I would be somewhat concerned that Piracetam might accelerate the development of sensitization and tolerance, if indeed a) Piracetam is an NMDA receptor agonist
[1] and/or induces long-term potentiation and b) the theory that the development of sensitization and/or tolerance is mediated by the activation of NMDA receptors which is behind the idea of using magnesium/dxm/memantine etc. to slow tolerance. (If the theory is true, I think it isn't the entire story -- 5-ht6 receptors are clearly also involved, and I suspect it is still further complicated.) There is some empirical evidence to support this theory.[2] Here's an abstract:
The present study evaluated in mice the possible modification of psychostimulant methamphetamine (MET) effects by co-administration of piracetam (PIR) and the development of behavioural sensitisation to the psychostimulant in the case of combined treatment. On the Day 1 mice were randomly allocated into 4 groups and control open field test was performed. On the Day 7, after 5 days without treatment, mice were intraperitoneally adiministered: a) saline; b) MET 2.5 mg/kg/day; c) PIR 300 mg/kg/day; d) MET+PIR. These doses were repeated for 6 following days. On the Day 14 the acute “challenge” dose of MET 2.5 mg/kg was given to all groups and locomotor activity was measured. On the Day 21, after 6 days of withdrawal, MET challenge was repeated. Data were analysed using two-way ANOVA and Bonferroni post-test. Significant increase in locomotion was recorded in mice treated with acute doses of MET+PIR compared with animals treated with MET (p<0.05). The increased locomotor responses to MET challenge doses (a sign of behavioural sensitisation) after the repeated treatment were more pronounced in animals pre-treated with MET+PIR than in those pre-treated with just PIR or MET (p<0.01 and p<0.001). Piracetam in our experiment enhanced acute effects of methamphetamine as well as development of sensitisation to its stimulatory effects. Background of these pharmacological drug-drug interactions remains unclear. Although clinically piracetam itself shows minimal adverse effects and toxicity, its combination with methamphetamine could worsen the negative drug abuse consequences.
Assuming that the process of sensitization to the stimulatory effects is closely connected to increases in tolerance to the rewarding effects, the combination might increase tolerance. One study found that people addicted to cocaine increased their cocaine usage when given daily doses of piracetam (no wonder it shows up as a cutting agent so often!).
[3]
Another curiosity, unrelated to the above, is the fact that while piracetam has no antipsychotic activity on its own except in extremely high doses, it modifies the action of other antipsychotics that are co-adminstered.
[4] This doesn't always happen in the same direction -- administered before or after haloperidal or fluphenazine, it increases their dopamine blocking effects; administered after sulpride, it also increases its dopamine receptor antagonism; administered before sulpride, it
reduces its dopamine blocking ability. Additionally,
Concerning the 1 mg/kg apomorphine test, in which hypothermia was due to presynaptic dopaminergic stimulation [Puech et al., 1978], piracetam increased the overall action of sulpiride and haloperidol but had no influence on the action of fluphenazine which presents a strong affinity for DA-1 receptors. It may thus be supposed that piracetam occupies nonspecific sites and allows a better affinity of haloperidol and suJpiride for dopaminergic receptors. This may be explained by the fact that the pK3 of piracetam (-1.85) is close to that of fluphenazine (3.90) and different from that of sulpiride (8.90) and haloperidol (8.66).
I'm not sure what to make of this but it is certainly interesting.
references:
[1] Kuba, K., Kumamoto, E. 1990. Longterm potentiations in vertebrate synapses: a variety of cascades with common subprocesses.
Prog. Neurobiol. 34: 197-269
[2] Machalova, Alena, et al. 2011. Enhancement of psychostimulant effect and development of behavioural sensitisation to methamphetamine in mice by combined treatment with piracetam.
Activitas Nervosa Superior Rediviva, 53(1), 27-31.
[3] Kampman K, Majewska MD, Tourian K, et al. A pilot trial of piracetam and ginkgo biloba for the treatment of cocaine dependence.
Addictive Behaviors. 2003;28(3):437–448. doi:10.1016/S0306-4603(02)00226-5.
[4] Bourin M, Poisson L, Larousse C. Piracetam Interactions with Neuroleptics in Psychopharmacological Tests.
Neuropsychobiology. 1986;16(2-3):93–96. doi:10.1159/000118305.
