine. However, no differences in peak ratings of potentially abuse-related subjective drug effects (e.g., drug liking, drug high, stimulation, happy, well-being, and self-confidence) were observed after lisdexamfetamine administration compared with d-amphetamine administration. Lisdexamfetamine and d-amphetamine also produced similar peak increases in mean arterial blood pressure, heart rate, body temperature, pupil size, and adverse effects.
Conclusion: The pharmacokinetics and pharmacodynamics of lisdexamfetamine are similar to d-amphetamine administered 1h later. Lisdexamfetamine is likely associated with a similar risk of oral abuse as d-amphetamine. The study was registered at ClinicalTrials.gov (NCT02668926).

On the primary and secondary efficacy variables of behaviour, attention and problem solving, lisdexamfetamine delivered equivalent or better efficacy than MES-amphetamine XR with both drugs being maximally effective at 2 h post-dose (Biederman et al., 2007a)[1]. However, on the problem-solving endpoints, it was also evident that lisdexamfetamine maintained its maximum effect for at least 12 h, whereas the effect of MES-amphetamine XR showed a clear decline after 6–8 h (Biederman et al., 2007a). An exceptionally long duration of effect of lisdexamfetamine was observed by Wigal et al. (2009, 2010b), who reported that significant improvements in deportment and attention in children with ADHD were observed as early as 1 h after lisdexamfetamine administration, with its efficacy on behaviour, attention and problem solving maintained for up to 13 h. A post-hoc analysis of the data also showed that the sex and age of the subjects had no significant influence on the efficacy of lisdexamfetamine.
d-Amphetamine’s effects on striatal dopamine efflux and locomotor activity are superimposable (Figure 5), that is, the rapid release of dopamine translates directly into an immediate and substantial increase of locomotor activity.

[1]: Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study
Dextroamphetamine vs Amphetamine
I noticed a sharper spike of sensation with Adderall. That’s likely due to the dosing & release mechanisms, but I’m interested in the pharmacological differences between the 2 isomers as well:

d-amphetamine: dextro-amphetamine
l-amphetamine: levo-amphetamine

Dextroamphetamine is available in IR & XR forms as Dexedrine & Dexedrine Spansules respectively.
Vyvanse is lisdexamphetamine, which is processed into dextro.
Adderall is a 3:1 ratio of d- & l-, and is available in IR & XR forms.
It sounds like d- works on dopamine, while l- works on noradrenaline
Amphetamine, past and present — a pharmacological and clinical perspective

Currently, the only use of l-amphetamine in ADHD medications is in mixed salts/mixed enantiomers amphetamine (MES-amphetamine), which consists of a 3:1 enantiomeric mixture d-amphetamine:l-amphetamine salts that is available in both immediate-release (Adderall®, generic) and extended-release (Adderall XR®, generic) formulations.
The metabolic route of lisdexamfetamine is unusual because after absorption into the bloodstream it is metabolised by red blood cells to yield d-amphetamine and the natural amino acid, L-lysine, by rate- limited, enzymatic hydrolysis (Pennick, 2010).
Comparing the relative potencies of d- and l-amphetamine, Heikkila et al. (1975) and Easton et al. (2007) reported that the d-isomer was approximately fourfold more potent than the l-isomer as a releaser of [3H]dopamine. In contrast, l-amphetamine was either as potent, or more so, than d-amphetamine as a releaser of [3H]noradrenaline (Easton et al., 2007; Heikkila et al., 1975).
Comparisons of the isomers of amphetamine reveal that l-amphetamine is 3.2–7-fold less potent than d-amphetamine as a dopamine reuptake inhibitor (Easton et al., 2007; Kula and Baldessarini, 1991; Richelson and Pfenning, 1984), but it is only 1.8-fold less potent against noradrenaline (Richelson and Pfenning, 1984).
In vivo experiments have also been performed to explore the interaction between the 3:1 ratio of d- and l-isomers in this formulation (Glaser et al., 2005; Joyce et al., 2007). The experiments were performed in anaesthetised rats using in vivo voltammetry to determine the extracellular concentration of dopamine in the striatum and nucleus accumbens. Using this technique, Joyce et al. (2007) demonstrated that the dynamics of d-amphetamine on dopamine efflux were not altered by the presence of the l-isomer in the 1:1 ratio present in the racemate, but as the 3:1 d- to l-isomer mixture, l-amphetamine significantly enhanced and prolonged the efflux of dopamine in the rat striatum produced by d-amphetamine.
It is generally accepted that the efficacy of the amphetamines is not different from that of methylphenidate (Faraone et al., 2006; James et al., 2001; Pelham et al., 2005), which is the other major stimulant used to treat ADHD. However, a meta-analysis by Faraone and Buitelaar (2010) did show moderately greater efficacy for amphetamine medications.
All of the stimulants have biological half-lives that require at least twice-daily dosing to deliver efficacy over 12–14 h. … Examples of once-daily amphetamine medications include MES-amphetamine XR and the d-amphetamine prodrug, lisdexamfetamine.

This image shows the effects of administration of d-amphetamine and lisdexamfetamine on the extracellular concentration of dopamine in the striatum and locomotor activity of freely moving rats. It’s a good example of the sensation too. Adderall is more “jittery”, more of the feeling of too much coffee, though not as intense at that. Vyvanse is much more “I fele normal, and also I can focus better”. Adderall sometimes feels like my attention is a laser pointer that I’m in control of. Vyvanse is a 90W lightbulb. Unmedicated is a 40W bulb, or a flickering light in a horror movie, or a helium laser, but you don’t get to pick which it is at any given time.
l-Amphetamine improves poor sustained attention while d-amphetamine reduces overactivity and impulsiveness as well as improves sustained attention in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD)

Most significantly, d-amphetamine reduced overactivity and impulsiveness more efficiently than comparable doses of l-amphetamine. The lowest dose of d-amphetamine and low-to-medium doses of l-amphetamine improved sustained attention.
The present results indicate that overactivity and impulsiveness may to some extent be associated with imbalances in neural circuits that differ from those causing poor sustained attention and that the two amphetamine isomers may affect the different neuromodulators differently. While d-amphetamine improved SHR overactivity, impulsiveness as well as sustained attention, the behavioral effects of l-amphetamine were relatively more specific for improving sustained attention than for the other 2 symptoms.
Without medication, SHRs showed poorer sustained attention than WKY controls. In contrast to the effects on activity and impulsiveness, … sustained attention appeared to improve in the SHR following low-to-medium doses only (Figure 5).
d-Amphetamine was more than twice as potent as l-amphetamine in reducing SHR hyperactivity and impulsivity. Low-to-medium doses of d- and l-amphetamine, improved sustained attention in the SHR while the highest dose did not. The highest doses reduced hyperactivity and impulsiveness. It is, however, likely that the highest dose of d-amphetamine caused severely drugged behavior in the SHR during the initial half of the session. Thus, only low-to-medium doses produced what might be regarded as real improvements in behavior.

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